Econstudentlog

100 Cases in Orthopaedics and Rheumatology (II)

Below I have added some links related to the last half of the book’s coverage, as well as some more observations from the book.

Scaphoid fracture. Watson’s test. Dorsal intercalated segment instability. (“Non-union is not uncommon as a complication after scaphoid fractures because the blood supply to this bone is poor. Smokers have a higher incidence of non-union. Occasionally, the blood supply is poor enough to lead to avascular necrosis. If non-union is not detected, subsequent arthritis in the wrist can develop.”)
Septic arthritis. (“Septic arthritis is an orthopaedic emergency. […] People with septic arthritis are typically unwell with fevers and malaise and the joint pain is severe. […] Any acutely hot or painful joint is septic arthritis until proven otherwise.”)
Rheumatoid arthritis. (“[RA is] the most common of the inflammatory arthropathies. […] early-morning stiffness and pain, combined with soft-tissue rather than bony swelling, are classic patterns for inflammatory disease. Although […] RA affects principally the small joints of the hands (and feet), it may progress to involve any synovial joint and may be complicated by extra-articular features […] family history [of the disease] is not unusual due to the presence of susceptibility genes such as HLA-DR. […] Not all patients with RA have rheumatoid factor (RF), and not all patients with RF have RA; ACPA has greater specificity for RA than rheumatoid factor. […] Medical therapy focuses on disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, sulphasalazine, leflunomide and hydroxychloroquine which may be used individually or in combination. […] Disease activity in RA is measured by the disease activity score (DAS), which is a composite score of the clinical evidence of synovitis, the current inflammatory response and the patient’s own assessment of their health. […] Patients who have high disease activity as determined by the DAS and have either failed or failed to tolerate standard disease modifying therapy qualify for biologic therapy – monoclonal antibodies that are directed against key components of the inflammatory response. […] TNF-α blockade is highly effective in up to 70 per cent of patients, reducing both inflammation and the progressive structural damage associated with severe active disease.”)
Ankylosing spondylitis. Ankylosis. Schober’s index. Costochondritis.
Mononeuritis multiplex. (“Mononeuritis multiplex arises due to interruption of the vasa nervorum, the blood supply to peripheral nerves […] Mononeuritis multiplex is commonly caused by diabetes or vasculitis. […] Vasculitis – inflammation of blood vessels and subsequent obstruction to blood flow – can be primary (idiopathic) or secondary, in which case it is associated with an underlying condition such as rheumatoid arthritis. The vasculitides are classified according to the size of the vessel involved. […] Management of mononeuritis multiplex is based on potent immunosuppression […] and the treatment of underlying infections such as hepatitis.”)
Multiple myeloma. Bence-Jones protein. (“The combination of bone pain and elevated ESR and calcium is suggestive of multiple myeloma.”)
Osteoporosis. DEXA scan. T-score. (“Postmenopausal bone loss is the most common cause of osteoporosis, but secondary osteoporosis may occur in the context of a number of medical conditions […] Steroid-induced osteoporosis is a significant problem in medical practice. […] All patients receiving corticosteroids should have bone protection […] Pharmacological treatment in the form of calcium supplementation and biphosphonates to reduce osteoclast activity is effective but compliance is typically poor.”)
Osteomalacia. Rickets. Craniotabes.
Paget’s disease (see also this post). (“In practical terms, the main indication to treat Paget’s disease is pain […] although bone deformity or compression syndromes (or risk thereof) would also prompt therapy. The treatment of choice is a biphosphonate to diminish osteoclast activity”).
Stress fracture. Female athlete triad. (“Stress fractures are overuse injuries and occur when periosteal resorption exceeds bone formation. They are commonly seen in two main patient groups: soldiers may suffer so-called march fractures in the metatarsals, while athletes may develop them in different sites according to their sporting activity. Although the knee is a common site in runners due to excess mechanical loading, stress fractures may also result in non-weight-bearing sites due to repetitive and excessive traction […]. The classic symptom […] is of pain that occurs throughout running and crucially persists with rest; this is in contrast to shin splints, a traction injury to the tibial periosteum in which the pain diminishes somewhat with continued activity […] The crucial feature of rehabilitation is a graded return to sport to prevent progression or recurrence.”)
Psoriatic arthritis. (“Arthropathy and rash is a common combination in rheumatology […] Psoriatic arthritis is a common inflammatory arthropathy that affects up to 15 per cent of those with psoriasis. […] Nail disease is very helpful in differentiating psoriatic arthritis from other forms of inflammatory arthropathy.”)
Ehlers–Danlos syndromes. Marfan syndrome. Beighton (hypermobility) score.
Carpal tunnel syndrome. (“Carpal tunnel syndrome is the most common entrapment neuropathy […] The classic symptoms are of tingling in the sensory distribution of the median nerve (i.e. the lateral three and a half digits); loss of thumb abduction is a late feature. Symptoms are often worse at night (when the hand might be quite painful) and in certain postures […] The majority of cases are idiopathic, but pregnancy and rheumatoid arthritis are very common precipitating causes […] The majority of patients will respond well to conservative management […] If these measures fail, corticosteroid injection into the carpal tunnel can be very effective in up to 80 per cent of patients. Surgical decompression should be reserved for those with persistent disabling symptoms or motor loss.”)
Mixed connective tissue disease.
Crystal arthropathy. Tophus. Uric acid nephropathyChondrocalcinosis. (“In any patient presenting with an acutely painful and swollen joint, the most important diagnoses to consider are septic arthritis and crystal arthropathy. Crystal arthropathy such as gout is more common than septic arthritis […] Gout may be precipitated by diuretics, renal impairment and aspirin use”).
Familial Mediterranean fever. Amyloidosis.
Systemic lupus erythematosus (see also this). Jaccoud arthropathy. Lupus nephritis. (“Renal disease is the most feared complication of SLE.”)
Scleroderma. Raynaud’s phenomenon. (“Scleroderma is an uncommon disorder characterized by thickening of the skin and, to a greater or lesser degree, fibrosis of internal organs.”)
Henoch-Schönlein purpura. Cryoglobulinemia. (“Purpura are the result of a spontaneous extravasation of blood from the capillaries into the skin. If small they are known as petechiae, when they are large they are termed ecchymoses. There is an extensive differential diagnosis for purpura […] The combination of palpable purpura (distributed particularly over the buttocks and extensor surfaces of legs), abdominal pain, arthritis and renal disease is a classic presentation of Henoch–Schönlein purpura (HSP). HSP is a distinct and frequently self-limiting small-vessel vasculitis that can affect any age; but the majority of cases present in children aged 2–10 years, in whom the prognosis is more benign than the adult form, often remitting entirely within 3–4 months. The abdominal pain may mimic a surgical abdomen and can presage intussusception, haemorrhage or perforation. The arthritis, in contrast, is relatively mild and tends to affect the knees and ankles.”)
Rheumatic fever.
Erythema nodosum. (“Mild idiopathic erythema nodosum […] needs no specific treatment”).
Rheumatoid lung disease. Bronchiolitis obliterans. Methotrexate-induced pneumonitis. Hamman–Rich syndrome.
Antiphospholipid syndrome. Sapporo criteria. (“Antiphospholipid syndrome is a hypercoagulable state characterized by recurrent arteriovenous thrombosis and/or pregnancy morbidity in the presence of either a lupus anticoagulant or anticardiolipin antibody (both phospholipid-related proteins). […] The most common arteriovenous thrombotic events in antiphospholipid syndrome are deep venous thrombosis and pulmonary embolus […], but any part of the circulation may be involved, with arterial events such as myocardial infarction and stroke carrying a high mortality rate. Poor placental circulation is thought to be responsible for the high pregnancy morbidity, with recurrent first- and second-trimester loss and a higher rate of pre-eclampsia being typical clinical features.”)
Still’s disease. (“Consider inflammatory disease in cases of pyrexia of unknown origin.”)
Polymyalgia rheumatica. Giant cell arteritis. (“[P]olymyalgia rheumatica (PMR) [is] a systemic inflammatory syndrome affecting the elderly that is characterized by bilateral pain and stiffness in the shoulders and hip girdles. The stiffness can be profound and limits mobility although true muscle weakness is not a feature. […] The affected areas are diffusely tender, with movements limited by pain. […] care must be taken not to attribute joint inflammation to PMR until other diagnoses have been excluded; for example, a significant minority of RA patients may present with a polymyalgic onset. […] The treatment for PMR is low-dose corticosteroids. […] Many physicians would consider a dramatic response to low-dose prednisolone as almost diagnostic for PMR, so if a patients symptoms do not improve rapidly it is wise to re-evaluate the original diagnosis.”)
Relapsing polychondritis. (“Relapsing polychondritis is characterized histologically by inflammatory infiltration and later fibrosis of cartilage. Any cartilage, in any location, is at risk. […] Treatment of relapsing polychondritis is with corticosteroids […] Surgical reconstruction of collapsed structures is not an option as the deformity tends to continue postoperatively.”)
Dermatomyositis. Gottron’s Papules.
Enteropathic arthritis. (“A seronegative arthritis may develop in up to 15 per cent of patients with any form of inflammatory bowel disease, including ulcerative colitis (UC), Crohn’s disease or microscopic and collagenous colitis. The most common clinical presentations are a peripheral arthritis […] and spondyloarthritis.”)
Reflex sympathetic dystrophy.
Whipple’s disease. (“Although rare, consider Whipple’s disease in any patient presenting with malabsorption, weight loss and arthritis.”)
Wegener’s granulomatosis. (“Small-vessel vasculitis may cause a pulmonary-renal syndrome. […] The classic triad of Weneger’s granulomatosis is the presence of upper and lower respiratory tract disease and renal impairment.”)
Reactive arthritis. Reiter’s syndrome. (“Consider reactive arthritis in any patient presenting with a monoarthropathy. […] Reactive arthritis is generally benign, with up to 80 per cent making a full recovery.”)
Sarcoidosis. Löfgren syndrome.
Polyarteritis nodosa. (“Consider mesenteric ischaemia in any patient presenting with a systemic illness and postprandial abdominal pain.”)
Sjögren syndrome. Schirmer’s test.
Behçet syndrome.
Lyme disease. Erythema chronicum migrans. (“The combination of rash leading to arthralgia and cranial neuropathy is a classic presentation of Lyme disease.”)
Takayasu arteritis. (“Takayasu’s arteritis is an occlusive vasculitis leading to stenoses of the aorta and its principal branches. The symptoms and signs of the disease depend on the distribution of the affected vessel but upper limbs are generally affected more commonly than the iliac tributaries. […] the disease is a chronic relapsing and remitting condition […] The mainstay of treatment is high-dose corticosteroids plus a steroid-sparing agent such as methotrexate. […] Cyclophosphamide is reserved for those patients who do not achieve remission with standard therapy. Surgical intervention such as bypass or angioplasty may improve ischaemic symptoms once the inflammation is under control.”)
Lymphoma.
Haemarthrosis. (“Consider synovial tumours in a patient with unexplained haemarthrosis.”)
Juvenile idiopathic arthritis.
Drug-induced lupus erythematosus. (“Drug-induced lupus (DIL) generates a different spectrum of clinical manifestations from idiopathic disease. DIL is less severe than idiopathic SLE, and nephritis or central nervous system involvement is very rare. […] The most common drugs responsible for a lupus-like syndrome are procainamide, hydralazine, quinidine, isoniazid, methyldopa, chlorpromazine and minocycline. […] Treatment involves stopping the offending medication and the symptoms will gradually resolve.”)
Churg–Strauss syndrome.

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July 8, 2018 Posted by | Books, Cancer/oncology, Cardiology, Gastroenterology, Immunology, Medicine, Nephrology, Neurology, Ophthalmology, Pharmacology | Leave a comment

100 Cases in Orthopaedics and Rheumatology (I)

This book was decent, but it’s not as good as some of the books I’ve previously read in this series; in some of the books in the series the average length of the answer section is 2-3 pages, which is a format I quite like, whereas in this book the average is more like 1-2 pages – which is a bit too short in my opinion.

Below I have added some links related to the first half of the book’s coverage and a few observations from the book.

Acute haematogenous osteomyelitis. (“There are two principal types of acute osteomyelitis: •haematogenous osteomyelitis •direct or contiguous inoculation osteomyelitis. Acute haematogenous osteomyelitis is characterized by an acute infection of the bone caused by the seeding of the bacteria within the bone from a remote source. This condition occurs primarily in children. […] In general, osteomyelitis has a bimodal age distribution. Acute haematogenous osteomyelitis is primarily a disease in children. Direct trauma and contiguous focus osteomyelitis are more common among adults and adolescents than in children. Spinal osteomyelitis is more common in individuals older than 45 years.”)
Haemophilic arthropathy. (“Haemophilic arthropathy is a condition associated with clotting disorder leading to recurrent bleeding in the joints. Over time this can lead to joint destruction.”)
Avascular necrosis of the femoral head. Trendelenburg’s sign. Gaucher’s disease. Legg–Calvé–Perthes disease. Ficat and Arlet classification of avascular necrosis of femoral head.
Osteosarcoma. Codman triangle. Enneking Classification. (“A firm, irregular mass fixed to underlying structures is more suspicious of a malignant lesion.”)
Ewing’s sarcomaHaversian canal. (“This condition [ES] typically occurs in young patients and presents with pain and fever. [It] is the second most common primary malignant bone tumour (the first being osteosarcoma). The tumour is more common in males and affects children and young adults. The majority develop this between the ages of 10 and 20 years. […] The earliest symptom is pain, which is initially intermittent but becomes intense. Rarely, a patient may present with a pathological fracture. Eighty-five per cent of patients have chromosomal translocations associated with the 11/22 chromosome. Ewing’s sarcoma is potentially the most aggressive form of the primary bone tumours. […] Patients are usually assigned to one of two groups, the tumour being classified as either localized or metastatic disease. Tumours in the pelvis typically present late and are therefore larger with a poorer prognosis. Treatment comprises chemotherapy, surgical resection and/or radiotherapy. […] With localized disease, wide surgical excision of the tumour is preferred over radiotherapy if the involved bone is expendable (e.g. fibular, rib), or if radiotherapy would damage the growth plate. […] Non-metastatic disease survival rates are 55–70 per cent, compared to 22–33 per cent for metastatic disease. Patients require careful follow-up owing to the risk of developing osteosarcoma following radiotherapy, particularly in children in whom it can occur in up to 20 per cent of cases.”
Clavicle Fracture. Floating Shoulder.
Proximal humerus fractures.
Lateral condyle fracture of the humerus. Salter-Harris fracture. (“Humeral condyle fractures occur most commonly between 6 and 10 years of age. […] fractures often appear subtle on radiographs. […] Operative management is essential for all displaced fractures“).
Distal radius fracture. (“Colles’ fractures account for over 90 per cent of distal radius fractures. Any injury to the median nerve can produce paraesthesia in the thumb, index finger, and middle and radial border of the ring finger […]. There is a bimodal age distribution of fractures to the distal radius with two peaks occurring. The first peak occurs in people aged 18–25 years, and a second peak in older people (>65 years). High-energy injuries are more common in the younger group and low-energy injuries in the older group. Osteoporosis may play a role in the occurrence of this later fracture. In the group of patients between 60 and 69 years, women far outnumber men. […] Assessment with plain radiographs is all that is needed for most fractures. […] The majority of distal radius fractures can be treated conservatively.”)
Gamekeeper’s thumb. Stener lesion.
Subtrochanteric Hip Fracture.
Supracondylar Femur Fractures. (“There is a bimodal distribution of fractures based on age and gender. Most high-energy distal femur fractures occur in males aged between 15 and 50 years, while most low-energy fractures occur in osteoporotic women aged 50 or above. The most common high-energy mechanism of injury is a road traffic accident (RTA), and the most common low-energy mechanism is a fall. […] In general, […] non-operative treatment does not work well for displaced fractures. […] Operative intervention is also indicated in the presence of open fractures and injuries associated with vascular injury. […] Total knee replacement is effective in elderly patients with articular fractures and significant osteoporosis, or pre-existing arthritis that is not amenable to open reduction and internal fixation. Low-demand elderly patients with non- or minimally displaced fractures can be managed conservatively. […] In general, this fracture can take a minimum of 3-4 months to unite.”)
Supracondylar humerus fracture. Gartland Classification of Supracondylar Humerus Fractures. (“Prior to the treatment of supracondylar fractures, it is essential to identify the type. Examination of the degree of swelling and deformity as well as a neurological and vascular status assessment of the forearm is essential. A vascular injury may present with signs of an acute compartment syndrome with pain, paraesthesia, pallor, and pulseless and tight forearm. Injury to the brachial artery may present with loss of the distal pulse. However, in the presence of a weak distal pulse, major vessel injury may still be present owing to the collateral circulation. […] Vascular insult can lead to Volkmann ischaemic contracture of the forearm. […] Malunion of the fracture may lead to cubitus varus deformity.”)
Femoral Shaft Fractures.
Femoral Neck Fractures. Garden’s classification. (“Hip fractures are the most common reason for admission to an orthopaedic ward, usually caused by a fall by an elderly person. The average age of a person with a hip fracture is 77 years. Mortality is high: about 10 per cent of people with a hip fracture die within 1 month, and about one-third within 12 months. However, fewer than half of deaths are attributable to the fracture, reflecting the high prevalence of comorbidity. The mental status of the patient is also important: senility is associated with a three-fold increased risk of sepsis and dislocation of prosthetic replacement when compared with mentally alert patients. The one-year mortality rate in these patients is considerable, being reported as high as 50 per cent.”)
Tibia Shaft Fractures. (“The tibia is the most frequent site of a long-bone fracture in the body. […] Open fractures are surgical emergencies […] Most closed tibial fractures can be treated conservatively using plaster of Paris.”)
Tibial plateau fracture. Schatzker classification.
Compartment syndrome. (“This condition is an orthopaedic emergency and can be limb- and life-threatening. Compartment syndrome occurs when perfusion pressure falls below tissue pressure in a closed fascial compartment and results in microvascular compromise. At this point, blood flow through the capillaries stops. In the absence of flow, oxygen delivery stops. Hypoxic injury causes cells to release vasoactive substances (e.g. histamine, serotonin), which increase endothelial permeability. Capillaries allow continued fluid loss, which increases tissue pressure and advances injury. Nerve conduction slows, tissue pH falls due to anaerobic metabolism, surrounding tissue suffers further damage, and muscle tissue suffers necrosis, releasing myoglobin. In untreated cases the syndrome can lead to permanent functional impairment, renal failure secondary to rhabdomyolysis, and death. Patients at risk of compartment syndrome include those with high-velocity injuries, long-bone fractures, high-energy trauma, penetrating injuries such as gunshot wounds and stabbing, and crush injuries, as well as patients on anticoagulants with trauma. The patient usually complains of severe pain that is out of proportion to the injury. An assessment of the affected limb may reveal swelling which feels tense, or hard compartments. Pain on passive range of movement of fingers or toes of the affected limb is a typical feature. Late signs comprise pallor, paralysis, paraesthesia and a pulseless limb. Sensory nerves begin to lose conductive ability, followed by motor nerves. […] Fasciotomy is the definitive treatment for compartment syndrome. The purpose of fasciotomy is to achieve prompt and adequate decompression so as to restore the tissue perfusion.”)
Talus fracture. Hawkins sign. Avascular necrosis.
Calcaneal fracture. (“The most common situation leading to calcaneal fracture is a young adult who falls from a height and lands on his or her feet. […] Patients often sustain occult injuries to their lumbar or cervical spine, and the proximal femur. A thorough clinical and radiological investigation of the spine area is mandatory in patients with calcaneal fracture.”)
Idiopathic scoliosis. Adam’s forward bend test. Romberg test. Cobb angle.
Cauda equina syndrome. (“[Cauda equina syndrome] is an orthopaedic emergency. The condition is characterized by the red-flag signs comprising low back pain, unilateral or bilateral sciatica, saddle anaesthesia with sacral sparing, and bladder and bowel dysfunctions. Urinary retention is the most consistent finding. […] Urgent spinal orthopaedic or neurosurgical consulation is essential, with transfer to a unit capable of undertaking any definitive surgery considered necessary. In the long term, residual weakness, incontinence, impotence and/or sensory abnormalities are potential problems if therapy is delayed. […] The prognosis improves if a definitive cause is identified and appropriate surgical spinal decompression occurs early. Late surgical compression produces varying results and is often associated with a poorer outcome.”)
Developmental dysplasia of the hip.
OsteoarthritisArthroplasty. OsteotomyArthrodesis. (“Early-morning stiffness that gradually diminishes with activity is typical of osteoarthritis. […] Patients with hip pathology can sometimes present with knee pain without any groin or thigh symptoms. […] Osteoarthritis most commonly affects middle-aged and elderly patients. Any synovial joint can develop osteoarthritis. This condition can lead to degeneration of articular cartilage and is often associated with stiffness.”)
Prepatellar bursitis.
Baker’s cyst.
Meniscus tear. McMurray test. Apley’s test. Lachman test.
Anterior cruciate ligament injury.
Achilles tendon rupture. Thompson Test.
Congenital Talipes EquinovarusPonseti method. Pirani score. (“Club foot is bilateral in about 50 per cent of cases and occurs in approximately 1 in 800 births.”)
Charcot–Marie–Tooth disease. Pes cavus. Claw toe deformity. Pes planus.
Hallux valgus. Hallux Rigidus.
Mallet toe deformity. Condylectomy. Syme amputation. (“Mallet toes are common in diabetics with peripheral neuropathy. […] Pain and/or a callosity is often the presenting complaint. This may also lead to nail deformity on the toe. Most commonly the deformity is present in the second toe. […] Footwear modification […] should be tried first […] Surgical management of mallet toe is indicated if the deformity becomes painful.”)
Hammer Toe.
Lisfranc injury. Fleck sign. (“The Lisfranc joint, which represents the articulation between the midfoot and forefoot, is composed of the five TMT [tarsometatarsal] joints. […] A Lisfranc injury encompasses everything from a sprain to a complete disruption of normal anatomy through the TMT joints. […] Lisfranc injuries are commonly undiagnosed and carry a high risk of chronic secondary disability.”)
Charcot joint. (“Charcot arthropathy results in progressive destruction of bone and soft tissues at weight-bearing joints. In its most severe form it may cause significant disruption of the bony architecture, including joint dislocations and fractures. Charcot arthropathy can occur at any joint but most commonly affects the lower regions: the foot and ankle. Bilateral disease occurs in fewer than 10 per cent of patients. Any condition that leads to a sensory or autonomic neuropathy can cause a Charcot joint. Charcot arthropathy can occur as a complication of diabetes, syphilis, alcoholism, leprosy, meningomyleocele, spinal cord injury, syringomyelia, renal dialysis and congenital insensitivity to pain. In the majority of cases, non-operative methods are preferred. The principles of management are to provide immobilization of the affected joint and reduce any areas of stress on the skin. Immobilization is usually accomplished by casting.”)
Lateral epicondylitis (tennis elbow). (“For work-related lateral epicondylitis, a systematic review identified three risk factors: handling tools heavier than 1 kg, handling loads heavier than 20 kg at least ten times per day, and repetitive movements for more than two hours per day. […] Up to 95 per cent of patients with tennis elbow respond to conservative measures.”)
Medial Epicondylitis.
De Quervain’s tenosynovitis. Finkelstein test. Intersection syndrome. Wartenberg’s syndrome.
Trigger finger.
Adhesive capsulitis (‘frozen shoulder’). (“Frozen shoulder typically has three phases: the painful phase, the stiffening phase and the thawing phase. During the initial phase there is a gradual onset of diffuse shoulder pain lasting from weeks to months. The stiffening phase is characterized by a progressive loss of motion that may last up to a year. The majority of patients lose glenohumeral external rotation, internal rotation and abduction during this phase. The final, thawing phase ranges from weeks to months and constitutes a period of gradual motion improvement. Once in this phase, the patient may require up to 9 months to regain a fully functional range of motion. There is a higher incidence of frozen shoulder in patients with diabetes compared with the general population. The incidence among patients with insulin-dependent diabetes is even higher, with an increased frequency of bilateral frozen shoulder. Adhesive capsulitis has also been reported in patients with hyperthyroidism, ischaemic heart disease, and cervical spondylosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended in the initial treatment phase. […] A subgroup of patients with frozen shoulder syndrome often fail to improve despite conservative measures. In these cases, interventions such as manipulation, distension arthrography or open surgical release may be beneficial.” [A while back I covered some papers on adhesive capsulitis and diabetes here (part iii) – US].
Dupuytren’s Disease. (“Dupuytren’s contracture is a benign, slowly progressive fibroproliferative disease of the palmar fascia. […] The disease presents most commonly in the ring and little fingers and is bilateral in 45 per cent of cases. […] Dupuytren’s disease is more common in males and people of northern European origin. It can be associated with prior hand trauma, alcoholic cirrhosis, epilepsy (due to medications such as phenytoin), and diabetes. [“Dupuytren’s disease […] may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D” – I usually don’t like such unspecific reported prevalences (what does ‘up to’ really mean?), but the point is that this is not a 1 in a 100 complication among diabetics; it seems to be a relatively common complication in type 1 DM – US] The prevalence increases with age. Mild cases may not need any treatment. Surgery is indicated in progressive contractures and established deformity […] Recurrence or extension of the disease after operation is not uncommon”).

July 1, 2018 Posted by | Books, Cancer/oncology, Diabetes, Medicine, Neurology | Leave a comment

Gastrointestinal complications of diabetes (I)

I really liked this book. It covered a lot of stuff also covered in Horowitz & Samsom’s excellent book on these topics, but it’s shorter and so probably easier for the relevant target group to justify reading. I recommend the book if you want to know more about these topics but don’t quite feel like reading a long textbook on these topics.

Below I’ve added some observations from the first half of the book. In the quotes below I’ve added some links and highlighted some key observations by the use of bold text.

Gastrointestinal (GI) symptoms occur more commonly in patients with diabetes than in the general population [2]. […] GI symptoms such as nausea, abdominal pain, bloating, diarrhea, constipation, and delayed gastric emptying occur in almost 75 % of patients with diabetes [3]. A majority of patients with GI symptoms stay undiagnosed or undertreated due to a lack of awareness of these complications among clinicians. […] Diabetes can affect the entire GI tract from the oral cavity and esophagus to the large bowel and anorectal region, either in isolation or in a combination. The extent and the severity of the presenting symptoms may vary widely depending upon which part of the GI tract is involved. In patients with long-term type 1 DM, upper GI symptoms seem to be particularly common [4]. Of the different types […] gastroparesis seems to be the most well known and most serious complication, occurring in about 50 % of patients with diabetes-related GI complications [5].”

The enteric nervous system (ENS) is an independent network of neurons and glial cells that spread from the esophagus up to the internal anal sphincter. […] the ENS regulates GI tract functions including motility, secretion, and participation in immune regulation [12, 13]. GI complications and their symptoms in patients with diabetes arise secondary to both abnormalities of gastric function (sensory and motor modality), as well as impairment of GI hormonal secretion [14], but these abnormalities are complex and incompletely understood. […] It has been known for a long time that diabetic autonomic neuropathy […] leads to abnormalities in the GI motility, sensation, secretion, and absorption, serving as the main pathogenic mechanism underlying GI complications. Recently, evidence has emerged to suggest that other processes might also play a role. Loss of the pacemaker interstitial cells of Cajal, impairment of the inhibitory nitric oxide-containing nerves, abnormal myenteric neurotransmission, smooth muscle dysfunction, and imbalances in the number of excitatory and inhibitory enteric neurons can drastically alter complex motor functions causing dysfunction of the enteric system [7, 11, 15, 16]. This dysfunction can further lead to the development of dysphagia and reflux esophagitis in the esophagus, gastroparesis, and dyspepsia in the stomach, pseudo-obstruction of the small intestine, and constipation, diarrhea, and incontinence in the colon. […] Compromised intestinal vascular flow arising due to ischemia and hypoxia from microvascular disease of the GI tract can also cause abdominal pain, bleeding, and mucosal dysfunction. Mitochondrial dysfunction has been implicated in the pathogenesis of gastric neuropathy. […] Another possible association between DM and the gastrointestinal tract can be infrequent autoimmune diseases associated with type I DM like autoimmune chronic pancreatitis, celiac disease (2–11 %), and autoimmune gastropathy (2 % prevalence in general population and three- to fivefold increase in patients with type 1 DM) [28, 29]. GI symptoms are often associated with the presence of other diabetic complications, especially autonomic and peripheral neuropathy [2, 30, 31]. In fact, patients with microvascular complications such as retinopathy, nephropathy, or neuropathy should be presumed to have GI abnormalities until proven otherwise. In a large cross-sectional questionnaire study of 1,101 subjects with DM, 57 % of patients reported at least one GI complication [31]. Poor glycemic control has also been found to be associated with increased severity of the upper GI symptoms. […] management of DM-induced GI complications is challenging, is generally suboptimal, and needs improvement.

Diabetes mellitus (DM) has multiple clinically important effects on the esophagus. Diabetes results in several esophageal motility disturbances, increases the risk of esophageal candidiasis, and increases the risk of Barrett’s esophagus and esophageal carcinoma. Finally, “black esophagus,” or acute esophageal necrosis, is also associated with DM. […] Esophageal dysmotility has been shown to be associated with diabetic neuropathy; however, symptomatic esophageal dysmotility is not often considered an important complication of diabetes. […] In general, the manometric effects of diabetes on the esophagus are not specific and mostly related to speed and strength of peristalsis. […] The pathological findings which amount to loss of cholinergic stimulation are consistent with the manometric findings in the esophagus, which are primarily related to slowed or weakened peristalsis. […] The association between DM and GERD is complex and conflicting. […] A recent meta-analysis suggests an overall positive association in Western countries [12]. […] The underlying pathogenesis of DM contributing to GERD is not fully elucidated, but is likely related to reduced acid clearance due to slow, weakened esophageal peristalsis. The association between DM and gastroesophageal reflux (GER) is well established, but the link between DM and GERD, which requires symptoms or esophagitis, is more complex because sensation may be blunted in diabetics with neuropathy. Asymptomatic gastroesophageal reflux (GER) confirmed by pH studies is significantly more frequent in diabetic patients than in healthy controls [13]. […] long-standing diabetics with neuropathy are at higher risk for GERD even if they have no symptoms. […] Abnormal pH and motility studies do not correlate very well with the GI symptoms of diabetics, possibly due to DM-related sensory dysfunction.”

Gastroparesis is defined as a chronic disorder characterized by delayed emptying of the stomach occurring in the absence of mechanical obstruction. It is a well-known and potentially serious complication of diabetes. […] Diabetic gastroparesis affects up to 40 % of patients with type 1 diabetes and up to 30 % of patients with type 2 diabetes [1, 2]. Diabetic gastroparesis generally affects patients with longstanding diabetes mellitus, and patients often have other diabetic complications […] For reasons that remain unclear, approximately 80 % of patients with gastroparesis are women [3]. […] In diabetes, delayed gastric emptying can often be asymptomatic. Therefore, the term gastroparesis should only be reserved for patients that have both delayed gastric emptying and upper gastrointestinal symptoms. Additionally, discordance between the pattern and type of symptoms and the magnitude of delayed gastric emptying is a well-established phenomenon. Accelerating gastric emptying may not improve symptoms, and patients can have symptomatic improvement while gastric emptying time remains unchanged. Furthermore, patients with severe symptoms can have mild delays in gastric emptying. Clinical features of gastroparesis include nausea, vomiting, bloating, abdominal pain, and malnutrition. […] Gastroparesis affects oral drug absorption and can cause hyperglycemia that is challenging to manage, in addition to unexplained hypoglycemia. […] Nutritional and caloric deficits are common in patients with gastroparesis […] Possible complications of gastroparesis include volume depletion with renal failure, malnutrition, electrolyte abnormalities, esophagitis, Mallory–Weiss tear (from vomiting), or bezoar formation. […] Unfortunately, there is a dearth of medications available to treat gastroparesis. Additionally, many of the medications used are based on older trials with small sample sizes […and some of them have really unpleasant side effects – US]. […] Gastroparesis can be associated with abdominal pain in as many as 50 % of patients with gastroparesis at tertiary care centers. There are no trials to guide the choice of agents. […] Abdominal pain […] is often difficult to treat [3]. […] In a subset of patients with diabetes [less than 10%, according to Horowitz & Samsom – US], gastric emptying can be abnormally accelerated […]. Symptoms are often difficult to distinguish from those with delayed gastric emptying. […] Worsening symptoms with a prokinetic agent can be a sign of possible accelerated emptying.”

“Diabetic enteropathy encompasses small intestinal and colorectal dysfunctions such as diarrhea, constipation, and/or fecal incontinence. It is more commonly seen in patients with long-standing diabetes, especially in those with gastroparesis. Development of diabetic enteropathy is complex and multifactorial. […] gastrointestinal symptoms and complications do not always correlate with the duration of diabetes, glycemic control, or with the presence of autonomic neuropathy, which is often assumed to be the major cause of many gastrointestinal symptoms. Other pathophysiologic processes operative in diabetic enteropathy include enteric myopathy and neuropathy; however, causes of these abnormalities are unknown [1]. […] Collectively, the effects of diabetes on several targets cause aberrations in gastrointestinal function and regulation. Loss of ICC, autonomic neuropathy, and imbalances in the number of excitatory and inhibitory enteric neurons can drastically alter complex motor functions such as peristalsis, reflexive relaxation, sphincter tone, vascular flow, and intestinal segmentation [5]. […] Diarrhea is a common complaint in DM. […] Etiologies of diarrhea in diabetes are multifactorial and include rapid intestinal transit, drug-induced diarrhea, small-intestine bacterial overgrowth, celiac disease, pancreatic exocrine insufficiency, dietary factors, anorectal dysfunction, fecal incontinence, and microscopic colitis [1]. […] It is important to differentiate whether diarrhea is caused by rapid intestinal transit vs. SIBO. […] This differentiation has key clinical implications with regard to the use of antimotility agents or antibiotics in a particular case. […] Constipation is a common problem seen with long-standing DM. It is more common than in general population, where the incidence varies from 2 % to 30 % [30]. It affects 60 % of the patients with DM and is more common than diarrhea [14]. […] There are no specific treatments for diabetes-associated constipation […] In most cases, patients are treated in the same way as those with idiopathic chronic constipation. […] Colorectal cancer is the third most common cancer in men and the second in women [33]. Individuals with type 2 DM have an increased risk of colorectal cancer when compared with their nondiabetic counterparts […] According to a recent large observational population-based cohort study, type 2 DM was associated with a 1.3-fold increased risk of colorectal cancer compared to the general population.”

Nonalcoholic fatty liver disease (NAFLD) is the main hepatic complication of obesity, insulin resistance, and diabetes and soon to become the leading cause for end-stage liver disease in the United States [1]. […] NAFLD is a spectrum of disease that ranges from steatosis (hepatic fat without significant hepatocellular injury) to nonalcoholic steatohepatitis (NASH; hepatic fat with hepatocellular injury) to advanced fibrosis and cirrhosis. As a direct consequence of the obesity epidemic, NAFLD is the most common cause of chronic liver disease, while NASH is the second leading indication for liver transplantation [1]. NAFLD prevalence is estimated at 25 % globally [2] and up to 30 % in the United States [3–5]. Roughly 30 % of individuals with NAFLD also have NASH, the progressive subtype of NAFLD. […] NASH is estimated at 22 % among patients with diabetes, compared to 5 % of the general population [4, 14]. […] Insulin resistance is strongly associated with NASH. […] Simple steatosis (also known as nonalcoholic fatty liver) is characterized by the presence of steatosis without ballooned hepatocytes (which represents hepatocyte injury) or fibrosis. Mild inflammation may be present. Simple steatosis is associated with a very low risk of progressive liver disease and liver-related mortality. […] Patients with NASH are at risk for progressive liver fibrosis and liver-related mortality, cardiovascular complications, and hepatocellular carcinoma (HCC) even in the absence of cirrhosis [26]. Liver fibrosis stage progresses at an estimated rate of one stage every 7 years [27]. Twenty percent of patients with NASH will eventually develop liver cirrhosis [9]. […] The risk of cardiovascular disease is increased across the entire NAFLD spectrum. […] Cardiovascular risk reduction should be aggressively managed in all patients.

 

June 17, 2018 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Gastroenterology, Medicine, Neurology | Leave a comment

Alcohol and Aging (II)

I gave the book 3 stars on goodreads.

As is usual for publications of this nature, the book includes many chapters that cover similar topics and so the coverage can get a bit repetitive if you’re reading it from cover to cover the way I did; most of the various chapter authors obviously didn’t read the other contributions included in the book, and as each chapter is meant to stand on its own you end up with a lot of chapter introductions which cover very similar topics. If you can disregard such aspects it’s a decent book, which covers a wide variety of topics.

Below I have added some observations from some of the chapters of the book which I did not cover in my first post.

It is widely accepted that consuming heavy amounts of alcohol and binge drinking are detrimental to the brain. Animal studies that have examined the anatomical changes that occur to the brain as a consequence of consuming alcohol indicate that heavy alcohol consumption and binge drinking leads to the death of existing neurons [10, 11] and prevents production of new neurons [12, 13]. […] While animal studies indicate that consuming even moderate amounts of alcohol is detrimental to the brain, the evidence from epidemiological studies is less clear. […] Epidemiological studies that have examined the relationship between late life alcohol consumption and cognition have frequently reported that older adults who consume light to moderate amounts of alcohol are less likely to develop dementia and have higher cognitive functioning compared to older adults who do not consume alcohol. […] In a meta-analysis of 15 prospective cohort studies, consuming light to moderate amounts of alcohol was associated with significantly lower relative risk (RR) for Alzheimer’s disease (RR=0.72, 95% CI=0.61–0.86), vascular dementia (RR=0.75, 95% CI=0.57–0.98), and any type of dementia (RR=0.74, 95% CI=0.61–0.91), but not cognitive decline (RR=0.28, 95 % CI=0.03–2.83) [31]. These findings are consistent with a previous meta-analysis by Peters et al. [33] in which light to moderate alcohol consumption was associated with a decreased risk for dementia (RR=0.63, 95 % CI=0.53–0.75) and Alzheimer’s disease (RR=0.57, 95 % CI=0.44–0.74), but not vascular dementia (RR=0.82, 95% CI=0.50–1.35) or cognitive decline RR=0.89, 95% CI=0.67–1.17). […] Mild cognitive impairment (MCI) has been used to describe the prodromal stage of Alzheimer’s disease […]. There is no strong evidence to suggest that consuming alcohol is protective against MCI [39, 40] and several studies have reported non-significant findings [41–43].”

The majority of research on the relationship between alcohol consumption and cognitive outcomes has focused on the amount of alcohol consumed during old age, but there is a growing body of research that has examined the relationship between alcohol consumption during middle age and cognitive outcomes several years or decades later. The evidence from this area of research is mixed with some studies not detecting a significant relationship [17, 58, 59], while others have reported that light to moderate alcohol consumption is associated with preserved cognition [60] and decreased risk for cognitive impairment [31, 61, 62]. […] Several epidemiological studies have reported that light to moderate alcohol consumption is associated with a decreased risk for stroke, diabetes, and heart disease [36, 84, 85]. Similar to the U-shaped relationship between alcohol consumption and dementia, heavy alcohol consumption has been associated with poor health [86, 87]. The decreased risk for several metabolic and vascular health conditions for alcohol consumers has been attributed to antioxidants [54], greater concentrations of high-density lipoprotein cholesterol in the bloodstream [88], and reduced blood clot formation [89]. Stroke, diabetes, heart disease, and related conditions have all been associated with lower cognitive functioning during old age [90, 91]. The reduced prevalence of metabolic and vascular health conditions among light to moderate alcohol consumers may contribute to the decreased risk for dementia and cognitive decline for older adults who consume alcohol. A limitation of the hypothesis that the reduced risk for dementia among light and moderate alcohol consumers is conferred through the reduced prevalence of adverse health conditions associated with dementia is the possibility that this relationship is confounded by reverse causality. Alcohol consumption decreases with advancing age and adults may reduce their alcohol consumption in response to the onset of adverse health conditions […] the higher prevalence of dementia and lower cognitive functioning among abstainers may be due in part to their worse health rather than their alcohol consumption.”

A limitation of large cohort studies is that subjects who choose not to participate or are unable to participate are often less healthy than those who do participate. Non-response bias becomes more pronounced with age because only subjects who have survived to old age and are healthy enough to participate are observed. Studies on alcohol consumption and cognition are sensitive to non-response bias because light and moderate drinkers who are not healthy enough to participate in the study will not be observed. Adults who survive to old age despite consuming very high amounts of alcohol represent an even more select segment of the general population because they may have genetic, behavioral, health, social, or other factors that protect them against the negative effects of heavy alcohol consumption. As a result, the analytic sample of epidemiological studies is more likely to be comprised of “healthy” drinkers, which biases results in favor of finding a positive effect of light to moderate alcohol consumption for cognition and health in general. […] The incidence of Alzheimer’s disease doubles every 5 years after 65 years of age [94] and nearly 40% of older adults aged 85 and over are diagnosed with Alzheimer’s disease [7]. The relatively old age of onset for most dementia cases means the observed protective effect of light to moderate alcohol consumption for dementia may be due to alcohol consumers being more likely to die or drop out of a study as a result of their alcohol consumption before they develop dementia. This bias may be especially strong for heavy alcohol consumers. Not properly accounting for death as a competing outcome has been observed to artificially increase the risk of dementia among older adults with diabetes [95] and the effect that death and other competing outcomes may have on the relationship between alcohol consumption and dementia risk is unclear. […] The majority of epidemiological studies that have studied the relationship between alcohol consumption and cognition treat abstainers as the reference category. This can be problematic because often times the abstainer or non-drinking category includes older adults who stopped consuming alcohol because of poor health […] Not differentiating former alcohol consumers from lifelong abstainers has been found to explain some but not all of the benefit of alcohol consumption for preventing mortality from cardiovascular causes [96].”

“It is common for people to engage in other behaviors while consuming alcohol. This complicates the relationship between alcohol consumption and cognition because many of the behaviors associated with alcohol consumption are positively and negatively associated with cognitive functioning. For example, alcohol consumers are more likely to smoke than non-drinkers [104] and smoking has been associated with an increased risk for dementia and cognitive decline [105]. […] The relationship between alcohol consumption and cognition may also differ between people with or without a history of mental illness. Depression reduces the volume of the hippocampus [106] and there is growing evidence that depression plays an important role in dementia. Depression during middle age is recognized as a risk factor for dementia [107], and high depressive symptoms during old age may be an early symptom of dementia [108]. Middle aged adults with depression or other mental illness who self-medicate with alcohol may be at especially high risk for dementia later in life because of synergistic effects that alcohol and depression has on the brain. […] While current evidence from epidemiological studies indicates that consuming light to moderate amounts of alcohol, in particular wine, does not negatively affect cognition and in many cases is associated with cognitive health, adults who do not consume alcohol should not be encouraged to increase their alcohol consumption until further research clarifies these relationships. Inconsistencies between studies on how alcohol consumption categories are defined make it difficult to determine the “optimal” amount of alcohol consumption to prevent dementia. It is likely that the optimal amount of alcohol varies according to a person’s gender, as well as genetic, physiological, behavioral, and health characteristics, making the issue extremely complex.”

Falls are the leading cause of both fatal and nonfatal injuries among older adults, with one in three older adults falling each year, and 20–30% of people who fall suffer moderate to severe injuries such as lacerations, hip fractures, and head traumas. In fact, falls are the foremost cause of both fractures and traumatic brain injury (TBI) among older adults […] In 2013, 2.5 million nonfatal falls among older adults were treated in ED and more than 734,000 of these patients were hospitalized. […] Our analysis of the 2012 Nationwide Emergency Department Sample (NEDS) data set show that fall-related injury was a presenting problem among 12% of all ED visits by those aged 65+, with significant differences among age groups: 9% among the 65–74 age group, 12 % among the 75–84 age group, and 18 % among the 85+ age group [4]. […] heavy alcohol use predicts fractures. For example, among those 55+ years old in a health survey in England, men who consumed more than 8 units of alcohol and women who consumed more than 6 units on their heaviest drinking day in the past week had significantly increased odds of fractures (OR =1.65, 95% CI =1.37–1.98 for men and OR=2.07, 95% CI =1.28–3.35 for women) [63]. […] The 2008–2009 Canadian Community Health Survey-Healthy Aging also showed that consumption of at least one alcoholic drink per week increased the odds of falling by 40 % among those 65+ years [57].”

I at first was not much impressed by the effect sizes mentioned above because there are surely 100 relevant variables they didn’t account for/couldn’t account for, but then I thought a bit more about it. An important observation here – they don’t mention it in the coverage, but it sprang to mind – is that if sick or frail elderly people consume less alcohol than their more healthy counterparts, and are more likely to not consume alcohol (which they do, and which they are, we know this), and if frail or sick(er) elderly people are more likely to suffer a fall/fracture than are people who are relatively healthy (they are, again, we know this), well, then you’d expect consumption of alcohol to be found to have a ‘protective effect’ simply due to confounding by (reverse) indication (unless the researchers were really careful about adjusting for such things, but no such adjustments are mentioned in the coverage, which makes sense as these are just raw numbers being reported). The point is that the null here should not be that ‘these groups should be expected to have the same fall rate/fracture rate’, but rather ‘people who drink alcohol should be expected to be doing better, all else equal’ – but they aren’t, quite the reverse. So ‘the true effect size’ here may be larger than what you’d think.

I’m reasonably sure things are a lot more complicated than the above makes it appear (because of those 100 relevant variables we were talking about…), but I find it interesting anyway. Two more things to note: 1. Have another look at the numbers above if they didn’t sink in the first time. This is more than 10% of emergency department visits for that age group. Falls are a really big deal. 2. Fractures in the elderly are also a potentially really big deal. Here’s a sample quote: “One-fifth of hip fracture victims will die within 6 months of the injury, and only 50% will return to their previous level of independence.” (link). In some contexts, a fall is worse news than a cancer diagnosis, and they are very common events in the elderly. This also means that even relatively small effect sizes here can translate into quite large public health effects, because baseline incidence is so high.

The older adult population is a disproportionate consumer of prescription and over-the-counter medications. In a nationally representative sample of community-dwelling adults aged 57–84 years from the National Social Life, Health, and Aging Project (NSHAP) in 2005–2006, 81 % regularly used at least one prescription medication on a regular basis and 29% used at least five prescription medications. Forty-two percent used at least one nonprescription medication and concurrent use with a prescription medication was common, with 46% of prescription medication users also using OTC medications [2]. Prescription drug use by older adults in the U.S. is also growing. The percentage of older adults taking at least one prescription drug in the last 30 days increased from 73.6% in 1988–1994 to 89.7 % in 2007–2010 and the percentage taking five or more prescription drugs in the last 30 days increased from 13.8% in 1988–1994 to 39.7 % in 2007–2010 [3].”

The aging process can affect the response to a medication by altering its pharmacokinetics and pharmacodynamics [9, 10]. Reduced gastrointestinal motility and gastric acidity can alter the rate or extent of drug absorption. Changes in body composition, including decreased total body water and increased body fat can alter drug distribution. For alcohol, changes in body composition result in higher blood alcohol levels in older adults compared to younger adults after the same dose or quantity  of alcohol consumed. Decreased size of the liver, hepatic blood flow, and function of Phase I (oxidation, reduction, and hydrolysis) metabolic pathways result in reduced drug metabolism and increased drug exposure for drugs that undergo Phase I metabolism. Phase II hepatic metabolic pathways are generally preserved with aging. Decreased size of the kidney, renal blood flow, and glomerular filtration result in slower elimination of medications and metabolites by the kidney and increased drug exposure for medications that undergo renal elimination. Age-related impairment of homeostatic mechanisms and changes in receptor number and function can result in changes in pharmacodynamics as well. Older adults are generally more sensitive to the effects of medications and alcohol which act on the central nervous system for example. The consequences of these physiologic changes with aging are that older adults often experience increased drug exposure for the same dose (higher drug concentrations over time) and increased sensitivity to medications (greater response at a given drug concentration) than their younger counterparts.”

“Aging-related changes in physiology are not the only sources of variability in pharmacokinetics and pharmacodynamics that must be considered for an individual person. Older adults experience more chronic diseases that may decrease drug metabolism and renal elimination than younger cohorts. Frailty may result in further decline in drug metabolism, including Phase II metabolic pathways in the liver […] Drug interactions must also be considered […] A drug interaction is defined as a clinically meaningful change in the effect of one drug when coadministered with another drug [12]. Many drugs, including alcohol, have the potential for a drug interaction when administered concurrently, but whether a clinically meaningful change in effect occurs for a specific person depends on patient-specifc factors including age. Drug interactions are generally classified as pharmacokinetic interactions, where one drug alters the absorption, distribution, metabolism, or elimination of another drug resulting in increased or decreased drug exposure, or pharmacodynamic interactions, where one drug alters the response to another medication through additive or antagonistic pharmacologic effects [13]. An adverse drug event occurs when a pharmacokinetic or pharmacodynamic interaction or combination of both results in changes in drug exposure or response that lead to negative clinical outcomes. The adverse drug event could be a therapeutic failure if drug exposure is decreased or the pharmacologic response is antagonistic. The adverse drug event could be drug toxicity if the drug exposure is increased or the pharmacologic response is additive or synergistic. The threshold for experiencing an adverse event is often lower in older adults due to physiologic changes with aging and medical comorbidities, increasing their risk of experiencing an adverse drug event when medications are taken concurrently.”

“A large number of potential medication–alcohol interactions have been reported in the literature. Mechanisms of these interactions range from pharmacokinetic interactions affecting either alcohol or medication exposure to pharmacodynamics interactions resulting in exaggerated response. […] Epidemiologic evidence suggests that concurrent use of alcohol and medications among older adults is common. […] In a nationally representative U.S. sample of community-dwelling older adults in the National Social Life, Health and Aging Project (NSHAP) 2005–2006, 41% of participants reported consuming alcohol at least once per week and 20% were at risk for an alcohol–medication interaction because they were using both alcohol and alcohol-interacting medications on a regular basis [17]. […] Among participants in the Pennsylvania Assistance Contract for the Elderly program (aged 65–106 years) taking at least one prescription medication, 77% were taking an alcohol-interacting medication and 19% of the alcohol-interacting medication users reported concurrent use of alcohol [18]. […] Although these studies do not document adverse outcomes associated with alcohol–medication interactions, they do document that the potential exists for many older adults. […] High prevalence of concurrent use of alcohol and alcohol-interacting medications have also been reported in Australian men (43% of sedative or anxiolytic users were daily drinkers) [19], in older adults in Finland (42% of at-risk alcohol users were also taking alcohol-interacting medications) [20], and in older Irish adults (72% of participants were exposed to alcohol-interacting medications and 60% of these reported concurrent alcohol use) [21]. Drinking and medication use patterns in older adults may differ across countries, but alcohol–medication interactions appear to be a worldwide concern. […] Polypharmacy in general, and psychotropic burden specifically, has been associated with an increased risk of experiencing a geriatric syndrome such as falls or delirium, in older adults [26, 27]. Based on its pharmacology, alcohol can be considered as a psychotropic drug, and alcohol use should be assessed as part of the medication regimen evaluation to support efforts to prevent or manage geriatric syndromes. […] Combining alcohol and CNS active medications can be particularly problematic […] Older adults suffering from sleep problems or pain may be a particular risk for alcohol–medication interaction-related adverse events.”

In general, alcohol use in younger couples has been found to be highly concordant, that is, individuals in a relationship tend to engage in similar drinking behaviors [67,68]. Less is known, however, about alcohol use concordance between older couples. Graham and Braun [69] examined similarities in drinking behavior between spouses in a study of 826 community-dwelling older adults in Ontario, Canada. Results showed high concordance of drinking between spouses — whether they drank at all, how much they drank, and how frequently. […] Social learning theory suggests that alcohol use trajectories are strongly influenced by attitudes and behaviors of an individual’s social networks, particularly family and friends. When individuals engage in social activities with family and friends who approve of and engage in drinking, alcohol use, and misuse are reinforced [58, 59]. Evidence shows that among older adults, participation in social activities is correlated with higher levels of alcohol consumption [34, 60]. […] Brennan and Moos [29] […] found that older adults who reported less empathy and support from friends drank more alcohol, were more depressed, and were less self-confident. More stressors involving friends were associated with more drinking problems. Similar to the findings on marital conflict […], conflict in close friendships can prompt alcohol-use problems; conversely, these relationships can suffer as a result of alcohol-related problems. […] As opposed to social network theory […], social selection theory proposes that alcohol consumption changes an individual’s social context [33]. Studies among younger adults have shown that heavier drinkers chose partners and friends who approve of heavier drinking [70] and that excessive drinking can alienate social networks. The Moos study supports the idea that social selection also has a strong influence on drinking behavior among older adults.”

Traditionally, treatment studies in addiction have excluded patients over the age of 65. This bias has left a tremendous gap in knowledge regarding treatment outcomes and an understanding of the neurobiology of addiction in older adults.

Alcohol use causes well-established changes in sleep patterns, such as decreased sleep latency, decreased stage IV sleep, and precipitation or aggravation of sleep apnea [101]. There are also age-associated changes in sleep patterns including increased REM episodes, a decrease in REM length, a decrease in stage III and IV sleep, and increased awakenings. Age-associated changes in sleep can all be worsened by alcohol use and depression. Moeller and colleagues [102] demonstrated in younger subjects that alcohol and depression had additive effects upon sleep disturbances when they occurred together [102]. Wagman and colleagues [101] also have demonstrated that abstinent alcoholics did not sleep well because of insomnia, frequent awakenings, and REM fragmentation [101]; however, when these subjects ingested alcohol, sleep periodicity normalized and REM sleep was temporarily suppressed, suggesting that alcohol use could be used to self-medicate for sleep disturbances. A common anecdote from patients is that alcohol is used to help with sleep problems. […] The use of alcohol to self-medicate is considered maladaptive [34] and is associated with a host of negative outcomes. […] The use of alcohol to aid with sleep has been found to disrupt sleep architecture and cause sleep-related problems and daytime sleepiness [35, 36, 46]. Though alcohol is commonly used to aid with sleep initiation, it can worsen sleep-related breathing disorders and cause snoring and obstructive sleep apnea [36].”

Epidemiologic studies have clearly demonstrated that comorbidity between alcohol use and other psychiatric symptoms is common in younger age groups. Less is known about comorbidity between alcohol use and psychiatric illness in late life [88]. […] Blow et al. [90] reviewed the diagnosis of 3,986 VA patients between ages 60 and 69 presenting for alcohol treatment [90]. The most common comorbid psychiatric disorder was an affective disorder found in 21 % of the patients. […] Blazer et al. [91] studied 997 community dwelling elderly of whom only 4.5% had a history of alcohol use problems [91]; […] of these subjects, almost half had a comorbid diagnosis of depression or dysthymia. Comorbid depressive symptoms are not only common in late life but are also an important factor in the course and prognosis of psychiatric disorders. Depressed alcoholics have been shown to have a more complicated clinical course of depression with an increased risk of suicide and more social dysfunction than non-depressed alcoholics [9296]. […]  Alcohol use prior to late life has also been shown to influence treatment of late life depression. Cook and colleagues [94] found that a prior history of alcohol use problems predicted a more severe and chronic course for depression [94]. […] The effect of past heavy alcohol use is [also] highlighted in the findings from the Liverpool Longitudinal Study demonstrating a fivefold increase in psychiatric illness among elderly men who had a lifetime history of 5 or more years of heavy drinking [24]. The association between heavy alcohol consumption in earlier years and psychiatric morbidity in later life was not explained by current drinking habits. […] While Wernicke-Korsakoff’s syndrome is well described and often caused by alcohol use disorders, alcohol-related dementia may be difficult to differentiate from Alzheimer’s disease. Clinical diagnostic criteria for alcohol-related dementia (ARD) have been proposed and now validated in at least one trial, suggesting a method for distinguishing ARD, including Wernicke-Korsakoff’s syndrome, from other types of dementia [97, 98]. […] Finlayson et al. [100] found that 49 of 216 (23%) elderly patients presenting for alcohol treatment had dementia associated with alcohol use disorders [100].”

 

May 24, 2018 Posted by | Books, Demographics, Epidemiology, Medicine, Neurology, Pharmacology, Psychiatry, Statistics | Leave a comment

100 cases in emergency medicine and critical care (I)

“This book has been written for medical students, doctors and nurse practitioners. One of the best methods of learning is case-based learning. This book presents a hundred such ‘cases’ or ‘patients’ which have been arranged by system. Each case has been written to stand alone […] the focus of each case is to recognise the initial presentation, the underlying pathophysiology, and to understand broad treatment principles.”

I really liked the book; as was also the case for the surgery book I recently read the cases included in these publications are slightly longer than they were in some of the previous publications in the series I’ve read, and I think this makes a big difference in terms of how much you actually get out of each case.

Below I have added some links and quotes related to the first half of the book’s coverage.

Tracheostomy.
Malnutrition (“it is estimated that around a quarter of hospital inpatients are inadequately nourished. This may be due to increased nutritional requirements […], nutritional losses (e.g. malabsorption, vomiting, diarrhoea) or reduced intake […] A patient’s basal energy expenditure is doubled in head injuries and burns.”)
Acute Adult Supraglottitis. (“It is important to appreciate that halving the radius of the airway will increase its resistance by 16 times (Poiseuille’s equation), and hearing stridor means there is around 75% airway obstruction.”)
Out-of-hospital cardiac arrest. (“After successful resuscitation from an OHCA, only 10% of patients will survive to discharge, and many of these individuals will have significant neurologic disability.”)
Bacterial meningitis. (“Meningococcal meningitis has a high mortality, with 10%-15% of patients dying of the disease despite appropriate therapy.”)
Diabetic ketoacidosis.
Anaphylaxis (“Always think of anaphylaxis when seeing patients with skin/mucosal symptoms, respiratory difficulty and/or hypotension, especially after exposure to a potential allergen.”)
Early goal-directed therapy. (“While randomised evidence on the benefit of [this approach] is conflicting, it is standard practice in most centres.” I’m not sure I’d agree with the authors that the evidence is ‘conflicting’, it looks to me like it’s reasonably clear at this point: “In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics.”)
Cardiac tamponade. Hypovolaemic shock. Permissive hypotensionFocused Assessment with Sonography in Trauma (FAST). (“Shock refers to inadequate tissue perfusion and tissue oxygenation. The commonest cause in an injured patient is hypovolaemic shock due to blood loss, but other causes include cardiogenic shock due to myocardial dysfunction, neurogenic shock due to sympathetic dysfunction or obstructive shock due to obstruction of the great vessels or heart. […] tachycardia, cool skin and reduced pulse pressure are early signs of shock until proven otherwise.”)
Intravenous therapy. A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit.
Thermal burns. Curling’s ulcer. Escharotomy. Wallace rule of nines. Fluid management in major burn injuries. (“Alkali burns are more harmful than acidic. […] Electrical burns cause more destruction than the external burn may suggest. They are associated with internal destruction, as the path of least resistance is nerves and blood vessels. They can also cause arrhythmias and an electrocardiogram should be performed.”)
Steven Johnson syndrome. Nikolsky’s sign. SCORTEN scale.
Cardiac arrest. (“The mantra in the ED is that ‘you are not dead until you are warm and dead'”).
Myocardial infarction. (“The most important goal of the acute management of STEMI is coronary reperfusion, which may be achieved either by percutaneous coronary intervention (PCI) or use of fibrinolytic agents (thrombolysis). PCI is the preferred strategy if it can be delivered within 120 minutes of first medical contact (and ideally within 90 minutes) […] several randomised trials have shown that PCI provides improved short- and long-term survival outcomes compared to fibrinolysis, providing it can be performed within the appropriate time frame.”)
Asthma exacerbation. (“the prognosis for asthmatics admitted to the Intensive Care Unit is guarded, with an in-hospital mortality of 7% in those who are mechanically ventilated.”)
Acute exacerbation of COPD. Respiratory Failure.
Pulmonary embolism. CT pulmonary angiography. (“Obstructive cardiopulmonary disease is the main diagnosis to exclude in patients presenting with shortness of breath and syncope.”)
Sepsis. Sepsis Six. qSOFA. (“The main clinical features of sepsis include hypotension […], tachycardia […], a high (>38.3°C) or low (<36°C) temperature, altered mental status and signs of peripheral shutdown (cool skin, prolonged capillary refill, cyanosis) in severe cases. […] Sepsis is associated with substantial in-hospital morbidity and mortality, and an increased risk of death and re-admission to hospital even if the patient survives until discharge. Prognostic factors in sepsis include patient factors (increasing age, higher comorbidity), site of infection (urosepsis is associated with better outcomes compared to other sources), type of pathogen (nosocomial infections have higher mortality), early administration of antibiotics (which may reduce mortality by 50%) and restoration of perfusion.”)
Acute kidney injury. (“Classically there are three major causative categories of AKI: (i) pre-renal (i.e. hypoperfusion), (ii) renal (i.e. an intrinsic process with the kidneys) and (iii) post-renal (i.e. urinary tract obstruction). The initial evaluation should attempt to determine which of these are leading to AKI in the patient. […] two main complications that arise with AKI [are] volume and electrolyte issues.”)
Acute chest syndrome.
Thrombotic thrombocytopenic purpura. Schistocyte. Plasmapheresis.
Lower gastrointestinal bleeding. WarfarinProthrombin complex concentrate. (“Warfarin is associated with a 1%-3% risk of bleeding each year in patients with atrial fibrillation, and the main risk factors for this include presence of comorbities, interacting medications, poor patient compliance, acute illness and dietary variation in vitamin K intake.”)
Acute back pain. Malignant spinal cord compression (-MSCC). (“Acute back pain is not an uncommon reason for presentation to the Emergency Department […] Although the majority of such presentations represent benign pathology, it is important to exclude more serious pathology such as cord or cauda equina compression, infection or abscess. Features in the history warranting greater concern include a prior history of cancer, recent infection or steroid use, fever, pain in the thoracic region, pain that improves with rest and the presence of urinary symptoms. Similarly, ‘red flag’ examination findings include gait ataxia, generalized weakness, upper motor neurone signs (clonus, hyper-reflexia, extensor plantars), a palpable bladder, saddle anaesthesia and reduced anal tone. […] MSCC affects up to 5% of all cancer patients and is the first manifestation of cancer in a fifth of patients.”)
Neutropenic sepsis. (“Neutropaenic sepsis […] arises as a result of cytotoxic chemotherapy suppressing the bone marrow, leading to depletion of white blood cells and leaving the individual vulnerable to infection. It is one of the most common complications of cancer therapy, carrying a significant mortality rate of ~5%-10%, and should be regarded as a medical emergency. Any patient receiving chemotherapy and presenting with a fever should be assumed to have neutropaenic sepsis until proven otherwise.”)
Bacterial Pneumonia. CURB-65 Pneumonia Severity Score.
Peptic ulcer diseaseUpper gastrointestinal bleeding. Glasgow-Blatchford score. Rockall score.
Generalised tonic-clonic seizure. Status Epilepticus.
“Chest pain is an extremely common presentation in the ED […] Key features that may help point towards particular diagnoses include • Location and radiation – Central chest pain that radiates to the face, neck or arms is classic for MI, whereas the pain may be more posterior (between should blades) in aortic dissection and unilateral in lung disease. • Onset – Sudden or acute onset pain usually indicates a vascular cause (e.g. PE or aortic dissection), whereas cardiac chest pain is typically more subacute in onset and increases over time. • Character – Cardiac pain is usually described as crushing but may often be a gnawing discomfort, whereas pain associated with aortic dissection and gastrointestinal disorders is usually tearing/ripping and burning, respectively. • Exacerbation/alleviation […] myocardial ischaemia will manifest as pain brought on by exercise and relieved by rest, which is a good discriminator between cardiac and non-cardiac pain.”
Syncope. Mobitz type II AV block. (The differential diagnosis for syncope is seizure, and the two may be distinguished by the absence of a quick or spontaneous recovery with a seizure, where a post-ictal state (sleepiness, confusion, lethargy) is present.”)
Atrial Fibrillation. CHADSVASC and HASBLED risk scores. (“AF with rapid ventricular rates is generally managed with control of heart rates through use of beta-blockers or calcium-channel blockers. • Unstable patients with AF may require electrical cardioversion to restore sinus rhythm.”)
Typhoid fever. Dysentery.
Alcohol toxicity. (“Differentials which may mimic acute alcohol intoxication include • Hypoglycemia • Electrolyte disturbance • Vitamin depletion (B12/folate) • Head trauma • Sepsis • Other toxins or drug overdose • Other causes for CNS depression”)
Tricyclic Antidepressant Toxicity. (“Over 50% of suicidal overdoses involve more than one medication and are often taken with alcohol.”)
Suicide. SADPERSONS scale. (“Intentional self-harm results in around 150,000 attendances to the ED [presumably ‘every year’ – US]. These patients are 100 times more likely to commit suicide within the next year compared to the general population. Self-harm and suicide are often used interchangeably, but are in fact two separate entities. Suicide is a self-inflicted intentional act to cause death, whereas self-harm is a complex behaviour to inflict harm but not associated with the thought of dying – a method to relieve mental stress by inflicting physical pain.”)
Cauda equina syndrome (-CES). (“signs and symptoms of lower extremity weakness and pain developing acutely after heavy lifting should raise suspicion for a herniated intervertebral disc, which is the commonest cause of CES. […] CES is a neurosurgical emergency. The goal is to prevent irreversible loss of bowel and bladder function and motor function of the lower extremities. […] A multitude of alternative diagnoses may masquerade as CES – stroke, vascular claudication, deep venous thrombosis, muscle cramps and peripheral neuropathy.”)
Concussion.
Subarachnoid hemorrhage. Arteriovenous malformation.
Ischemic Stroke. AlteplaseMechanical thrombectomy for acute ischemic stroke. (“evaluation and treatment should be based on the understanding that the damage that is done (infarcted brain) is likely to be permanent, and the goal is to prevent further damage (ischaemic brain) and treat reversible causes (secondary prevention). Along those lines, time is critical to the outcome of the patient.”)
Mechanical back pain. Sciatica.
Dislocated shoulder. Bankart lesion. Hill-Sachs lesion. Kocher’s method.
Supracondylar Humerus Fractures. (“Supracondular fractures in the adult are relatively uncommon but are seen in major trauma or in elderly patients where bone quality may be compromised. Elbow fractures need careful neurovascular evaluation […] There are three major nerves that pass through the region: 1. The median nerve […] 2. The radial nerve […] 3. The ulnar nerve […] It is important to assess these three nerves and to document their function individually. The brachial artery passes through the cubital fossa and may be directly injured by bone fragments or suffer intimal damage. […] This is a true orthopaedic and vascular emergency as the upper limb can only tolerate an ischaemia time of around 90 minutes before irreparable damage is sustained.”)
Boxer’s fracture.

May 2, 2018 Posted by | Books, Cancer/oncology, Cardiology, Infectious disease, Medicine, Nephrology, Neurology, Psychiatry, Studies | Leave a comment

Endocrinology (part 6 – neuroendocrine disorders and Paget’s disease)

I’m always uncertain as to how much content to cover when covering books like this one, and I usually cover handbooks in less detail (relatively) than I cover other books because of the amount of work it takes to cover all topics of interest – however I didn’t feel after writing my last post in the series that I had really finished with this book, in terms of blogging it; in fact I remember distinctly feeling a bit annoyed towards the end of writing my fifth post by the fact that I didn’t find that I could justify covering the detailed account of Paget’s disease included in the last part of the chapter, even though all of that stuff was new knowledge to me, and quite interesting – but these posts take some effort, and sometimes I cut them short just to at least blog something, rather than just have an unpublished draft lying around.

In this post I’ll first include some belated coverage of Paget’s disease, which is from the book’s chapter 6, and then I’ll cover some of the stuff included in chapter 8 of the book, about neuroendocrine disorders. Chapter 8 deals exclusively with various types of (usually quite rare) tumours. I decided to not cover chapter 7, which is devoted to paediatric endocrinology.

“Paget’s disease is the result of greatly local bone turnover, which occurs particularly in the elderly […] The 1° abnormality in Paget’s disease is gross overactivity of the osteoclasts, resulting in greatly increased ↑ bone resorption. This secondarily results in ↑ osteoblastic activity. The new bone is laid down in a highly disorganized manner […] Paget’s disease can affect any bone in the skeleton […] In most patients, it affects several sites, but, in about 20% of cases, a single bone is affected (monostotic disease). Typically, the disease will start in one end of a long bone and spread along the bone at a rate of about 1cm per year. […] Paget’s disease alters the mechanical properties of the bone. Thus, pagetic bones are more likely to bend under normal physiological loads and are thus liable to fracture. […] Pagetic bones are also larger than their normal counterparts. This can lead to ↑ arthritis at adjacent joints and to pressure on nerves, leading to neurological compression syndromes and, when it occurs in the skull base, sensorineural deafness.”

“Paget’s disease is present in about 2% of the UK population over the age of 55. It’s prevalence increases with age, and it is more common in ♂ than ♀. Only about 10% of affected patients will have symptomatic disease. […] Most notable feature is pain. […] The diagnosis of Paget’s disease is primarily radiological. […] An isotope bone scan is frequently helpful in assessing the extent of skeletal involvement […] Deafness is present in up to half of cases of skull base Paget’s. • Other neurological complications are rare. […] Osteogenic sarcoma [is a] very rare complication of Paget’s disease. […] Any increase of pain in a patient with Paget’s disease should arouse suspicion of sarcomatous degeneration. A more common cause, however, is resumption of activity of disease. […] Treatment with agents that decrease bone turnover reduces disease activity […] Although such treatment has been shown to help pain, there is little evidence that it benefits other consequences of Paget’s disease. In particular, the deafness of Paget’s disease does not regress after treatment […] Bisphosphonates have become the mainstay of treatment. […] Goals of treatment [are to:] • Minimize symptoms. • Prevent long-term complications. • Normalize bone turnover. • Alkaline phosphatase in normal range. • No actual evidence that treatment achieves this.”

The rest of this post will be devoted to covering topics from chapter 8:

Neuroendocrine cells are found in many sites throughout the body. They are particularly prominent in the GI tract and pancreas and […] have the ability to synthesize, store, and release peptide hormones. […] the majority of neuroendocrine tumours occur within the gastroenteropancreatic axis. […] >50% are traditionally termed carcinoid tumours […] with the remainder largely comprising pancreatic islet cell tumours. • Carcinoid and islet cell tumours are generally slow-growing. […] There is a move towards standardizing the terminology of these tumours […] The term NEN [neuroendocrine neoplasia] included low- and intermediate-grade neoplasia (previously referred to as carcinoid or atypical carcinoid) which are now referred to as neuroendocrine tumours (NETs) and high-grade neoplasia (neuroendocrine carcinoma, NEC). There is a confusing array of classifications of NENs, based on anatomical origin, histology, and secretory activity. • Many of these classifications are well established and widely used.”

“It is important to understand the differences between ‘differentiation’, which is the extent to which the neoplastic cells resemble their non-tumourous counterparts, and ‘grade’, which is the inherent agressiveness of the tumour. […] Neuroendocrine carcinomas are the most aggressive NENs and can be either small or large cell type. […] NENs are diagnosed based on histological features of biopsy specimens. The presenting features of the tumours vary like any other tumour, based on their anatomical location, such as abdominal pain, intestinal obstruction. Many are incidentally discovered during endoscopy or imaging for unrelated conditions. In a database study, 49% of NENs were localized, 24% had regional metastases, and 27% had distant metastases. […] These tumours rarely manifest themselves due to their secretory effect. [This is quite different from some of the other tumours they covered elsewhere in the book – US]  [….] Only a third of patients with neuroendocrine tumours develop symptoms due to hormone secretion.”

“Surgery is the treatment of choice for NENs grades 1 and 2, except in the presence of widespread distant metastases and extensive local invasion. […] Somatostatin analogues (SSA) have relatively minor side effects and provide long-term symptom control. •Octreotide and lanreotide […] reduce the level of biochemical tumour markers in the majority of patients and control symptoms in around 70% of cases. […] A combination of interferon with octreotide has been shown to produce biochemical and symptomatic improvement in patients who have previously had no significant benefit from either drug alone. […] Cytotoxic chemotherapy may be considered in patients with progressive, advanced, or uncontrolled symptomatic disease.”

“Despite the changes in nomenclature of NENs […] the ‘carcinoid crisis’ [apparently also termed ‘malignant carcinoid syndrome‘, US] is still an important descriptive term. It is a potentially life-threatening condition that should be prevented, where possible, and treated as an emergency. • Clinical features include hypotension, tachycardia, arrhythmias, flushing, diarrhoea, broncospasm, and altered sensoriom. […] carcinoid crisis can be triggered by manipulation of the tumours, such as during biopsy, surgery, or palpation. • These result in the release of biologically active compounds from the tumours. […] Carcinoid heart disease […] result in valvular stenosis or regurgitation and eventually heart failure. This condition is seen in 40-50% of patients with carcinoid syndrome and 3-4% of patients with neuroendocrine tumours”.

“An insulinoma is a functioning neuroendocrine tumour of the pancreas that causes hypoglycemia through inappropriate secretion of insulin. • Unlike other neuroendocrine tumours of the pancreas, more than 90% of insulinomas are benign. […] annual incidence of insulinomas is of the order of 1-2 per million population. […] The treatment of choice in all, but poor, surgical candidates is operative removal. […] In experienced surgical hands, the mortality is less than 1%. […] Following the removal of solitary insulinoma [>80% of cases], life expectancy is restored to normal. Malignant insulinomas, with metastases usually to the liver, have a natural history of years, rather than months, and may be controlled with medical therapy or specific antitumour therapy […] • Average 5-year survival estimated to be approximately 35% for malignant insulinomas. […] Gastrinomas are the most common functional malignant pancreatic endocrine tumours. […] The incidence of gastrinomas is 0.5-2/million population/year. […] Gastrin […] is the principal gut hormone stimulating gastric acid secretion. • The Zollinger-Ellison (ZE) syndrome is characterized by gastric acid oversecretion and manifests itself as severe peptic ulcer disease (PUD), gastro-oesophageal reflux, and diarrhoea. […] 10-year survival [in patients with gastrinomas] without liver metastases is 95%. […] Where there are diffuse metastases, […] a 10-year survival of approximately 15% [is observed].”

One of the things I was thinking about before deciding whether or not to blog this chapter was whether the (fortunately!) rare conditions encountered in the chapter really ‘deserved’ to be covered. Unlike what is the case for, say, breast cancer or colon cancer, most people won’t know someone who’ll die from malignant insulinoma. However although these conditions are very rare, I also can’t stop myself from thinking they’re also quite interesting, and I don’t care much about whether I know someone with a disease I’ve read about. And if you think these conditions are rare, well, for glucagonomas “The annual incidence is estimated at 1 per 20 million population”. These very rare conditions really serve as a reminder of how great our bodies are at dealing with all kinds of problems we’ve never even thought about. We don’t think about them precisely because a problem so rarely arises – but just now and then, well…

Let’s talk a little bit more about those glucagonomas:

“Glucagonomas are neuroendocrine tumours that usually arise from the α cells of the pancreas and produce the glucagonoma syndrome through the secretion of glucagon and other peptides derived from the preproglucagon gene. • The large majority of glucagonomas are malignant, but they are also very indolent tumours, and the diagnosis may be overlooked for many years. • Up to 90% of patients will have lymph node or liver metastases at the time of presentation. • They are classically associated with the rash of necrolytic migratory erythema. […] The characteristic rash [….] occurs in >70% of cases […] glucose intolerance is a frequent association (>90%). • Sustained gluconeogenesis also causes amino acid deficiencies and results in protein catabolism which can be associated with unrelenting weight loss in >60% of patients. • Glucagon has a direct suppressive effect on the bone marrow, resulting in a normochromic normocytic anaemia in almost all patients. […] Surgery is the only curative option, but the potential for a complete cure may be as low as 5%.”

“In 1958, Verner and Morrison1 first described a syndrome consisting of refractory watery diarrhoea and hypokalaemia, associated with a neuroendocrine tumour of the pancreas. • The syndrome of watery diarrhea, hypokalaemia and acidosis (WDHA) is due to secretion of vasoactive intestinal polypeptide (VIP). • Tumours that secrete VIP are known as VIPomas. VIPomas account for <10% of islet cell tumours and mainly occur as solitary tumours. >60% are malignant […] The most prominent symptom in most patients is profuse watery diarrhoea […] Surgery to remove the tumour is the treatment of first choice […] and may be curative in around 40% of patients. […] Somatostatin analogues produce effective symptomatic relief from the diarrhoea in most patients. Long-term use does not result in tumour regression. […] Chemotherapy […] has resulted in response rates of >30%.”

So by now we know that somatostatin analogues can provide symptom relief in a variety of contexts when you’re dealing with these conditions. But wait, what happens if you get a functional tumour of the cells that produce somatostatins? Will this mean that you just feel great all the time, or that you at least don’t have any symptoms of disease? Well, not exactly…

Somatostatinomas are very rare neuroendocrine tumours, occurring both in the pancreas and in the duodenum. • >60% are large tumours located in the head or body of the pancreas. • The clinical syndrome may be diagnosed late in the course of disease when metastatic spread to local lymph nodes and the liver has already occurred. […] • Glucose intolerance or frank diabetes mellitus may have been observed for many years prior to the diagnosis and retrospectively often represents the first clinical sign. It is probably due to the inhibitory effect of somatostatin on insulin secretion. • A high incidence of gallstones has been described similar to that seen as a side effect with long-term somatostatin analogue therapy. • Diarrhoea, steatorrhoea, and weight loss appear to be consistent clinical features […this despite the fact that you use the hormone produced by these tumours to manage diarrhea in other endocrine tumours – it’s stuff like this which makes these rare disorders far from boring to read about! US] and may be associated with inhibition of the exocrine pancreas by somatostatin.”

May 1, 2018 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Epidemiology, Medicine, Neurology, Pharmacology | Leave a comment

100 cases in surgery (II)

Below I have added some links and quotes related to the last half of the book’s coverage.

Ischemic rest pain. (“Rest pain indicates inadequate tissue perfusion. *Urgent investigation and treatment is required to salvage the limb. […] The material of choice for bypass grafting is autogenous vein. […] The long-term patency of prosthetic grafts is inferior compared with autogenous vein.”)
Deep vein thrombosis.
Lymphedema. (“In lymphoedema, the vast majority of patients (>90 per cent) are treated conservatively. […] Debulking operations […] are only considered for a selected few patients where the function of the limb is impaired or those with recurrent attacks of severe cellulitis.”)
Varicose veins. Trendelenburg Test. (“Surgery on the superficial venous system should be avoided in patients with an incompetent deep venous system.”)
Testicular Torsion.
Benign Prostatic Hyperplasia.
Acute pyelonephritis. (“In patients with recurrent infection in the urinary system, significant pathology needs excluding such as malignancy, urinary tract stone disease and abnormal urinary tract anatomy.”)
Renal cell carcinomavon Hippel-Lindau syndrome. (“Approximately one-quarter to one-third of patients with renal cell carcinomas have metastases at presentation. […] The classic presenting triad of loin pain, a mass and haematuria only occurs in about 10 per cent of patients. More commonly, one of these features appears in isolation.”)
Haematuria. (“When taking the history, it is important to elicit the following: •Visible or non-visible: duration of haematuria • Age: cancers are more common with increasing age •Sex: females more likely to have urinary tract infections• Location: during micturition, was the haematuria always present (indicative of renal, ureteric or bladder pathology) or was it only present initially (suggestive of anterior urethral pathology) or present at the end of the stream (posterior urethra, bladder neck)? •Pain: more often associated with infection/inflammation/calculi, whereas malignancy tends to be painless •Associated lower urinary tract symptoms that will be helpful in determining aetiology •History of trauma Travel abroad […] •Previous urological surgery/history/recent instrumentation/prostatic biopsy •Medication, e.g. anticoagulants •Family history •Occupational history, e.g. rubber/dye occupational hazards are risk factors for developing transitional carcinoma of the bladder […] •Smoking status: increased risk, particularly of bladder cancer •General status, e.g. weight loss, reduced appetite […] Anticoagulation can often unmask other pathology in the urinary tract. […] Patients on oral anticoagulation who develop haematuria still require investigation.”)
Urinary retention. (“Acute and chronic retention are usually differentiated by the presence or absence of pain. Acute retention is painful, unlike chronic retention, when the bladder accommodates the increase in volume over time.”)
Colles’ fracture/Distal Radius Fractures. (“In all fractures the distal neurological and vascular status should be assessed.”)
Osteoarthritis. (“Radiological evidence of osteoarthritis is common, with 80 per cent of individuals over 80 years demonstrating some evidence of the condition. […] The commonest symptoms are pain, a reduction in mobility, and deformity of the affected joint.”)
Simmonds’ test.
Patella fracture.
Dislocated shoulder.
Femur fracture. (“Fractured neck of the femur is a relatively common injury following a fall in the elderly population. The rate of hip fracture doubles every decade from the age of 50 years. There is a female preponderance of three to one. […] it is important to take a comprehensive history, concentrating on the mechanism of injury. It is incorrect to assume that all falls are mechanical; it is not uncommon to find that the cause of the fall is actually due to a urinary or chest infection or even a silent myocardial infarction.”)
The Ottawa Ankle Rules.
Septic arthritis.
Carpal tunnel syndrome. Tinel’s test. Phalen’s Test. (“It is important, when examining a patient with suspected carpal tunnel syndrome, to carefully examine their neck, shoulder, and axilla. […] the source of the neurological compression may be proximal to the carpal tunnel”)
Acute Compartment Syndrome. (“Within the limbs there are a number of myofascial compartments. These consist of muscles contained within a relatively fixed-volume structure, bounded by fascial layers and bone. After trauma the pressure in the myofascial compartment increases. This pressure may exceed the venous capillary pressure, resulting in a loss of venous outflow from the compartment. The failure to clear metabolites also leads to the accumulation of fluid as a result of osmosis. If left untreated, the pressure will eventually exceed arterial pressure, leading to significant tissue ischaemia. The damage is irreversible after 4–6 h. Tibial fractures are the commonest cause of an acute compartment syndrome, which is thought to complicate up to 20 per cent of these injuries. […] The classical description of ‘pain out of proportion to the injury’ may [unfortunately] be difficult to determine if the clinician is inexperienced.”)
Hemarthrosis. (“Most knee injuries result in swelling which develops over hours rather than minutes. [A] history of immediate knee swelling suggests that there is a haemarthrosis.”)
Sickle cell crisis.
Cervical Spine Fracture. Neurogenic shock. NEXUS Criteria for C-Spine Imaging.
Slipped Capital Femoral Epiphysis. Trethowan sign. (“At any age, a limp in a child should always be taken seriously.”)

ATLS guidelines. (“The ATLS protocol should be followed even in the presence of obvious limb deformity, to ensure a potentially life-threatening injury is not missed.”)
Peritonsillar Abscess.
Epistaxis. Little’s area.
Croup. Acute epiglottitis. (“Acute epiglottitis is an absolute emergency and is usually caused by Haemophilus influenzae. There is significant swelling, and any attempt to examine the throat may result in airway obstruction. […] In adults it tends to cause a supraglottitis. It has a rapid progression and can lead to total airway obstruction. […] Stridor is an ominous sign and needs to be taken seriously.”)
Bell’s palsy.
Subarachnoid hemorrhageInternational subarachnoid aneurysm trial.
Chronic subdural hematoma. (“This condition is twice as common in men as women. Risk factors include chronic alcoholism, epilepsy, anticoagulant therapy (including aspirin) and thrombocytopenia. CSDH is more common in elderly patients due to cerebral atrophy. […] Initial misdiagnosis is, unfortunately, quite common. […] a chronic subdural haematoma should be suspected in confused patients with a history of a fall.”)
Extradural Haematoma. Cushing response. (“A direct blow to the temporo-parietal area is the commonest cause of an extradural haematoma. The bleed is normally arterial in origin. In 85 per cent of cases there is an associated skull fracture that causes damage to the middle meningeal artery. […] This situation represents a neurosurgical emergency. Without urgent decompression the patient will die. Unlike the chronic subdural, which can be treated with Burr hole drainage, the more dense acute arterial haematoma requires a craniotomy in order to evacuate it.”)
Cauda equina syndromeNeurosurgery for Cauda Equina Syndrome.
ASA classification. (“Patients having an operation within 3 months of a myocardial infarction carry a 30 per cent risk of reinfarction or cardiac death. This drops to 5 per cent after 6 months. […] Patients with COPD have difficulty clearing secretions from the lungs during the postoperative period. They also have a higher risk of basal atelectasis and are more prone to chest infections. These factors in combination with postoperative pain (especially in thoracic or abdominal major surgery) make them prone to respiratory complications. […] Patients with diabetes have an increased risk of postoperative complications because of the presence of microvascular and macrovascular disease: •Atherosclerosis: ischaemic heart disease/peripheral vascular disease/cerebrovascular disease •Nephropathy: renal insufficiency […] •Autonomic neuropathy: gastroparesis, decreased bladder tone •Peripheral neuropathy: lower-extremity ulceration, infection, gangrene •Poor wound healingIncreased risk of infection Tight glycaemic control (6–10 mmol/L) and the prevention of hypoglycaemia are critical in preventing perioperative and postoperative complications. The patient with diabetes should be placed first on the operating list to avoid prolonged fasting.
“)
MalnutritionHartmann’s procedure. (“Malnutrition leads to delayed wound healing, reduced ventilatory capacity, reduced immunity and an increased risk of infection. […] The two main methods of feeding are either by the enteral route or the parenteral route. Enteral feeding is via the gastrointestinal tract. It is less expensive and is associated with fewer complications than feeding by the parenteral route. […] The parenteral route should only be used if there is an inability to ingest, digest, absorb or propulse nutrients through the gastrointestinal tract. It can be administered by either a peripheral or central line. Peripheral parenteral nutrition can cause thrombophlebitis […] Sepsis is the most frequent and serious complication of centrally administered parenteral nutrition.”)
Acute Kidney Injury. (“The aetiology of acute renal failure can be thought of in three main categories: •Pre-renal: the glomerular filtration is reduced because of poor renal perfusion. This is usually caused by hypovolaemia as a result of acute blood loss, fluid depletion or hypotension. […] • Renal: this is the result of damage directly to the glomerulus or tubule. The use of drugs such as NSAIDs, contrast agents or aminoglycosides all have direct nephrotoxic effects. Acute tubular necrosis can occur as a result of prolonged hypoperfusion […]. Pre-existing renal disease such as diabetic nephropathy or glomerulonephritis makes patients more susceptible to further renal injury. •Post-renal: this can be simply the result of a blocked catheter. […] Calculi, blood clots, ureteric ligation and prostatic hypertrophy can also all lead to obstruction of urinary flow.”)
Post-operative ileus.

Pulmonary embolism.

April 18, 2018 Posted by | Books, Cancer/oncology, Cardiology, Gastroenterology, Infectious disease, Medicine, Nephrology, Neurology | Leave a comment

A few (more) diabetes papers of interest

Earlier this week I covered a couple of papers, but the second paper turned out to include a lot of interesting stuff so I decided to cut the post short and postpone my coverage of the other papers I’d intended to cover in that post until a later point in time; this post includes some of those other papers I’d intended to cover in that post.

i. TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes.

“Although the autoimmune destruction of β-cells has a major role in the development of type 1 diabetes, there is growing evidence that the differences in clinical, metabolic, immunologic, and genetic characteristics among patients (1) likely reflect diverse etiology and pathogenesis (2). Factors that govern this heterogeneity are poorly understood, yet these may have important implications for prognosis, therapy, and prevention.

The transcription factor 7 like 2 (TCF7L2) locus contains the single nucleotide polymorphism (SNP) most strongly associated with type 2 diabetes risk, with an ∼30% increase per risk allele (3). In a U.S. cohort, heterozygous and homozygous carriers of the at-risk alleles comprised 40.6% and 7.9%, respectively, of the control subjects and 44.3% and 18.3%, respectively, of the individuals with type 2 diabetes (3). The locus has no known association with type 1 diabetes overall (48), with conflicting reports in latent autoimmune diabetes in adults (816). […] Our studies in two separate cohorts have shown that the type 2 diabetes–associated TCF7L2 genetic variant is more frequent among specific subsets of individuals with autoimmune type 1 diabetes, specifically those with fewer markers of islet autoimmunity (22,23). These observations support a role of this genetic variant in the pathogenesis of diabetes at least in a subset of individuals with autoimmune diabetes. However, whether individuals with type 1 diabetes and this genetic variant have distinct metabolic abnormalities has not been investigated. We aimed to study the immunologic and metabolic characteristics of individuals with type 1 diabetes who carry a type 2 diabetes–associated allele of the TCF7L2 locus.”

“We studied 810 TrialNet participants with newly diagnosed type 1 diabetes and found that among individuals 12 years and older, the type 2 diabetes–associated TCF7L2 genetic variant is more frequent in those presenting with a single autoantibody than in participants who had multiple autoantibodies. These TCF7L2 variants were also associated with higher mean C-peptide AUC and lower mean glucose AUC levels at the onset of type 1 diabetes. […] These findings suggest that, besides the well-known link with type 2 diabetes, the TCF7L2 locus may play a role in the development of type 1 diabetes. The type 2 diabetes–associated TCF7L2 genetic variant identifies a subset of individuals with autoimmune type 1 diabetes and fewer markers of islet autoimmunity, lower glucose, and higher C-peptide at diagnosis. […] A possible interpretation of these data is that TCF7L2-encoded diabetogenic mechanisms may contribute to diabetes development in individuals with limited autoimmunity […]. Because the risk of progression to type 1 diabetes is lower in individuals with single compared with multiple autoantibodies, it is possible that in the absence of this type 2 diabetes–associated TCF7L2 variant, these individuals may have not manifested diabetes. If that is the case, we would postulate that disease development in these patients may have a type 2 diabetes–like pathogenesis in which islet autoimmunity is a significant component but not necessarily the primary driver.”

“The association between this genetic variant and single autoantibody positivity was present in individuals 12 years or older but not in children younger than 12 years. […] The results in the current study suggest that the type 2 diabetes–associated TCF7L2 genetic variant plays a larger role in older individuals. There is mounting evidence that the pathogenesis of type 1 diabetes varies by age (31). Younger individuals appear to have a more aggressive form of disease, with faster decline of β-cell function before and after onset of disease, higher frequency and severity of diabetic ketoacidosis, which is a clinical correlate of severe insulin deficiency, and lower C-peptide at presentation (3135). Furthermore, older patients are less likely to have type 1 diabetes–associated HLA alleles and islet autoantibodies (28). […] Taken together, we have demonstrated that individuals with autoimmune type 1 diabetes who carry the type 2 diabetes–associated TCF7L2 genetic variant have a distinct phenotype characterized by milder immunologic and metabolic characteristics than noncarriers, closer to those of type 2 diabetes, with an important effect of age.”

ii. Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes.

“Concerns about cardiovascular disease in type 2 diabetes have traditionally focused on atherosclerotic vasculo-occlusive events, such as myocardial infarction, stroke, and limb ischemia. However, one of the earliest, most common, and most serious cardiovascular disorders in patients with diabetes is heart failure (1). Following its onset, patients experience a striking deterioration in their clinical course, which is marked by frequent hospitalizations and eventually death. Many sudden deaths in diabetes are related to underlying ventricular dysfunction rather than a new ischemic event. […] Heart failure and diabetes are linked pathophysiologically. Type 2 diabetes and heart failure are each characterized by insulin resistance and are accompanied by the activation of neurohormonal systems (norepinephrine, angiotensin II, aldosterone, and neprilysin) (3). The two disorders overlap; diabetes is present in 35–45% of patients with chronic heart failure, whether they have a reduced or preserved ejection fraction.”

“Treatments that lower blood glucose do not exert any consistently favorable effect on the risk of heart failure in patients with diabetes (6). In contrast, treatments that increase insulin signaling are accompanied by an increased risk of heart failure. Insulin use is independently associated with an enhanced likelihood of heart failure (7). Thiazolidinediones promote insulin signaling and have increased the risk of heart failure in controlled clinical trials (6). With respect to incretin-based secretagogues, liraglutide increases the clinical instability of patients with existing heart failure (8,9), and the dipeptidyl peptidase 4 inhibitors saxagliptin and alogliptin are associated with an increased risk of heart failure in diabetes (10). The likelihood of heart failure with the use of sulfonylureas may be comparable to that with thiazolidinediones (11). Interestingly, the only two classes of drugs that ameliorate hyperinsulinemia (metformin and sodium–glucose cotransporter 2 inhibitors) are also the only two classes of antidiabetes drugs that appear to reduce the risk of heart failure and its adverse consequences (12,13). These findings are consistent with experimental evidence that insulin exerts adverse effects on the heart and kidneys that can contribute to heart failure (14). Therefore, physicians can prevent many cases of heart failure in type 2 diabetes by careful consideration of the choice of agents used to achieve glycemic control. Importantly, these decisions have an immediate effect; changes in risk are seen within the first few months of changes in treatment. This immediacy stands in contrast to the years of therapy required to see a benefit of antidiabetes drugs on microvascular risk.”

“As reported by van den Berge et al. (4), the prognosis of patients with heart failure has improved over the past two decades; heart failure with a reduced ejection fraction is a treatable disease. Inhibitors of the renin-angiotensin system are a cornerstone of the management of both disorders; they prevent the onset of heart failure and the progression of nephropathy in patients with diabetes, and they reduce the risk of cardiovascular death and hospitalization in those with established heart failure (3,15). Diabetes does not influence the magnitude of the relative benefit of ACE inhibitors in patients with heart failure, but patients with diabetes experience a greater absolute benefit from treatment (16).”

“The totality of evidence from randomized trials […] demonstrates that in patients with diabetes, heart failure is not only common and clinically important, but it can also be prevented and treated. This conclusion is particularly significant because physicians have long ignored heart failure in their focus on glycemic control and their concerns about the ischemic macrovascular complications of diabetes (1).”

iii. Closely related to the above study: Mortality Reduction Associated With β-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes.

“Diabetes increases mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. Studies have questioned the safety of β-adrenoceptor blockers (β-blockers) in some patients with diabetes and reduced left ventricular ejection fraction. We examined whether β-blockers and ACE inhibitors (ACEIs) are associated with differential effects on mortality in CHF patients with and without diabetes. […] We conducted a prospective cohort study of 1,797 patients with CHF recruited between 2006 and 2014, with mean follow-up of 4 years.”

RESULTS Patients with diabetes were prescribed larger doses of β-blockers and ACEIs than were patients without diabetes. Increasing β-blocker dose was associated with lower mortality in patients with diabetes (8.9% per mg/day; 95% CI 5–12.6) and without diabetes (3.5% per mg/day; 95% CI 0.7–6.3), although the effect was larger in people with diabetes (interaction P = 0.027). Increasing ACEI dose was associated with lower mortality in patients with diabetes (5.9% per mg/day; 95% CI 2.5–9.2) and without diabetes (5.1% per mg/day; 95% CI 2.6–7.6), with similar effect size in these groups (interaction P = 0.76).”

“Our most important findings are:

  • Higher-dose β-blockers are associated with lower mortality in patients with CHF and LVSD, but patients with diabetes may derive more benefit from higher-dose β-blockers.

  • Higher-dose ACEIs were associated with comparable mortality reduction in people with and without diabetes.

  • The association between higher β-blocker dose and reduced mortality is most pronounced in patients with diabetes who have more severely impaired left ventricular function.

  • Among patients with diabetes, the relationship between β-blocker dose and mortality was not associated with glycemic control or insulin therapy.”

“We make the important observation that patients with diabetes may derive more prognostic benefit from higher β-blocker doses than patients without diabetes. These data should provide reassurance to patients and health care providers and encourage careful but determined uptitration of β-blockers in this high-risk group of patients.”

iv. Diabetes, Prediabetes, and Brain Volumes and Subclinical Cerebrovascular Disease on MRI: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

“Diabetes and prediabetes are associated with accelerated cognitive decline (1), and diabetes is associated with an approximately twofold increased risk of dementia (2). Subclinical brain pathology, as defined by small vessel disease (lacunar infarcts, white matter hyperintensities [WMH], and microhemorrhages), large vessel disease (cortical infarcts), and smaller brain volumes also are associated with an increased risk of cognitive decline and dementia (37). The mechanisms by which diabetes contributes to accelerated cognitive decline and dementia are not fully understood, but contributions of hyperglycemia to both cerebrovascular disease and primary neurodegenerative disease have been suggested in the literature, although results are inconsistent (2,8). Given that diabetes is a vascular risk factor, brain atrophy among individuals with diabetes may be driven by increased cerebrovascular disease. Brain magnetic resonance imaging (MRI) provides a noninvasive opportunity to study associations of hyperglycemia with small vessel disease (lacunar infarcts, WMH, microhemorrhages), large vessel disease (cortical infarcts), and brain volumes (9).”

“Overall, the mean age of participants [(n = 1,713)] was 75 years, 60% were women, 27% were black, 30% had prediabetes (HbA1c 5.7 to <6.5%), and 35% had diabetes. Compared with participants without diabetes and HbA1c <5.7%, those with prediabetes (HbA1c 5.7 to <6.5%) were of similar age (75.2 vs. 75.0 years; P = 0.551), were more likely to be black (24% vs. 11%; P < 0.001), have less than a high school education (11% vs. 7%; P = 0.017), and have hypertension (71% vs. 63%; P = 0.012) (Table 1). Among participants with diabetes, those with HbA1c <7.0% versus ≥7.0% were of similar age (75.4 vs. 75.1 years; P = 0.481), but those with diabetes and HbA1c ≥7.0% were more likely to be black (39% vs. 28%; P = 0.020) and to have less than a high school education (23% vs. 16%; P = 0.031) and were more likely to have a longer duration of diabetes (12 vs. 8 years; P < 0.001).”

“Compared with participants without diabetes and HbA1c <5.7%, those with diabetes and HbA1c ≥7.0% had smaller total brain volume (β −0.20 SDs; 95% CI −0.31, −0.09) and smaller regional brain volumes, including frontal, temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus (all P < 0.05) […]. Compared with participants with diabetes and HbA1c <7.0%, those with diabetes and HbA1c ≥7.0% had smaller total brain volume (P < 0.001), frontal lobe volume (P = 0.012), temporal lobe volume (P = 0.012), occipital lobe volume (P = 0.008), parietal lobe volume (P = 0.015), deep gray matter volume (P < 0.001), Alzheimer disease signature region volume (0.031), and hippocampal volume (P = 0.016). Both participants with diabetes and HbA1c <7.0% and those with prediabetes (HbA1c 5.7 to <6.5%) had similar total and regional brain volumes compared with participants without diabetes and HbA1c <5.7% (all P > 0.05). […] No differences in the presence of lobar microhemorrhages, subcortical microhemorrhages, cortical infarcts, and lacunar infarcts were observed among the diabetes-HbA1c categories (all P > 0.05) […]. Compared with participants without diabetes and HbA1c <5.7%, those with diabetes and HbA1c ≥7.0% had increased WMH volume (P = 0.016). The WMH volume among participants with diabetes and HbA1c ≥7.0% was also significantly greater than among those with diabetes and HbA1c <7.0% (P = 0.017).”

“Those with diabetes duration ≥10 years were older than those with diabetes duration <10 years (75.9 vs. 75.0 years; P = 0.041) but were similar in terms of race and sex […]. Compared with participants with diabetes duration <10 years, those with diabetes duration ≥10 years has smaller adjusted total brain volume (β −0.13 SDs; 95% CI −0.20, −0.05) and smaller temporal lobe (β −0.14 SDs; 95% CI −0.24, −0.03), parietal lobe (β − 0.11 SDs; 95% CI −0.21, −0.01), and hippocampal (β −0.16 SDs; 95% CI −0.30, −0.02) volumes […]. Participants with diabetes duration ≥10 years also had a 2.44 times increased odds (95% CI 1.46, 4.05) of lacunar infarcts compared with those with diabetes duration <10 years”.

Conclusions
In this community-based population, we found that ARIC-NCS participants with diabetes with HbA1c ≥7.0% have smaller total and regional brain volumes and an increased burden of WMH, but those with prediabetes (HbA1c 5.7 to <6.5%) and diabetes with HbA1c <7.0% have brain volumes and markers of subclinical cerebrovascular disease similar to those without diabetes. Furthermore, among participants with diabetes, those with more-severe disease (as measured by higher HbA1c and longer disease duration) had smaller total and regional brain volumes and an increased burden of cerebrovascular disease compared with those with lower HbA1c and shorter disease duration. However, we found no evidence that associations of diabetes with smaller brain volumes are mediated by cerebrovascular disease.

The findings of this study extend the current literature that suggests that diabetes is strongly associated with brain volume loss (11,2527). Global brain volume loss (11,2527) has been consistently reported, but associations of diabetes with smaller specific brain regions have been less robust (27,28). Similar to prior studies, the current results show that compared with individuals without diabetes, those with diabetes have smaller total brain volume (11,2527) and regional brain volumes, including frontal and occipital lobes, deep gray matter, and the hippocampus (25,27). Furthermore, the current study suggests that greater severity of disease (as measured by HbA1c and diabetes duration) is associated with smaller total and regional brain volumes. […] Mechanisms whereby diabetes may contribute to brain volume loss include accelerated amyloid-β and hyperphosphorylated tau deposition as a result of hyperglycemia (29). Another possible mechanism involves pancreatic amyloid (amylin) infiltration of the brain, which then promotes amyloid-β deposition (29). […] Taken together, […] the current results suggest that diabetes is associated with both lower brain volumes and increased cerebrovascular pathology (WMH and lacunes).”

v. Interventions to increase attendance for diabetic retinopathy screening (Cochrane review).

“The primary objective of the review was to assess the effectiveness of quality improvement (QI) interventions that seek to increase attendance for DRS in people with type 1 and type 2 diabetes.

Secondary objectives were:
To use validated taxonomies of QI intervention strategies and behaviour change techniques (BCTs) to code the description of interventions in the included studies and determine whether interventions that include particular QI strategies or component BCTs are more effective in increasing screening attendance;
To explore heterogeneity in effect size within and between studies to identify potential explanatory factors for variability in effect size;
To explore differential effects in subgroups to provide information on how equity of screening attendance could be improved;
To critically appraise and summarise current evidence on the resource use, costs and cost effectiveness.”

“We included 66 RCTs conducted predominantly (62%) in the USA. Overall we judged the trials to be at low or unclear risk of bias. QI strategies were multifaceted and targeted patients, healthcare professionals or healthcare systems. Fifty-six studies (329,164 participants) compared intervention versus usual care (median duration of follow-up 12 months). Overall, DRS [diabetic retinopathy screening] attendance increased by 12% (risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14; low-certainty evidence) compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted (RD 0.17, 95% CI 0.11 to 0.22) and general QI interventions (RD 0.12, 95% CI 0.09 to 0.15) were effective, particularly where baseline DRS attendance was low. All BCT combinations were associated with significant improvements, particularly in those with poor attendance. We found higher effect estimates in subgroup analyses for the BCTs ‘goal setting (outcome)’ (RD 0.26, 95% CI 0.16 to 0.36) and ‘feedback on outcomes of behaviour’ (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients, and ‘restructuring the social environment’ (RD 0.19, 95% CI 0.12 to 0.26) and ‘credible source’ (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting healthcare professionals.”

“Ten studies (23,715 participants) compared a more intensive (stepped) intervention versus a less intensive intervention. In these studies DRS attendance increased by 5% (RD 0.05, 95% CI 0.02 to 0.09; moderate-certainty evidence).”

“Overall, we found that there is insufficient evidence to draw robust conclusions about the relative cost effectiveness of the interventions compared to each other or against usual care.”

“The results of this review provide evidence that QI interventions targeting patients, healthcare professionals or the healthcare system are associated with meaningful improvements in DRS attendance compared to usual care. There was no statistically significant difference between interventions specifically aimed at DRS and those which were part of a general QI strategy for improving diabetes care.”

vi. Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication.

“The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10–20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. […] In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D.”

“Over the past three decades, the prevalence of diabetes in China has sharply increased. The prevalence of diabetes was reported to be less than 1% in 1980 (2), 5.5% in 2001 (3), 9.7% in 2008 (4), and 10.9% in 2013, according to the latest published nationwide survey (5) […]. The prevalence of diabetes was higher in the senior population, men, urban residents, individuals living in economically developed areas, and overweight and obese individuals. The estimated prevalence of prediabetes in 2013 was 35.7%, which was much higher than the estimate of 15.5% in the 2008 survey. Similarly, the prevalence of prediabetes was higher in the senior population, men, and overweight and obese individuals. However, prediabetes was more prevalent in rural residents than in urban residents. […] the 2013 survey also compared the prevalence of diabetes among different races. The crude prevalence of diabetes was 14.7% in the majority group, i.e., Chinese Han, which was higher than that in most minority ethnic groups, including Tibetan, Zhuang, Uyghur, and Muslim. The crude prevalence of prediabetes was also higher in the Chinese Han ethnic group. The Tibetan participants had the lowest prevalence of diabetes and prediabetes (4.3% and 31.3%).”

“[T]he prevalence of diabetes in young people is relatively high and increasing. The prevalence of diabetes in the 20- to 39-year age-group was 3.2%, according to the 2008 national survey (4), and was 5.9%, according to the 2013 national survey (5). The prevalence of prediabetes also increased from 9.0% in 2008 to 28.8% in 2013 […]. Young people suffering from diabetes have a higher risk of chronic complications, which are the major cause of mortality and morbidity in diabetes. According to a study conducted in Asia (6), patients with young-onset diabetes had higher mean concentrations of HbA1c and LDL cholesterol and a higher prevalence of retinopathy (20% vs. 18%, P = 0.011) than those with late-onset diabetes. In the Chinese, patients with early-onset diabetes had a higher risk of nonfatal cardiovascular disease (7) than did patients with late-onset diabetes (odds ratio [OR] 1.91, 95% CI 1.81–2.02).”

“As approximately 95% of patients with diabetes in China have T2D, the rapid increase in the prevalence of diabetes in China may be attributed to the increasing rates of overweight and obesity and the reduction in physical activity, which is driven by economic development, lifestyle changes, and diet (3,11). According to a series of nationwide surveys conducted by the China Physical Fitness Surveillance Center (12), the prevalence of overweight (BMI ≥23.0 to <27.5 kg/m2) in Chinese adults aged 20–59 years increased from 37.4% in 2000 to 39.2% in 2005, 40.7% in 2010, and 41.2% in 2014, with an estimated increase of 0.27% per year. The prevalence of obesity (BMI ≥27.5 kg/m2) increased from 8.6% in 2000 to 10.3% in 2005, 12.2% in 2010, and 12.9% in 2014, with an estimated increase of 0.32% per year […]. The prevalence of central obesity increased from 13.9% in 2000 to 18.3% in 2005, 22.1% in 2010, and 24.9% in 2014, with an estimated increase of 0.78% per year. Notably, T2D develops at a considerably lower BMI in the Chinese population than that in European populations. […] The relatively high risk of diabetes at a lower BMI could be partially attributed to the tendency toward visceral adiposity in East Asian populations, including the Chinese population (13). Moreover, East Asian populations have been found to have a higher insulin sensitivity with a much lower insulin response than European descent and African populations, implying a lower compensatory β-cell function, which increases the risk of progressing to overt diabetes (14).”

“Over the past two decades, linkage analyses, candidate gene approaches, and large-scale GWAS have successfully identified more than 100 genes that confer susceptibility to T2D among the world’s major ethnic populations […], most of which were discovered in European populations. However, less than 50% of these European-derived loci have been successfully confirmed in East Asian populations. […] there is a need to identify specific genes that are associated with T2D in other ethnic populations. […] Although many genetic loci have been shown to confer susceptibility to T2D, the mechanism by which these loci participate in the pathogenesis of T2D remains unknown. Most T2D loci are located near genes that are related to β-cell function […] most single nucleotide polymorphisms (SNPs) contributing to the T2D risk are located in introns, but whether these SNPs directly modify gene expression or are involved in linkage disequilibrium with unknown causal variants remains to be investigated. Furthermore, the loci discovered thus far collectively account for less than 15% of the overall estimated genetic heritability.”

“The areas under the receiver operating characteristic curves (AUCs) are usually used to assess the discriminative accuracy of an approach. The AUC values range from 0.5 to 1.0, where an AUC of 0.5 represents a lack of discrimination and an AUC of 1 represents perfect discrimination. An AUC ≥0.75 is considered clinically useful. The dominant conventional risk factors, including age, sex, BMI, waist circumference, blood pressure, family history of diabetes, physical activity level, smoking status, and alcohol consumption, can be combined to construct conventional risk factor–based models (CRM). Several studies have compared the predictive capacities of models with and without genetic information. The addition of genetic markers to a CRM could slightly improve the predictive performance. For example, one European study showed that the addition of an 11-SNP GRS to a CRM marginally improved the risk prediction (AUC was 0.74 without and 0.75 with the genetic markers, P < 0.001) in a prospective cohort of 16,000 individuals (37). A meta-analysis (38) consisting of 23 studies investigating the predictive performance of T2D risk models also reported that the AUCs only slightly increased with the addition of genetic information to the CRM (median AUC was increased from 0.78 to 0.79). […] Despite great advances in genetic studies, the clinical utility of genetic information in the prediction, early identification, and prevention of T2D remains in its preliminary stage.”

“An increasing number of studies have highlighted that early nutrition has a persistent effect on the risk of diabetes in later life (40,41). China’s Great Famine of 1959–1962 is considered to be the largest and most severe famine of the 20th century […] Li et al. (43) found that offspring of mothers exposed to the Chinese famine have a 3.9-fold increased risk of diabetes or hyperglycemia as adults. A more recent study (the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors [SPECT-China]) conducted in 2014, among 6,897 adults from Shanghai, Jiangxi, and Zhejiang provinces, had the same conclusion that famine exposure during the fetal period (OR 1.53, 95% CI 1.09–2.14) and childhood (OR 1.82, 95% CI 1.21–2.73) was associated with diabetes (44). These findings indicate that undernutrition during early life increases the risk of hyperglycemia in adulthood and this association is markedly exaggerated when facing overnutrition in later life.”

February 23, 2018 Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Health Economics, Immunology, Medicine, Neurology, Ophthalmology, Pharmacology, Studies | Leave a comment

Endocrinology (part 5 – calcium and bone metabolism)

Some observations from chapter 6:

“*Osteoclasts – derived from the monocytic cells; resorb bone. *Osteoblasts – derived from the fibroblast-like cells; make bone. *Osteocytes – buried osteoblasts; sense mechanical strain in bone. […] In order to ensure that bone can undertake its mechanical and metabolic functions, it is in a constant state of turnover […] Bone is laid down rapidly during skeletal growth at puberty. Following this, there is a period of stabilization of bone mass in early adult life. After the age of ~40, there is a gradual loss of bone in both sexes. This occurs at the rate of approximately 0.5% annually. However, in ♀ after the menopause, there is a period of rapid bone loss. The accelerated loss is maximal in the first 2-5 years after the cessation of ovarian function and then gradually declines until the previous gradual rate of loss is once again established. The excess bone loss associated with the menopause is of the order of 10% of skeletal mass. This menopause-associated loss, coupled with higher peak bone mass acquisition in ♂, largely explains why osteoporosis and its associated fractures are more common in ♀.”

“The clinical utility of routine measurements of bone turnover markers is not yet established. […] Skeletal radiology[:] *Useful for: *Diagnosis of fracture. *Diagnosis of specific diseases (e.g. Paget’s disease and osteomalacia). *Identification of bone dysplasia. *Not useful for assessing bone density. […] Isotope bone scans are useful for identifying localized areas of bone disease, such as fracture, metastases, or Paget’s disease. […] Isotope bone scans are particularly useful in Paget’s disease to establish the extent and sites of skeletal involvement and the underlying disease activity. […] Bone biopsy is occasionally necessary for the diagnosis of patients with complex metabolic bone diseases. […] Bone biopsy is not indicated for the routine diagnosis of osteoporosis. It should only be undertaken in highly specialist centres with appropriate expertise. […] Measurement of 24h urinary excretion of calcium provides a measure of risk of renal stone formation or nephrocalcinosis in states of chronic hypercalcaemia. […] 250H vitamin D […] is the main storage form of vitamin D, and the measurement of ‘total vitamin D’ is the most clinically useful measure of vitamin D status. Internationally, there remains controversy around a ‘normal’ or ‘optimal’ concentration of vitamin D. Levels over 50nmol/L are generally accepted as satisfactory and values <25nmol/L representing deficiency. True osteomalacia occurs with vitamin D values <15 nmol/L. Low levels of 250HD can result from a variety of causes […] Bone mass is quoted in terms of the number of standard deviations from an expected mean. […] A reduction of one SD in bone density will approximately double the risk of fracture.”

[I should perhaps add a cautionary note here that while this variable is very useful in general, it is more useful in some contexts than in others; and in some specific disease process contexts it is quite clear that it will tend to underestimate the fracture risk. Type 1 diabetes is a clear example. For more details, see this post.]

“Hypercalcaemia is found in 5% of hospital patients and in 0.5% of the general population. […] Many different disease states can lead to hypercalcaemia. […] In asymptomatic community-dwelling subjects, the vast majority of hypercalcaemia is the result of hyperparathyroidism. […] The clinical features of hypercalcaemia are well recognized […]; unfortunately, they are non-specific […] [They include:] *Polyuria. *Polydipsia. […] *Anorexia. *Vomiting. *Constipation. *Abdominal pain. […] *Confusion. *Lethargy. *Depression. […] Clinical signs of hypercalcaemia are rare. […] the presence of bone pain or fracture and renal stones […] indicate the presence of chronic hypercalcaemia. […] Hypercalcaemia is usually a late manifestation of malignant disease, and the primary lesion is usually evident by the time hypercalcaemia is expressed (50% of patients die within 30 days).”

“Primary hyperparathyroidism [is] [p]resent in up to 1 in 500 of the general population where it is predominantly a disease of post-menopausal ♀ […] The normal physiological response to hypocalcaemia is an increase in PTH secretion. This is termed 2° hyperparathyroidism and is not pathological in as much as the PTH secretion remains under feedback control. Continued stimulation of the parathyroid glands can lead to autonomous production of PTH. This, in turn, causes hypercalcaemia which is termed tertiary hyperparathyroidism. This is usually seen in the context of renal disease […] In majority of patients [with hyperparathyroidism] without end-organ damage, disease is benign and stable. […] Investigation is, therefore, primarily aimed at determining the presence of end-organ damage from hypercalcaemia in order to determine whether operative intervention is indicated. […] It is generally accepted that all patients with symptomatic hyperparathyroidism or evidence of end-organ damage should be considered for parathyroidectomy. This would include: *Definite symptoms of hypercalcaemia. […] *Impaired renal function. *Renal stones […] *Parathyroid bone disease, especially osteitis fibrosis cystica. *Pancreatitis. […] Patients not managed with surgery require regular follow-up. […] <5% fail to become normocalcaemic [after surgery], and these should be considered for a second operation. […] Patients rendered permanently hypoparathyroid by surgery require lifelong supplements of active metabolites of vitamin D with calcium. This can lead to hypercalciuria, and the risk of stone formation may still be present in these patients. […] In hypoparathyroidism, the target serum calcium should be at the low end of the reference range. […] any attempt to raise the plasma calcium well into the normal range is likely to result in unacceptable hypercalciuria”.

“Although hypocalcaemia can result from failure of any of the mechanisms by which serum calcium concentration is maintained, it is usually the result of either failure of PTH secretion or because of the inability to release calcium from bone. […] The clinical features of hypocalcaemia are largely as a result of neuromuscular excitability. In order of  severity, these include: *Tingling – especially of fingers, toes, or lips. *Numbness – especially of fingers, toes, or lips. *Cramps. *Carpopedal spasm. *Stridor due to laryngospasm. *Seizures. […] symptoms of hypocalcaemia tend to reflect the severity and rapidity of onset of the metabolic abnormality. […] there may be clinical signs and symptoms associated with the underlying condition: *Vitamin D deficiency may be associated with generalized bone pain, fractures, or proximal myopathy […] *Hypoparathyroidism can be accompanied by mental slowing and personality disturbances […] *If hypocalcaemia is present during the development of permanent teeth, these may show areas of enamel hypoplasia. This can be a useful physical sign, indicating that the hypocalcaemia is long-standing. […] Acute symptomatic hypocalcaemia is a medical emergency and demands urgent treatment whatever the cause […] *Patients with tetany or seizures require urgent IV treatment with calcium gluconate […] Care must be taken […] as too rapid elevation of the plasma calcium can cause arrhythmias. […] *Treatment of chronic hypocalcaemia is more dependent on the cause. […] In patients with mild parathyroid dysfunction, it may be possible to achieve acceptable calcium concentrations by using calcium supplements alone. […] The majority of patients will not achieve adequate control with such treatment. In those cases, it is necessary to use vitamin D or its metabolites in pharmacological doses to maintain plasma calcium.”

“Pseudohypoparathyroidism[:] *Resistance to parathyroid hormone action. *Due to defective signalling of PTH action via cell membrane receptor. *Also affects TSH, LH, FSH, and GH signalling. […] Patients with the most common type of pseudohypoparathyroidism (type 1a) have a characteristic set of skeletal abnormalities, known as Albright’s hereditary osteodystrophy. This comprises: *Short stature. *Obesity. *Round face. *Short metacarpals. […] The principles underlying the treatment of pseudohypoparathyroidism are the same as those underlying hypoparathyroidism. *Patients with the most common form of pseudohypoparathyroidism may have resistance to the action of other hormones which rely on G protein signalling. They, therefore, need to be assessed for thyroid and gonadal dysfunction (because of defective TSH and gonadotrophin action). If these deficiencies are present, they need to be treated in the conventional manner.”

“Osteomalacia occurs when there is inadequate mineralization of mature bone. Rickets is a disorder of the growing skeleton where there is inadequate mineralization of bone as it is laid down at the epiphysis. In most instances, osteomalacia leads to build-up of excessive unmineralized osteoid within the skeleton. In rickets, there is build-up of unmineralized osteoid in the growth plate. […] These two related conditions may coexist. […] Clinical features [of osteomalacia:] *Bone pain. *Deformity. *Fracture. *Proximal myopathy. *Hypocalcaemia (in vitamin D deficiency). […] The majority of patients with osteomalacia will show no specific radiological abnormalities. *The most characteristic abnormality is the Looser’s zone or pseudofracture. If these are present, they are virtually pathognomonic of osteomalacia. […] Oncogenic osteomalacia[:] Certain tumours appear to be able to produce FGF23 which is phosphaturic. This is rare […] Clinically, such patients usually present with profound myopathy as well as bone pain and fracture. […] Complete removal of the tumour results in resolution of the biochemical and skeletal abnormalities. If this is not possible […], treatment with vitamin D metabolites and phosphate supplements […] may help the skeletal symptoms.”

Hypophosphataemia[:] Phosphate is important for normal mineralization of bone. In the absence of sufficient phosphate, osteomalacia results. […] In addition, phosphate is important in its own right for neuromuscular function, and profound hypophosphataemia can be accompanied by encephalopathy, muscle weakness, and cardiomyopathy. It must be remembered that, as phosphate is primarily an intracellular anion, a low plasma phosphate does not necessarily represent actual phosphate depletion. […] Mainstay [of treatment] is phosphate replacement […] *Long-term administration of phosphate supplements stimulates parathyroid activity. This can lead to hypercalcaemia, a further fall in phosphate, with worsening of the bone disease […] To minimize parathyroid stimulation, it is usual to give one of the active metabolites of vitamin D in conjunction with phosphate.”

“Although the term osteoporosis refers to the reduction in the amount of bony tissue within the skeleton, this is generally associated with a loss of structural integrity of the internal architecture of the bone. The combination of both these changes means that osteoporotic bone is at high risk of fracture, even after trivial injury. […] Historically, there has been a primary reliance on bone mineral density as a threshold for treatment, whereas currently there is far greater emphasis on assessing individual patients’ risk of fracture that incorporates multiple clinical risk factors as well as bone mineral density. […] Osteoporosis may arise from a failure of the body to lay down sufficient bone during growth and maturation; an earlier than usual onset of bone loss following maturity; or an rate of that loss. […] Early menopause or late puberty (in ♂ or ♀) is associated with risk of osteoporosis. […] Lifestyle factors affecting bone mass [include:] *weight-bearing exercise [increase bone mass] […] *Smoking. *Excessive alcohol. *Nulliparity. *Poor calcium nutrition. [These all decrease bone mass] […] The risk of osteoporotic fracture increases with age. Fracture rates in ♂ are approximately half of those seen in ♀ of the same age. An ♀ aged 50 has approximately a 1:2 chance [risk, surely… – US] of sustaining an osteoporotic fracture in the rest of her life. The corresponding figure for a ♂ is 1:5. […] One-fifth of hip fracture victims will die within 6 months of the injury, and only 50% will return to their previous level of independence.”

“Any fracture, other than those affecting fingers, toes, or face, which is caused by a fall from standing height or less is called a fragility (low-trauma) fracture, and underlying osteoporosis should be considered. Patients suffering such a fracture should be considered for investigation and/or treatment for osteoporosis. […] [Osteoporosis is] [u]sually clinically silent until an acute fracture. *Two-thirds of vertebral fractures do not come to clinical attention. […] Osteoporotic vertebral fractures only rarely lead to neurological impairment. Any evidence of spinal cord compression should prompt a search for malignancy or other underlying cause. […] Osteoporosis does not cause generalized skeletal pain. […] Biochemical markers of bone turnover may be helpful in the calculation of fracture risk and in judging the response to drug therapies, but they have no role in the diagnosis of osteoporosis. […] An underlying cause for osteoporosis is present in approximately 10-30% of women and up to 50% of men with osteoporosis. […] 2° causes of osteoporosis are more common in ♂ and need to be excluded in all ♂ with osteoporotic fracture. […] Glucocorticoid treatment is one of the major 2° causes of osteoporosis.”

February 22, 2018 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Pharmacology | Leave a comment

A few diabetes papers of interest

(I hadn’t expected to only cover two papers in this post, but the second paper turned out to include a lot of stuff I figured might be worth adding here. I might add another post later this week including some of the other studies I had intended to cover in this post.)

i. Burden of Mortality Attributable to Diagnosed Diabetes: A Nationwide Analysis Based on Claims Data From 65 Million People in Germany.

“Diabetes is among the 10 most common causes of death worldwide (2). Between 1990 and 2010, the number of deaths attributable to diabetes has doubled (2). People with diabetes have a reduced life expectancy of ∼5 to 6 years (3). The most common cause of death in people with diabetes is cardiovascular disease (3,4). Over the past few decades, a reduction of diabetes mortality has been observed in several countries (59). However, the excess risk of death is still higher than in the population without diabetes, particularly in younger age-groups (4,9,10). Unfortunately, in most countries worldwide, reliable data on diabetes mortality are lacking (1). In a few European countries, such as Denmark (5) and Sweden (4), mortality analyses are based on national diabetes registries that include all age-groups. However, Germany and many other European countries do not have such national registries. Until now, age-standardized hazard ratios for diabetes mortality between 1.4 and 2.6 have been published for Germany on the basis of regional studies and surveys with small respondent numbers (1114). To the best of our knowledge, no nationwide estimates of the number of excess deaths due to diabetes have been published for Germany, and no information on older age-groups >79 years is currently available.

In 2012, changes in the regulation of data transparency enabled the use of nationwide routine health care data from the German statutory health insurance system, which insures ∼90% of the German population (15). These changes have allowed for new possibilities for estimating the burden of diabetes in Germany. Hence, this study estimates the number of excess deaths due to diabetes (ICD-10 codes E10–E14) and type 2 diabetes (ICD-10 code E11) in Germany, which is the number of deaths that could have been prevented if the diabetes mortality rate was as high as that of the population without diabetes.”

“Nationwide data on mortality ratios for diabetes and no diabetes are not available for Germany. […] the age- and sex-specific mortality rate ratios between people with diabetes and without diabetes were used from a Danish study wherein the Danish National Diabetes Register was linked to the individual mortality data from the Civil Registration System that includes all people residing in Denmark (5). Because the Danish National Diabetes Register is one of the most accurate diabetes registries in Europe, with a sensitivity of 86% and positive predictive value of 90% (5), we are convinced that the Danish estimates are highly valid and reliable. Denmark and Germany have a comparable standard of living and health care system. The diabetes prevalence in these countries is similar (Denmark 7.2%, Germany 7.4% [20]) and mortality of people with and without diabetes comparable, as shown in the European mortality database”

“In total, 174,627 excess deaths (137,950 from type 2 diabetes) could have been prevented in 2010 if mortality was the same in people with and without diabetes. Overall, 21% of all deaths in Germany were attributable to diabetes, and 16% were attributable to type 2 diabetes […] Most of the excess deaths occurred in the 70- to 79- and 80- to 89-year-old age-groups (∼34% each) […]. Substantial sex differences were found in diabetes-related excess deaths. From the age of ∼40 years, the number of male excess deaths due to diabetes started to grow, but the number of female excess deaths increased with a delay. Thus, the highest number of male excess deaths due to diabetes occurred at the age of ∼75 years, whereas the peak of female excess deaths was ∼10 years later. […] The diabetes mortality rates increased with age and were always higher than in the population without diabetes. The largest differences in mortality rates between people with and without diabetes were observed in the younger age-groups. […] These results are in accordance with previous studies worldwide (3,4,7,9) and regional studies in Germany (1113).”

“According to official numbers from the Federal Statistical Office, 858,768 people died in Germany in 2010, with 23,131 deaths due to diabetes, representing 2.7% of the all-cause mortality (26). Hence, in Germany, diabetes is not ranked among the top 10 most common causes of death […]. We found that 21% of all deaths were attributable to diabetes and 16% were attributable to type 2 diabetes; hence, we suggest that the number of excess deaths attributable to diabetes is strongly underestimated if we rely on reported causes of death from death certificates, as official statistics do. Estimating diabetes-related mortality is challenging because most people die as a result of diabetes complications and comorbidities, such as cardiovascular disease and renal failure, which often are reported as the underlying cause of death (1,23). For this reason, another approach is to focus not only on the underlying cause of death but also on the multiple causes of death to assess any mention of a disease on the death certificate (27). In a study from Italy, the method of assessing multiple causes of death revealed that in 12.3% of all studied death certificates, diabetes was mentioned, whereas only 2.9% reported diabetes as the underlying cause of death (27), corresponding to a four times higher proportion of death related to diabetes. Another nationwide analysis from Canada found that diabetes was more than twice as likely to be a contributing factor to death than the underlying cause of death from the years 2004–2008 (28). A recently published study from the U.S. that was based on two representative surveys from 1997 to 2010 found that 11.5% of all deaths were attributable to diabetes, which reflects a three to four times higher proportion of diabetes-related deaths (29). Overall, these results, together with the current calculations, demonstrate that deaths due to diabetes contribute to a much higher burden than previously assumed.”

ii. Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange.

“Type 1 diabetes is a life-threatening, autoimmune disease that strikes children and adults and can be fatal. People with type 1 diabetes have to test their blood glucose multiple times each day and dose insulin via injections or an infusion pump 24 h a day every day. Too much insulin can result in hypoglycemia, seizures, coma, or death. Hyperglycemia over time leads to kidney, heart, nerve, and eye damage. Even with diligent monitoring, the majority of people with type 1 diabetes do not achieve recommended target glucose levels. In the U.S., approximately one in five children and one in three adults meet hemoglobin A1c (HbA1c) targets and the average patient spends 7 h a day hyperglycemic and over 90 min hypoglycemic (13). […] HbA1c is a well-accepted surrogate outcome measure for evaluating the efficacy of diabetes therapies and technologies in clinical practice as well as in research (46). […] While HbA1c is used as a primary outcome to assess glycemic control and as a surrogate for risk of developing complications, it has limitations. As a measure of mean blood glucose over 2 or 3 months, HbA1c does not capture short-term variations in blood glucose or exposure to hypoglycemia and hyperglycemia in individuals with type 1 diabetes; HbA1c also does not capture the impact of blood glucose variations on individuals’ quality of life. Recent advances in type 1 diabetes technologies have made it feasible to assess the efficacy of therapies and technologies using a set of outcomes beyond HbA1c and to expand definitions of outcomes such as hypoglycemia. While definitions for hypoglycemia in clinical care exist, they have not been standardized […]. The lack of standard definitions impedes and can confuse their use in clinical practice, impedes development processes for new therapies, makes comparison of studies in the literature challenging, and may lead to regulatory and reimbursement decisions that fail to meet the needs of people with diabetes. To address this vital issue, the type 1 diabetes–stakeholder community launched the Type 1 Diabetes Outcomes Program to develop consensus definitions for a set of priority outcomes for type 1 diabetes. […] The outcomes prioritized under the program include hypoglycemia, hyperglycemia, time in range, diabetic ketoacidosis (DKA), and patient-reported outcomes (PROs).”

“Hypoglycemia is a significant — and potentially fatal — complication of type 1 diabetes management and has been found to be a barrier to achieving glycemic goals (9). Repeated exposure to severe hypoglycemic events has been associated with an increased risk of cardiovascular events and all-cause mortality in people with type 1 or type 2 diabetes (10,11). Hypoglycemia can also be fatal, and severe hypoglycemic events have been associated with increased mortality (1214). In addition to the physical aspects of hypoglycemia, it can also have negative consequences on emotional status and quality of life.

While there is some variability in how and when individuals manifest symptoms of hypoglycemia, beginning at blood glucose levels <70 mg/dL (3.9 mmol/L) (which is at the low end of the typical post-absorptive plasma glucose range), the body begins to increase its secretion of counterregulatory hormones including glucagon, epinephrine, cortisol, and growth hormone. The release of these hormones can cause moderate autonomic effects, including but not limited to shaking, palpitations, sweating, and hunger (15). Individuals without diabetes do not typically experience dangerously low blood glucose levels because of counterregulatory hormonal regulation of glycemia (16). However, in individuals with type 1 diabetes, there is often a deficiency of the counterregulatory response […]. Moreover, as people with diabetes experience an increased number of episodes of hypoglycemia, the risk of hypoglycemia unawareness, impaired glucose counterregulation (for example, in hypoglycemia-associated autonomic failure [17]), and level 2 and level 3 hypoglycemia […] all increase (18). Therefore, it is important to recognize and treat all hypoglycemic events in people with type 1 diabetes, particularly in populations (children, the elderly) that may not have the ability to recognize and self-treat hypoglycemia. […] More notable clinical symptoms begin at blood glucose levels <54 mg/dL (3.0 mmol/L) (19,20). As the body’s primary utilizer of glucose, the brain is particularly sensitive to decreases in blood glucose concentrations. Both experimental and clinical evidence has shown that, at these levels, neurogenic and neuroglycopenic symptoms including impairments in reaction times, information processing, psychomotor function, and executive function begin to emerge. These neurological symptoms correlate to altered brain activity in multiple brain areas including the prefrontal cortex and medial temporal lobe (2124). At these levels, individuals may experience confusion, dizziness, blurred or double vision, tremors, and tingling sensations (25). Hypoglycemia at this glycemic level may also increase proinflammatory and prothrombotic markers (26). Left untreated, these symptoms can become severe to the point that an individual will require assistance from others to move or function. Prolonged untreated hypoglycemia that continues to drop below 50 mg/dL (2.8 mmol/L) increases the risk of seizures, coma, and death (27,28). Hypoglycemia that affects cognition and stamina may also increase the risk of accidents and falls, which is a particular concern for older adults with diabetes (29,30).

The glycemic thresholds at which these symptoms occur, as well as the severity with which they manifest themselves, may vary in individuals with type 1 diabetes depending on the number of hypoglycemic episodes they have experienced (3133). Counterregulatory physiological responses may evolve in patients with type 1 diabetes who endure repeated hypoglycemia over time (34,35).”

“The Steering Committee defined three levels of hypoglycemia […] Level 1 hypoglycemia is defined as a measurable glucose concentration <70 mg/dL (3.9 mmol/L) but ≥54 mg/dL (3.0 mmol/L) that can alert a person to take action. A blood glucose concentration of 70 mg/dL (3.9 mmol/L) has been recognized as a marker of physiological hypoglycemia in humans, as it approximates the glycemic threshold for neuroendocrine responses to falling glucose levels in individuals without diabetes. As such, blood glucose in individuals without diabetes is generally 70–100 mg/dL (3.9–5.6 mmol/L) upon waking and 70–140 mg/dL (3.9–7.8 mmol/L) after meals, and any excursions beyond those levels are typically countered with physiological controls (16,37). However, individuals with diabetes who have impaired or altered counterregulatory hormonal and neurological responses do not have the same internal regulation as individuals without diabetes to avoid dropping below 70 mg/dL (3.9 mmol/L) and becoming hypoglycemic. Recurrent episodes of hypoglycemia lead to increased hypoglycemia unawareness, which can become dangerous as individuals cease to experience symptoms of hypoglycemia, allowing their blood glucose levels to continue falling. Therefore, glucose levels <70 mg/dL (3.9 mmol/L) are clinically important, independent of the severity of acute symptoms.

Level 2 hypoglycemia is defined as a measurable glucose concentration <54 mg/dL (3.0 mmol/L) that needs immediate action. At ∼54 mg/dL (3.0 mmol/L), neurogenic and neuroglycopenic hypoglycemic symptoms begin to occur, ultimately leading to brain dysfunction at levels <50 mg/dL (2.8 mmol/L) (19,20). […] Level 3 hypoglycemia is defined as a severe event characterized by altered mental and/or physical status requiring assistance. Severe hypoglycemia captures events during which the symptoms associated with hypoglycemia impact a patient to such a degree that the patient requires assistance from others (27,28). […] Hypoglycemia that sets in relatively rapidly, such as in the case of a significant insulin overdose, may induce level 2 or level 3 hypoglycemia with little warning (38).”

“The data regarding the effects of chronic hyperglycemia on long-term outcomes is conclusive, indicating that chronic hyperglycemia is a major contributor to morbidity and mortality in type 1 diabetes (41,4345). […] Although the correlation between long-term poor glucose control and type 1 diabetes complications is well established, the impact of short-term hyperglycemia is not as well understood. However, hyperglycemia has been shown to have physiological effects and in an acute-care setting is linked to morbidity and mortality in people with and without diabetes. Short-term hyperglycemia, regardless of diabetes diagnosis, has been shown to reduce survival rates among patients admitted to the hospital with stroke or myocardial infarction (47,48). In addition to increasing mortality, short-term hyperglycemia is correlated with stroke severity and poststroke disability (49,50).

The effects of short-term hyperglycemia have also been observed in nonacute settings. Evidence indicates that hyperglycemia alters retinal cell firing through sensitization in patients with type 1 diabetes (51). This finding is consistent with similar findings showing increased oxygen consumption and blood flow in the retina during hyperglycemia. Because retinal cells absorb glucose through an insulin-independent process, they respond more strongly to increases in glucose in the blood than other cells in patients with type 1 diabetes. The effects of acute hyperglycemia on retinal response may underlie part of the development of retinopathy known to be a long-term complication of type 1 diabetes.”

“The Steering Committee defines hyperglycemia for individuals with type 1 diabetes as the following:

  • Level 1—elevated glucose: glucose >180 mg/dL (10 mmol/L) and glucose ≤250 mg/dL (13.9 mmol/L)

  • Level 2—very elevated glucose: glucose >250 mg/dL (13.9 mmol/L) […]

Elevated glucose is defined as a glucose concentration >180 mg/dL (10.0 mmol/L) but ≤250 mg/dL (13.9 mmol/L). In clinical practice, measures of hyperglycemia differ based on time of day (e.g., pre- vs. postmeal). This program, however, focused on defining outcomes for use in product development that are universally applicable. Glucose profiles and postprandial blood glucose data for individuals without diabetes suggest that 140 mg/dL (7.8 mmol/L) is the appropriate threshold for defining hyperglycemia. However, data demonstrate that the majority of individuals without diabetes exceed this threshold every day. Moreover, people with diabetes spend >60% of their day above this threshold, which suggests that 140 mg/dL (7.8 mmol/L) is too low of a threshold for measuring hyperglycemia in individuals with diabetes. Current clinical guidelines for people with diabetes indicate that peak prandial glucose should not exceed 180 mg/dL (10.0 mmol/L). As such, the Steering Committee identified 180 mg/dL (10.0 mmol/L) as the initial threshold defining elevated glucose. […]

Very elevated glucose is defined as a glucose concentration >250 mg/dL (13.9 mmol/L). Evidence examining the impact of hyperglycemia does not examine the incremental effects of increasing blood glucose. However, blood glucose values exceeding 250 mg/dL (13.9 mmol/L) increase the risk for DKA (58), and HbA1c readings at that level have been associated with a high likelihood of complications.”

“An individual whose blood glucose levels rarely extend beyond the thresholds defined for hypo- and hyperglycemia is less likely to be subject to the short-term or long-term effects experienced by those with frequent excursions beyond one or both thresholds. It is also evident that if the intent of a given intervention is to safely manage blood glucose but the intervention does not reliably maintain blood glucose within safe levels, then the intervention should not be considered effective.

The time in range outcome is distinguished from traditional HbA1c testing in several ways (4,59). Time in range captures fluctuations in glucose levels continuously, whereas HbA1c testing is done at static points in time, usually months apart (60). Furthermore, time in range is more specific and sensitive than traditional HbA1c testing; for example, a treatment that addresses acute instances of hypo- or hyperglycemia may be detected in a time in range assessment but not necessarily in an HbA1c assessment. As a percentage, time in range is also more likely to be comparable across patients than HbA1c values, which are more likely to have patient-specific variations in significance (61). Finally, time in range may be more likely than HbA1c levels to correlate with PROs, such as quality of life, because the outcome is more representative of the whole patient experience (62). Table 3 illustrates how the concept of time in range differs from current HbA1c testing. […] [V]ariation in what is considered “normal” glucose fluctuations across populations, as well as what is realistically achievable for people with type 1 diabetes, must be taken into account so as not to make the target range definition too restrictive.”

“The Steering Committee defines time in range for individuals with type 1 diabetes as the following:

  • Percentage of readings in the range of 70–180 mg/dL (3.9–10.0 mmol/L) per unit of time

The Steering Committee considered it important to keep the time in range definition wide in order to accommodate variations across the population with type 1 diabetes — including different age-groups — but limited enough to preclude the possibility of negative outcomes. The upper and lower bounds of the time in range definition are consistent with the definitions for hypo- and hyperglycemia defined above. For individuals without type 1 diabetes, 70–140 mg/dL (3.9–7.8 mmol/L) represents a normal glycemic range (66). However, spending most of the day in this range is not generally achievable for people with type 1 diabetes […] To date, there is limited research correlating time in range with positive short-term and long-term type 1 diabetes outcomes, as opposed to the extensive research demonstrating the negative consequences of excursions into hyper- or hypoglycemia. More substantial evidence demonstrating a correlation or a direct causative relationship between time in range for patients with type 1 diabetes and positive health outcomes is needed.”

“DKA is often associated with hyperglycemia. In most cases, in an individual with diabetes, the cause of hyperglycemia is also the cause of DKA, although the two conditions are distinct. DKA develops when a lack of glucose in cells prompts the body to begin breaking down fatty acid reserves. This increases the levels of ketones in the body (ketosis) and causes a drop in blood pH (acidosis). At its most severe, DKA can cause cerebral edema, acute respiratory distress, thromboembolism, coma, and death (69,70). […] Although the current definition for DKA includes a list of multiple criteria that must be met, not all information currently included in the accepted definition is consistently gathered or required to diagnose DKA. The Steering Committee defines DKA in individuals with type 1 diabetes in a clinical setting as the following:

  • Elevated serum or urine ketones (greater than the upper limit of the normal range), and

  • Serum bicarbonate <15 mmol/L or blood pH <7.3

Given the seriousness of DKA, it is unnecessary to stratify DKA into different levels or categories, as the presence of DKA—regardless of the differences observed in the separate biochemical tests—should always be considered serious. In individuals with known diabetes, plasma glucose values are not necessary to diagnose DKA. Further, new therapeutic agents, specifically sodium–glucose cotransporter 2 inhibitors, have been linked to euglycemic DKA, or DKA with blood glucose values <250 mg/dL (13.9 mmol/L).”

“In guidance released in 2009 (72), the U.S. Food and Drug Administration (FDA) defined PROs as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.” In the same document, the FDA clearly acknowledged the importance of PROs, advising that they be used to gather information that is “best known by the patient or best measured from the patient perspective.”

Measuring and using PROs is increasingly seen as essential to evaluating care from a patient-centered perspective […] Given that type 1 diabetes is a chronic condition primarily treated on an outpatient basis, much of what people with type 1 diabetes experience is not captured through standard clinical measurement. Measures that capture PROs can fill these important information gaps. […] The use of validated PROs in type 1 diabetes clinical research is not currently widespread, and challenges to effectively measuring some PROs, such as quality of life, continue to confront researchers and developers.”

February 20, 2018 Posted by | Cardiology, Diabetes, Medicine, Neurology, Ophthalmology, Studies | Leave a comment

Prevention of Late-Life Depression (II)

Some more observations from the book:

In contrast to depression in childhood and youth when genetic and developmental vulnerabilities play a significant role in the development of depression, the development of late-life depression is largely attributed to its interactions with acquired factors, especially medical illness [17, 18]. An analysis of the WHO World Health Survey indicated that the prevalence of depression among medical patients ranged from 9.3 to 23.0 %, significantly higher than that in individuals without medical conditions [19]. Wells et al. [20] found in the Epidemiologic Catchment Area Study that the risk of developing lifetime psychiatric disorders among individuals with at least one medical condition was 27.9 % higher than among those without medical conditions. […] Depression and disability mutually reinforce the risk of each other, and adversely affect disease progression and prognosis [21, 25]. […] disability caused by medical conditions serves as a risk factor for depression [26]. When people lose their normal sensory, motor, cognitive, social, or executive functions, especially in a short period of time, they can become very frustrated or depressed. Inability to perform daily tasks as before decreases self-esteem, reduces independence, increases the level of psychological stress, and creates a sense of hopelessness. On the other hand, depression increases the risk for disability. Negative interpretation, attention bias, and learned hopelessness of depressed persons may increase risky health behaviors that exacerbate physical disorders or disability. Meanwhile, depression-related cognitive impairment also affects role performance and leads to functional disability [25]. For example, Egede [27] found in the 1999 National Health Interview Survey that the risk of having functional disability among patients with the comorbidity of diabetes and depression were approximately 2.5–5 times higher than those with either depression or diabetes alone. […]  A leading cause of disability among medical patients is pain and pain-related fears […] Although a large proportion of pain complaints can be attributed to physiological changes from physical disorders, psychological factors (e.g., attention, interpretation, and coping skills) play an important role in perception of pain […] Bair et al. [31] indicated in a literature review that the prevalence of pain was higher among depressed patients than non-depressed patients, and the prevalence of major depression was also higher among pain patients comparing to those without pain complaints.”

Alcohol use has more serious adverse health effects on older adults than other age groups, since aging-related physiological changes (e.g. reduced liver detoxification and renal clearance) affect alcohol metabolism, increase the blood concentration of alcohol, and magnify negative consequences. More importantly, alcohol interacts with a variety of frequently prescribed medications potentially influencing both treatment and adverse effects. […] Due to age-related changes in pharmacokinetics and pharmacodynamics, older adults are a vulnerable population to […] adverse drug effects. […] Adverse drug events are frequently due to failure to adjust dosage or to account for drug–drug interactions in older adults [64]. […] Loneliness […] is considered as an independent risk factor for depression [46, 47], and has been demonstrated to be associated with low physical activity, increased cardiovascular risks, hyperactivity of the hypothalamic-pituitary-adrenal axis, and activation of immune response [for details, see Cacioppo & Patrick’s book on these topics – US] […] Hopelessness is a key concept of major depression [54], and also an independent risk factor of suicidal ideation […] Hopelessness reduces expectations for the future, and negatively affects judgment for making medical and behavioral decisions, including non-adherence to medical regimens or engaging in unhealthy behaviors.”

Co-occurring depression and medical conditions are associated with more functional impairment and mortality than expected from the severity of the medical condition alone. For example, depression accompanying diabetes confers increased functional impairment [27], complications of diabetes [65, 66], and mortality [6771]. Frasure-Smith and colleagues highlighted the prognostic importance of depression among persons who had sustained a myocardial infarction (MI), finding that depression was a significant predictor of mortality at both 6 and 18 months post MI [72, 73]. Subsequent follow-up studies have borne out the increased risk conferred by depression on the mortality of patients with cardiovascular disease [10, 74, 75]. Over the course of a 2-year follow-up interval, depression contributed as much to mortality as did myocardial infarction or diabetes, with the population attributable fraction of mortality due to depression approximately 13 % (similar to the attributable risk associated with heart attack at 11 % and diabetes at 9 %) [76]. […] Although the bidirectional relationship between physical disorders and depression has been well known, there are still relatively few randomized controlled trials on preventing depression among medically ill patients. […] Rates of attrition [in post-stroke depression prevention trials has been observed to be] high […] Stroke, acute coronary syndrome, cancer, and other conditions impose a variety of treatment burdens on patients so that additional interventions without direct or immediate clinical effects may not be acceptable [95]. So even with good participation rates, lack of adherence to the intervention might limit effects.”

Late-life depression (LLD) is a heterogeneous disease, with multiple risk factors, etiologies, and clinical features. It has been recognized for many years that there is a significant relationship between the presence of depression and cerebrovascular disease in older adults [1, 2]. This subtype of LLD was eventually termed “vascular depression.” […] There have been a multitude of studies associating white matter abnormalities with depression in older adults using MRI technology to visualize lesions, or what appear as hyperintensities in the white matter on T2-weighted scans. A systematic review concluded that white matter hyperintensities (WMH) are more common and severe among older adults with depression compared to their non-depressed peers [9]. […] WMHs are associated with older age [13] and cerebrovascular risk factors, including diabetes, heart disease, and hypertension [14–17]. White matter severity and extent of WMH volume has been related to the severity of depression in late life [18, 19]. For example, among 639 older, community-dwelling adults, white matter lesion (WML) severity was found to predict depressive episodes and symptoms over a 3-year period [19]. […] Another way of investigating white matter integrity is with diffusion tensor imaging (DTI), which measures the diffusion of water in tissues and allows for indirect evidence of the microstructure of white matter, most commonly represented as fractional anisotropy (FA) and mean diffusivity (MD). DTI may be more sensitive to white matter pathology than is quantification of WMH […] A number of studies have found lower FA in widespread regions among individuals with LLD relative to controls [34, 36, 37]. […] lower FA has been associated with poorer performance on measures of cognitive functioning among patients with LLD [35, 38–40] and with measures of cerebrovascular risk severity. […] It is important to recognize that FA reflects the organization of fiber tracts, including fiber density, axonal diameter, or myelination in white matter. Thus, lower FA can result from multiple pathophysiological sources [42, 43]. […] Together, the aforementioned studies provide support for the vascular depression hypothesis. They demonstrate that white matter integrity is reduced in patients with LLD relative to controls, is somewhat specific to regions important for cognitive and emotional functioning, and is associated with cognitive functioning and depression severity. […] There is now a wealth of evidence to support the association between vascular pathology and depression in older age. While the etiology of depression in older age is multifactorial, from the epidemiological, neuroimaging, behavioral, and genetic evidence available, we can conclude that vascular depression represents one important subtype of LLD. The mechanisms underlying the relationship between vascular pathology and depression are likely multifactorial, and may include disrupted connections between key neural regions, reduced perfusion of blood to key brain regions integral to affective and cognitive processing, and inflammatory processes.”

Cognitive changes associated with depression have been the focus of research for decades. Results have been inconsistent, likely as a result of methodological differences in how depression is diagnosed and cognitive functioning measured, as well as the effects of potential subtypes and the severity of depression […], though deficits in executive functioning, learning and memory, and attention have been associated with depression in most studies [75]. In older adults, additional confounding factors include the potential presence of primary degenerative disorders, such as Alzheimer’s disease, which can pose a challenge to differential diagnosis in its early stages. […] LLD with cognitive dysfunction has been shown to result in greater disability than depressive symptoms alone [6], and MCI [mild cognitive impairment, US] with co-occurring LLD has been shown to double the risk of developing Alzheimer’s disease (AD) compared to MCI alone [86]. The conversion from MCI to AD also appears to occur earlier in patients with cooccurring depressive symptoms, as demonstrated by Modrego & Ferrandez [86] in their prospective cohort study of 114 outpatients diagnosed with amnestic MCI. […] Given accruing evidence for abnormal functioning of a number of cortical and subcortical networks in geriatric depression, of particular interest is whether these abnormalities are a reflection of the actively depressed state, or whether they may persist following successful resolution of symptoms. To date, studies have investigated this question through either longitudinal investigation of adults with geriatric depression, or comparison of depressed elders who are actively depressed versus those who have achieved symptom remission. Of encouragement, successful treatment has been reliably associated with normalization of some aspects of disrupted network functioning. For example, successful antidepressant treatment is associated with reduction of the elevated cerebral glucose metabolism observed during depressed states (e.g., [71–74]), with greater symptom reduction associated with greater metabolic change […] Taken together, these studies suggest that although a subset of the functional abnormalities observed during the LLD state may resolve with successful treatment, other abnormalities persist and may be tied to damage to the structural connectivity in important affective and cognitive networks. […] studies suggest a chronic decrement in cognitive functioning associated with LLD that is not adequately addressed through improvement of depressive symptoms alone.”

A review of the literature on evidence-based treatments for LLD found that about 50 % of patients improved on antidepressants, but that the number needed to treat (NNT) was quite high (NNT = 8, [139]) and placebo effects were significant [140]. Additionally, no difference was demonstrated in the effectiveness of one antidepressant drug class over another […], and in one-third of patients, depression was resistant to monotherapy [140]. The addition of medications or switching within or between drug classes appears to result in improved treatment response for these patients [140, 141]. A meta-analysis of patient-level variables demonstrated that duration of depressive symptoms and baseline depression severity significantly predicts response to antidepressant treatment in LLD, with chronically depressed older patients with moderate-to-severe symptoms at baseline experiencing more improvement in symptoms than mildly and acutely depressed patients [142]. Pharmacological treatment response appears to range from incomplete to poor in LLD with co-occurring cognitive impairment.”

“[C]ompared to other formulations of prevention, such as primary, secondary, or tertiary — in which interventions are targeted at the level of disease/stage of disease — the IOM conceptual framework involves interventions that are targeted at the level of risk in the population [2]. […] [S]elective prevention studies have an important “numbers” advantage — similar to that of indicated prevention trials: the relatively high incidence of depression among persons with key risk markers enables investigator to test interventions with strong statistical power, even with somewhat modest sample sizes. This fact was illustrated by Schoevers and colleagues [3], in which the authors were able to account for nearly 50 % of total risk of late-life depression with consideration of only a handful of factors. Indeed, research, largely generated by groups in the Netherlands and the USA, has identified that selective prevention may be one of the most efficient approaches to late-life depression prevention, as they have estimated that targeting persons at high risk for depression — based on risk markers such as medical comorbidity, low social support, or physical/functional disability — can yield theoretical numbers needed to treat (NNTs) of approximately 5–7 in primary care settings [4–7]. […] compared to the findings from selective prevention trials targeting older persons with general health/medical problems, […] trials targeting older persons based on sociodemographic risk factors have been more mixed and did not reveal as consistent a pattern of benefits for selective prevention of depression.”

Few of the studies in the existing literature that involve interventions to prevent depression and/or reduce depressive symptoms in older populations have included economic evaluations [13]. The identification of cost-effective interventions to provide to groups at high risk for depression is an important public health goal, as such treatments may avert or reduce a significant amount of the disease burden. […] A study by Katon and colleagues [8] showed that elderly patients with either subsyndromal or major depression had significantly higher medical costs during the previous 6 months than those without depression; total healthcare costs were $1,045 to $1,700 greater, and total outpatient/ambulatory costs ranged from being $763 to $979 more, on average. Depressed patients had greater usage of health resources in every category of care examined, including those that are not mental health-related, such as emergency department visits. No difference in excess costs was found between patients with a DSM-IV depressive disorder and those with depressive symptoms only, however, as mean total costs were 51 % higher in the subthreshold depression group (95 % CI = 1.39–1.66) and 49 % higher in the MDD/dysthymia group (95 % CI = 1.28–1.72) than in the nondepressed group [8]. In a similar study, the usage of various types of health services by primary care patients in the Netherlands was assessed, and average costs were determined to be 1,403 more in depressed individuals versus control patients [21]. Study investigators once again observed that patients with depression had greater utilization of both non-mental and mental healthcare services than controls.”

“In order for routine depression screening in the elderly to be cost-effective […] appropriate follow-up measures must be taken with those who screen positive, including a diagnostic interview and/or referral to a mental health professional [this – the necessity/requirement of proper follow-up following screens in order for screening to be cost-effective – is incidentally a standard result in screening contexts, see also Juth & Munthe’s book – US] [23, 25]. For example, subsequent steps may include initiation of psychotherapy or antidepressant treatment. Thus, one reason that the USPSTF does not recommend screening for depression in settings where proper mental health resources do not exist is that the evidence suggests that outcomes are unlikely to improve without effective follow-up care […]  as per the USPSTF suggestion, Medicare will only cover the screening when the appropriate supports for proper diagnosis and treatment are available […] In order to determine which interventions to prevent and treat depression should be provided to those who screen positive for depressive symptoms and to high-risk populations in general, cost-effectiveness analyses must be completed for a variety of different treatments and preventive measures. […] questions remain regarding whether annual versus other intervals of screening are most cost-effective. With respect to preventive interventions, the evidence to date suggests that these are cost-effective in settings where those at the highest risk are targeted.”

February 19, 2018 Posted by | Books, Cardiology, Diabetes, Health Economics, Neurology, Pharmacology, Psychiatry, Psychology | Leave a comment

Peripheral Neuropathy (II)

Chapter 3 included a great new (…new to me, that is…) chemical formula which I can’t not share here: (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanonemesylate. It’s a cannabinoid receptor agonist, the properties of which are briefly discussed in the book‘s chapter 3.

Anyway, some more observations from the book below:

Injuries affecting either the peripheral or the central nervous system (PNS, CNS) leads to neuropathic pain characterized by spontaneous pain and distortion or exaggeration of pain sensation. Peripheral nerve pathologies are considered generally easier to treat compared to those affecting the CNS, however peripheral neuropathies still remain a challenge to therapeutic treatment. […] Although first being thought as a disease of purely neuronal nature, several pre-clinical studies indicate that the mechanisms at the basis of the development and maintenance of neuropathic pain involve substantial contributions from the nonneuronal cells of both the PNS and CNS [22]. After peripheral nerve injury, microglia in the normal conditions (usually defined ‘‘resting’’ microglia) in the spinal dorsal horn proliferate and change their phenotype to an “activated” state through a series of cellular and molecular changes. Microglia shift their phenotype to the hypertrophic “activated” form following altered expression of several molecules including cell surface receptors, intracellular signalling molecules and diffusible factors. The activation process consists of distinct cellular functions aimed at repairing damaged neural cells and eliminating debris from the damaged area [23]. Damaged cells release chemo-attractant molecules that both increase the motility (i.e. chemo‐kinesis) and stimulate the migration (i.e. chemotaxis) of microglia, the combination of which recruits the microglia much closer to the damaged cells […] Once microglia become activated, they can exert both proinflammatory or anti-inflammatory/neuroprotective functions depending on the combination of the stimulation of several receptors and the expression of specific genes [31]. Thus, the activation of microglia following a peripheral injury can be considered as an adaptation to tissue stress and malfunction [32] that contribute to the development and subsequent maintenance of chronic pain [33, 34]. […] The signals responsible for neuron-microglia and/or astrocyte communication are being extensively investigated since they may represent new targets for chronic pain management.”

“In the past two decades a notable increase in the incidence of [upper extremity compression neuropathies] has occurred. […] it is mandatory to achieve a prompt diagnosis because they can produce important motor and sensory deficiencies that need to be treated before the development of complications, since, despite the capacity for regeneration bestowed on the peripheral nervous system, functions lost as a result of denervation are never fully restored. […] There are many different situations that may be a direct cause of nerve compression. Anatomically, nerves can be compressed when traversing fibro-osseous tunnels, passing between muscle layers, through traction as they cross joints or buckling during certain movements of the wrist and elbow. Other causes include trauma, direct pressure and space-occupying lesions at any level in the upper extremity. There are other situations that are not a direct cause of nerve compression, but may increase the risk and may predispose the nerve to be compressed specially when the soft tissues are swollen like synovitis, pregnancy, hypothyroidism, diabetes or alcoholism [1]. […] When nerve fibers undergo compression, the response depends on the force applied at the site and the duration. Acute, brief compression results in a focal conduction block as a result of local ischemia, being reversible if the duration of compression is transient. On the other hand, if the focal compression is prolonged, ischemic changes appear, followed by endoneurial edema and secondary perineurial thickening. These histological alterations will aggravate the changes in the microneural circulation and will increase the sensitivity of the neuron sheath to ischemia. If the compression continues, we will find focal demyelination, which typically results in a greater involvement of motor than sensory nerve fibers. […] As the duration of compression increases beyond several hours, more diffuse demyelination will appear […] This process begins at the distal end of compression or injury, a process termed wallerian degeneration. These neural changes may not appear at a uniform fashion among the whole neural sheath depending on the distribution of the compressive forces, causing mixed demyelinating and axonal injury resulting from a combination of mechanical distortion of the nerve, ischemic injury, and impaired axonal flow [2].”

Electrophysiologic testing is part of the evaluation [of compression neuropathies], but it never substitutes a complete history and a thorough physical examination. These tests can detect physiologic abnormalities in the course of motor and sensory axons. There are two main electrophysiologic tests: needle electromyography and nerve conduction […] The electromyography detects the voluntary or spontaneous generated electrical activity. The registry of this activity is made through the needle insertion, at rest and during muscular activity to assess duration, amplitude, configuration and recruitment after injury. […] Nerve conduction assesses for both sensory and motor nerves. This study consists in applying a voltage simulator to the skin over different points of the nerve in order to record the muscular action potential, analyzing the amplitude, duration, area, latency and conduction velocity. The amplitude indicates the number of available nerve fibers.”

There are three well-described entrapment syndromes involving the median nerve or its branches, namely pronator teres syndrome, anterior interosseous syndrome and carpal tunnel syndrome according to the level of entrapment. Each one of these syndromes presents with different clinical signs and symptoms, electrophysiologic results and requires different techniques for their release. […] [In pronator teres syndrome] [t]he onset is insidious and is suggested when the early sensory disturbances are greater on the thumb and index finger, mainly tingling, numbness and dysaesthesia in the median nerve distribution. Patients will also complain of increased pain in the proximal forearm and greater hand numbness with sustained power gripping or rotation […] Surgical decompression is the definitive treatment. […] [Anterior interosseous syndrome] presents principally as weakness of the index finger and thumb, and the patient may complain of diffuse pain in the proximal forearm, which may be exacerbated during exercise and diminished with rest. The vast majority of patients begin with pain in the upper arm, elbow and forearm, often preceding the motor symptoms. […] During physical exam, the patient will be unable to bend the tip of the thumb and tip of index finger. The typical symptom is the inability to form an “O” with the thumb and index finger. […] If the onset was spontaneous and there is no evident lesion on MRI, supportive care and corticosteroid injections with observation for 4 to 6 weeks is usually accepted management. The degree of recovery is unpredictable.”

“[Carpal tunnel syndrome] is the most frequently encountered compression neuropathy in the upper limb. It is a mechanical compression of the median nerve through the fixed space of the rigid carpal tunnel. The incidence in the United States has been estimated at 1 to 3 cases per 1,000 subjects per year, with a prevalence of 50 cases per 1,000 subjects per year. [10] It is more common in women than in men (2:1), perhaps because the carpal tunnel itself may be smaller in women than in men. The dominant hand is usually affected first and produces the most severe pain. It usually occurs in adults […] Abnormalities on electrophysiologic testing, in association with specific symptoms and signs, are considered the criterion standard for carpal tunnel syndrome diagnosis. Electrophysiologic testing also can provide an accurate assessment of how severe the damage to the nerve is, thereby directing management and providing objective criteria for the determination of prognosis. Carpal tunnel syndrome is usually divided into mild, moderate and severe. In general, patients with mild carpal tunnel syndrome have sensory abnormalities alone on electrophysiologic testing, and patients with sensory plus motor abnormalities have moderate carpal tunnel syndrome. However, any evidence of axonal loss is classified as severe carpal tunnel syndrome. […] No imaging studies are considered routine in the diagnosis of carpal tunnel syndrome. […] nonoperative treatment is based in splintage of the wrist in a neutral position for three weeks and steroid injections. This therapy has variable results, with a success rate up to 76% during one year, but with a recurrence rate as high as 94%. Non-operative treatment is indicated in patients with intermittent symptoms, initial stages and during pregnancy [17]. The only definitive treatment for carpal tunnel syndrome is surgical expansion of the carpal tunnel by transection of the transverse carpal ligament.”

Postural control can be defined as the control of the body’s position in space for the purposes of balance and orientation. Balance is the ability to maintain or return the body’s centre of gravity within the limits of stability that are determined by the base of support. Spatial orientation defines our natural ability to maintain our body orientation in relation to the surrounding environment, in static and dynamic conditions. The representation of the body’s static and dynamic geometry may be largely based on muscle proprioceptive inputs that continuously inform the central nervous system about the position of each part of the body in relation to the others. Posture is built up by the sum of several basic mechanisms. […] Postural balance is dependent upon integration of signals from the somatosensory, visual and vestibular systems, to generate motor responses, with cognitive demands that vary according to the task, the age of the individuals and their ability to balance. Descending postural commands are multivariate in nature, and the motion at each joint is affected uniquely by input from multiple sensors.
The proprioceptive system provides information on joint angles, changes in joint angles, joint position and muscle length and tension; while the tactile system is associated mainly with sensations of touch, pressure and vibration. Visual influence on postural control results from a complex synergy that receives multimodal inputs. Vestibular inputs tonically activate the anti-gravity leg muscles and, during dynamic tasks, vestibular information contributes to head stabilization to enable successful gaze control, providing a stable reference frame from which to generate postural responses. In order to assess instability or walking difficulty, it is essential to identify the affected movements and circumstances in which they occur (i.e. uneven surfaces, environmental light, activity) as well as any other associated clinical manifestation that could be related
to balance, postural control, motor control, muscular force, movement limitations or sensory deficiency. The clinical evaluation should include neurological examination; special care should be taken to identify visual and vestibular disorders, and to assess static and dynamic postural control and gait.”

Polyneuropathy modify the amount and the quality of the sensorial information that is necessary for motor control, with increased instability during both, upright stance and gait. Patients with peripheral neuropathy may have decreased stability while standing and when subjected to dynamic balance conditions. […] Balance and gait difficulties are the most frequently cited cause of falling […] Patients with polyneuropathy who have ankle weakness are more likely to experience multiple and injurious falls than are those without specific muscle weakness. […] During upright stance, compared to healthy subjects, recordings of the centre of pressure in patients with diabetic neuropathy have shown larger sway [95-96, 102], as well as increased oscillation […] Compared to healthy subjects, diabetic patients may have poorer balance during standing in diminished light compared to full light and no light conditions [105] […] compared to patients with diabetes but no peripheral neuropathy, patients with diabetic peripheral neuropathy are more likely to report an injury during walking or standing, which may be more frequent when walking on irregular surfaces [110]. Epidemiological surveys have established that a reduction of leg proprioception is a risk factor for falls in the elderly [111-112]. Symptoms and signs of peripheral neuropathy are frequently found during physical examination of older subjects. These clinical manifestations may be related to diabetes mellitus, alcoholism, nutritional deficiencies, autoimmune diseases, among other causes. In this group of patients, loss of plantar sensation may be an important contributor to the dynamic balance deficits and increased risk of falls [34, 109]. […] Apart from sensorymotor compromise, fear of falling may relate to restriction and avoidance of activities, which results in loss of strength especially in the lower extremities, and may also be predictive for future falls [117-119].”

“In patients with various forms of peripheral neuropathy, the use of a cane, ankle orthoses or touching a wall [has been shown to improve] spatial and temporal measures of gait regularity while walking under challenging conditions. Additional hand contact of external objects may reduce postural instability caused by a deficiency of one or more senses. […] Contact of the index finger with a stationary surface can greatly attenuate postural instability during upright stance, even when the level of force applied is far below that necessary to provide mechanical support [42]. […] haptic information about postural sway derived from contact with other parts of the body can also increase stability […] Studies evaluating preventive and treatment strategies through excercise [sic – US] that could improve balance in patients with polyneuropathy are scarce. However, evidence support that physical activity interventions that increase activity probably do not increase the risk of falling in patients with diabetic peripheral neuropathy, and in this group of patients, specific training may improve gait speed, balance, muscle strength and joint mobility.”

“Postherpetic neuralgia (PHN) is a form of refractory chronic neuralgia that […] currently lacks any effective prophylaxis. […] PHN has a variety of symptoms and significantly affects patient quality of life [3-12]. Various studies have statistically analyzed predictive factors for PHN [13-23], but neither obvious pathogenesis nor established treatment has been clarified or established. We designed and conducted a study on the premise that statistical identification of significant predictors for PHN would contribute to the establishment of an evidence-based medicine approach to the optimal treatment of PHN. […] Previous studies have shown that older age, female sex, presence of a prodrome, greater rash severity, and greater acute pain severity are predictors of increased PHN [14-18, 25]. Some other potential predictors (ophthalmic localization, presence of anxiety and depression, presence of allodynia, and serological/virological factors) have also been studied [14, 18]. […] The participants were 73 patients with herpes zoster who had been treated at the pain clinic of our hospital between January 2008 and June 2010. […] Multivariate ordered logistic regression analysis was performed to identify predictive factors for PHN. […] advanced age and deep pain at first visit were identified as predictive factors for PHN. DM [diabetes mellitus – US] and pain reduced by bathing should also be considered as potential predictors of PHN [24].”

February 14, 2018 Posted by | Books, Diabetes, Infectious disease, Medicine, Neurology | Leave a comment

Peripheral Neuropathy (I)

The objective of this book is to update health care professionals on recent advances in the pathogenesis, diagnosis and treatment of peripheral neuropathy. This work was written by a group of clinicians and scientists with large expertise in the field.

The book is not the first book about this topic I’ve read, so a lot of the stuff included was of course review – however it’s a quite decent text, and I decided to blog it in at least some detail anyway. It’s somewhat technical and it’s probably not a very good introduction to this topic if you know next to nothing about neurology – in that case I’m certain Said’s book (see the ‘not’-link above) is a better option.

I have added some observations from the first couple of chapters below. As InTech publications like these explicitly encourage people to share the ideas and observations included in these books, I shall probably cover the book in more detail than I otherwise would have.

“Within the developing world, infectious diseases [2-4] and trauma [5] are the most common sources of neuropathic pain syndromes. The developed world, in contrast, suffers more frequently from diabetic polyneuropathy (DPN) [6, 7], post herpetic neuralgia (PHN) from herpes zoster infections [8], and chemotherapy-induced peripheral neuropathy (CIPN) [9, 10]. There is relatively little epidemiological data regarding the prevalence of neuropathic pain within the general population, but a few estimates suggest it is around 7-8% [11, 12]. Despite the widespread occurrence of neuropathic pain, treatment options are limited and often ineffective […] Neuropathic pain can present as on-going or spontaneous discomfort that occurs in the absence of any observable stimulus or a painful hypersensitivity to temperature and touch. […] people with chronic pain have increased incidence of anxiety and depression and reduced scores in quantitative measures of health related quality of life [15]. Despite significant progress in chronic and neuropathic pain research, which has led to the discovery of several efficacious treatments in rodent models, pain management in humans remains ineffective and insufficient [16]. The lack of translational efficiency may be due to inadequate animal models that do not faithfully recapitulate human disease or from biological differences between rodents and humans […] In an attempt to increase the efficacy of medical treatment for neuropathic pain, clinicians and researchers have been moving away from an etiology based classification towards one that is mechanism based. It is current practice to diagnose a person who presents with neuropathic pain according to the underlying etiology and lesion topography [17]. However, this does not translate to effective patient care as these classification criteria do not suggest efficacious treatment. A more apt diagnosis might include a description of symptoms and the underlying pathophysiology associated with those symptoms.”

Neuropathic pain has been defined […] as “pain arising as the direct consequence of a lesion or disease affecting the somatosensory system” [18]. This is distinct from nociceptive pain – which signals tissue damage through an intact nervous system – in underlying pathophysiology, severity, and associated psychological comorbidities [13]. Individuals who suffer from neuropathic pain syndromes report pain of higher intensity and duration than individuals with non-neuropathic chronic pain and have significantly increased incidence of depression, anxiety, and sleep disorders [13, 19]. […] individuals with seemingly identical diseases who both develop neuropathic pain may experience distinct abnormal sensory phenotypes. This may include a loss of sensory perception in some modalities and increased activity in others. Often a reduction in the perception of vibration and light touch is coupled with positive sensory symptoms such as paresthesia, dysesthesia, and pain[20]. Pain may manifest as either spontaneous, with a burning or shock-like quality, or as a hypersensitivity to mechanical or thermal stimuli [21]. This hypersensitivity takes two forms: allodynia, pain that is evoked from a normally non-painful stimulus, and hyperalgesia, an exaggerated pain response from a moderately painful stimulus. […] Noxious stimuli are perceived by small diameter peripheral neurons whose free nerve endings are distributed throughout the body. These neurons are distinct from, although anatomically proximal to, the low threshold mechanoreceptors responsible for the perception of vibration and light touch.”

In addition to hypersensitivity, individuals with neuropathic pain frequently experience ongoing spontaneous pain as a major source of discomfort and distress. […] In healthy individuals, a quiescent neuron will only generate an action potential when presented with a stimulus of sufficient magnitude to cause membrane depolarization. Following nerve injury, however, significant changes in ion channel expression, distribution, and kinetics lead to disruption of the homeostatic electric potential of the membrane resulting in oscillations and burst firing. This manifests as spontaneous pain that has a shooting or burning quality […] There is reasonable evidence to suggest that individual ion channels contribute to specific neuropathic pain symptoms […] [this observation] provides an intriguing therapeutic possibility: unambiguous pharmacologic ion channel blockers to relieve individual sensory symptoms with minimal unintended effects allowing pain relief without global numbness. […] Central sensitization leads to painful hypersensitivity […] Functional and structural changes of dorsal horn circuitry lead to pain hypersensitivity that is maintained independent of peripheral sensitization [38]. This central sensitization provides a mechanistic explanation for the sensory abnormalities that occur in both acute and chronic pain states, such as the expansion of hypersensitivity beyond the innervation territory of a lesion site, repeated stimulation of a constant magnitude leading to an increasing pain response, and pain outlasting a peripheral stimulus [39-41]. In healthy individuals, acute pain triggers central sensitization, but homeostatic sensitivity returns following clearance of the initial insult. In some individuals who develop neuropathic pain, genotype and environmental factors contribute to maintenance of central sensitization leading to spontaneous pain, hyperalgesia, and allodynia. […] Similarly, facilitation also results in a lowered activation threshold in second order neurons”.

“Chronic pain conditions are associated with vast functional and structural changes of the brain, when compared to healthy controls, but it is currently unclear which comes first: does chronic pain cause distortions of brain circuitry and anatomy or do cerebral abnormalities trigger and/or maintain the perception of chronic pain? […] Brain abnormalities in chronic pain states include modification of brain activity patterns, localized decreases in gray matter volume, and circuitry rerouting [53]. […] Chronic pain conditions are associated with localized reduction in gray matter volume, and the topography of gray matter volume reduction is dictated, at least in part, by the particular pathology. […] These changes appear to represent a form of plasticity as they are reversible when pain is effectively managed [63, 67, 68].”

“By definition, neuropathic pain indicates direct pathology of the nervous system while nociceptive pain is an indication of real or potential tissue damage. Due to the distinction in pathophysiology, conventional treatments prescribed for nociceptive pain are not very effective in treating neuropathic pain and vice versa [78]. Therefore the first step towards meaningful pain relief is an accurate diagnosis. […] Treating neuropathic pain requires a multifaceted approach that aims to eliminate the underlying etiology, when possible, and manage the associated discomforts and emotional distress. Although in some cases it is possible to directly treat the cause of neuropathic pain, for example surgery to alleviate a constricted nerve, it is more likely that the primary cause is untreatable, as is the case with singular traumatic events such as stroke and spinal cord injury and diseases like diabetes. When this is the case, symptom management and pain reduction become the primary focus. Unfortunately, in most cases complete elimination of pain is not a feasible endpoint; a pain reduction of 30% is considered to be efficacious [21]. Additionally, many pharmacological treatments require careful titration and tapering to prevent adverse effects and toxicity. This process may take several weeks to months, and ultimately the drug may be ineffective, necessitating another trial with a different medication. It is therefore necessary that both doctor and patient begin treatment with realistic expectations and goals.”

First-line medications for the treatment of neuropathic pain are those that have proven efficacy in randomized clinical trials (RCTs) and are consistent with pooled clinical observations [81]. These include antidepressants, calcium channel ligands, and topical lidocaine [15]. Tricyclic antidepressants (TCAs) have demonstrated efficacy in treating neuropathic pain with positive results in RCTs for central post-stroke pain, PHN, painful diabetic and non-diabetic polyneuropathy, and post-mastectomy pain syndrome [82]. However they do not seem to be effective in treating painful HIV-neuropathy or CIPN [82]. Duloxetine and venlafaxine, two selective serotonin norepinephrine reuptake inhibitors (SSNRIs), have been found to be effective in DPN and both DPN and painful polyneuropathies, respectively [81]. […] Gabapentin and pregabalin have also demonstrated efficacy in several neuropathic pain conditions including DPN and PHN […] Topical lidocaine (5% patch or gel) has significantly reduced allodynia associated with PHN and other neuropathic pain syndromes in several RCTs [81, 82]. With no reported systemic adverse effects and mild skin irritation as the only concern, lidocaine is an appropriate choice for treating localized peripheral neuropathic pain. In the event that first line medications, alone or in combination, are not effective at achieving adequate pain relief, second line medications may be considered. These include opioid analgesics and tramadol, pharmaceuticals which have proven efficacy in RCTs but are associated with significant adverse effects that warrant cautious prescription [15]. Although opioid analgesics are effective pain relievers in several types of neuropathic pain [81, 82, 84], they are associated with misuse or abuse, hypogonadism, constipation, nausea, and immunological changes […] Careful consideration should be given when prescribing opiates to patients who have a personal or family history of drug or alcohol abuse […] Deep brain stimulation, a neurosurgical technique by which an implanted electrode delivers controlled electrical impulses to targeted brain regions, has demonstrated some efficacy in treating chronic pain but is not routinely employed due to a high risk-to-benefit ratio [91]. […] A major challenge in treating neuropathic pain is the heterogeneity of disease pathogenesis within an individual etiological classification. Patients with seemingly identical diseases may experience completely different neuropathic pain phenotypes […] One of the biggest barriers to successful management of neuropathic pain has been the lack of understanding in the underlying pathophysiology that produces a pain phenotype. To that end, significant progress has been made in basic science research.”

In diabetes mellitus, nerves and their supporting cells are subjected to prolonged hyperglycemia and metabolic disturbances and this culminates in reversible/irreversible nervous system dysfunction and damage, namely diabetic peripheral neuropathy (DPN). Due to the varying compositions and extents of neurological involvements, it is difficult to obtain accurate and thorough prevalence estimates of DPN, rendering this microvascular complication vastly underdiagnosed and undertreated [1-4]. According to American Diabetes Association, DPN occurs to 60-70% of diabetic individuals [5] and represents the leading cause of peripheral neuropathies among all cases [6, 7].”

A quick remark: This number seems really high to me. I won’t rule out that it’s accurate if you go with highly sensitive measures of neuropathy, but the number of patients who will experience significant clinical sequelae as a result of DPN is in my opinion likely to be significantly lower than that. On a peripherally related note, it should however on the other hand also be kept in mind that although diabetes-related neurological complications may display some clustering in patient groups – which will necessarily decrease the magnitude of the problem – no single test will ever completely rule out neurological complications in a diabetic; a patient with a negative Semmes-Weinstein monofilament test may still have autonomic neuropathy. So assessing the full disease burden in the context of diabetes-related neurological complications cannot be done using only a single instrument, and the full disease burden is likely to be higher than individual estimates encountered in the literature (unless a full neurological workup was done, which is unlikely to be the case). They do go into more detail about subgroups, clinical significance, etc. below, but I thought this observation was important to add early on in this part of the coverage.

Because diverse anatomic distributions and fiber types may be differentially affected in patients with diabetes, the disease manifestations, courses and pathologies of clinical and subclinical DPN are rather heterogeneous and encompass a broad spectrum […] Current consensus divides diabetes-associated somatic neuropathic syndromes into the focal/multifocal and diffuse/generalized neuropathies [6, 14]. The first category comprises a group of asymmetrical, acute-in-onset and self-limited single lesion(s) of nerve injury or impairment largely resulting from the increased vulnerability of diabetic nerves to mechanical insults (Carpal Tunnel Syndrome) […]. Such mononeuropathies occur idiopathically and only become a clinical problem in association with aging in 5-10% of those affected. Therefore, focal neuropathies are not extensively covered in this chapter [16]. The rest of the patients frequently develop diffuse neuropathies characterized by symmetrical distribution, insidious onset and chronic progression. In particular, a distal symmetrical sensorimotor polyneuropathy accounts for 90% of all DPN diagnoses in type 1 and type 2 diabetics and affects all types of peripheral sensory and motor fibers in a temporally non-uniform manner [6, 17].
Symptoms begin with prickling, tingling, numbness, paresthesia, dysesthesia and various qualities of pain associated with small sensory fibers at the very distal end (toes) of lower extremities [1, 18]. Presence of the above symptoms together with abnormal nociceptive response of epidermal C and A-δ fibers to pain/temperature (as revealed by clinical examination) constitute the diagnosis of small fiber sensory neuropathy, which produces both painful and insensate phenotypes [19]. Painful diabetic neuropathy is a prominent, distressing and chronic experience in at least 10-30% of DPN populations [20, 21]. Its occurrence does not necessarily correlate with impairment in electrophysiological or quantitative sensory testing (QST). […] Large myelinated sensory fibers that innervate the dermis, such as Aβ, also become involved later on, leading to impaired proprioception, vibration and tactile detection, and mechanical hypoalgesia [19]. Following this “stocking-glove”, length-dependent and dying-back evolvement, neurodegeneration gradually proceeds to proximal muscle sensory and motor nerves. Its presence manifests in neurological testings as reduced nerve impulse conductions, diminished ankle tendon reflex, unsteadiness and muscle weakness [1, 24].
Both the absence of protective sensory response and motor coordination predispose neuropathic foot to impaired wound healing and gangrenous ulceration — often ensued by limb amputation in severe and/or advanced cases […]. Although symptomatic motor deficits only appear in later stages of DPN [25], motor denervation and distal atrophy can increase the rate of fractures by causing repetitive minor trauma or falls [24, 28]. Other unusual but highly disabling late sequelae of DPN include limb ischemia and joint deformity [6]; the latter also being termed Charcot’s neuroarthropathy or Charcot’s joints [1]. In addition to significant morbidities, several separate cohort studies provided evidence that DPN [29], diabetic foot ulcers [30] and increased toe vibration perception threshold (VPT) [31] are all independent risk factors for mortality.”

Unfortunately, current therapy for DPN is far from effective and at best only delays the onset and/or progression of the disease via tight glucose control […] Even with near normoglycemic control, a substantial proportion of patients still suffer the debilitating neurotoxic consequences of diabetes [34]. On the other hand, some with poor glucose control are spared from clinically evident signs and symptoms of neuropathy for a long time after diagnosis [37-39]. Thus, other etiological factors independent of hyperglycemia are likely to be involved in the development of DPN. Data from a number of prospective, observational studies suggested that older age, longer diabetes duration, genetic polymorphism, presence of cardiovascular disease markers, malnutrition, presence of other microvascular complications, alcohol and tobacco consumption, and higher constitutional indexes (e.g. weight and height) interact with diabetes and make for strong predictors of neurological decline [13, 32, 40-42]. Targeting some of these modifiable risk factors in addition to glycemia may improve the management of DPN. […] enormous efforts have been devoted to understanding and intervening with the molecular and biochemical processes linking the metabolic disturbances to sensorimotor deficits by studying diabetic animal models. In return, nearly 2,200 articles were published in PubMed central and at least 100 clinical trials were reported evaluating the efficacy of a number of pharmacological agents; the majority of them are designed to inhibit specific pathogenic mechanisms identified by these experimental approaches. Candidate agents have included aldose reductase inhibitors, AGE inhibitors, γ-linolenic acid, α-lipoic acid, vasodilators, nerve growth factor, protein kinase Cβ inhibitors, and vascular endothelial growth factor. Notwithstanding a fruitful of knowledge and promising results in animals, none has translated into definitive clinical success […] Based on the records published by National Institute of Neurological Disorders and Stroke (NINDS), a main source of DPN research, about 16,488 projects were funded at the expense of over $8 billion for the fiscal years of 2008 through 2012. Of these projects, an estimated 72,200 animals were used annually to understand basic physiology and disease pathology as well as to evaluate potential drugs [255]. As discussed above, however, the usefulness of these pharmaceutical agents developed through such a pipeline in preventing or reducing neuronal damage has been equivocal and usually halted at human trials due to toxicity, lack of efficacy or both […]. Clearly, the pharmacological translation from our decades of experimental modeling to clinical practice with regard to DPN has thus far not even [been] close to satisfactory.”

Whereas a majority of the drugs investigated during preclinical testing executed experimentally desired endpoints without revealing significant toxicity, more than half that entered clinical evaluation for treating DPN were withdrawn as a consequence of moderate to severe adverse events even at a much lower dose. Generally, using other species as surrogates for human population inherently encumbers the accurate prediction of toxic reactions for several reasons […] First of all, it is easy to dismiss drug-induced non-specific effects in animals – especially for laboratory rodents who do not share the same size, anatomy and physical activity with humans. […]  Second, some physiological and behavioral phenotypes observable in humans are impossible for animals to express. In this aspect, photosensitive skin rash and pain serve as two good examples of non-translatable side effects. Rodent skin differs from that of humans in that it has a thinner and hairier epidermis and distinct DNA repair abilities [260]. Therefore, most rodent stains used in diabetes modeling provide poor estimates for the probability of cutaneous hypersensitivity reactions to pharmacological treatments […] Another predicament is to assess pain in rodents. The reason for this is simple: these animals cannot tell us when, where or even whether they are experiencing pain […]. Since there is not any specific type of behavior to which painful reaction can be unequivocally associated, this often leads to underestimation of painful side effects during preclinical drug screening […] The third problem is that animals and humans have different pharmacokinetic and toxicological responses.”

“Genetic or chemical-induced diabetic rats or mice have been a major tool for preclinical pharmacological evaluation of potential DPN treatments. Yet, they do not faithfully reproduce many neuropathological manifestations in human diabetics. The difficulty of such begins with the fact that it is not possible to obtain in rodents a qualitative and quantitative expression of the clinical symptoms that are frequently presented in neuropathic diabetic patients, including spontaneous pain of different characteristics (e.g. prickling, tingling, burning, squeezing), paresthesia and numbness. As symptomatic changes constitute an important parameter of therapeutic outcome, this may well underlie the failure of some aforementioned drugs in clinical trials despite their good performance in experimental tests […] Development of nerve dysfunction in diabetic rodents also does not follow the common natural history of human DPN. […] Besides the lack of anatomical resemblance, the changes in disease severity are often missing in these models. […] importantly, foot ulcers that occur as a late complication to 15% of all individuals with diabetes [14] do not spontaneously develop in hyperglycemic rodents. Superimposed injury by experimental procedure in the foot pads of diabetic rats or mice may lend certain insight in the impaired wound healing in diabetes [278] but is not reflective of the chronic, accumulating pathological changes in diabetic feet of human counterparts. Another salient feature of human DPN that has not been described in animals is the predominant sensory and autonomic nerve damage versus minimal involvement of motor fibers [279]. This should elicit particular caution as the selective susceptibility is critical to our true understanding of the etiopathogenesis underlying distal sensorimotor polyneuropathy in diabetes. In addition to the lack of specificity, most animal models studied only cover a narrow spectrum of clinical DPN and have not successfully duplicated syndromes including proximal motor neuropathy and focal lesions [279].
Morphologically, fiber atrophy and axonal loss exist in STZ-rats and other diabetic rodents but are much milder compared to the marked degeneration and loss of myelinated and unmyelinated nerves readily observed in human specimens [280]. Of significant note, rodents are notoriously resistant to developing some of the histological hallmarks seen in diabetic patients, such as segmental and paranodal demyelination […] the simultaneous presence of degenerating and regenerating fibers that is characteristic of early DPN has not been clearly demonstrated in these animals [44]. Since such dynamic nerve degeneration/regeneration signifies an active state of nerve repair and is most likely to be amenable to therapeutic intervention, absence of this property makes rodent models a poor tool in both deciphering disease pathogenesis and designing treatment approaches […] With particular respect to neuroanatomy, a peripheral axon in humans can reach as long as one meter [296] whereas the maximal length of the axons innervating the hind limb is five centimeters in mice and twelve centimeters in rats. This short length makes it impossible to study in rodents the prominent length dependency and dying-back feature of peripheral nerve dysfunction that characterizes human DPN. […] For decades the cytoarchitecture of human islets was assumed to be just like those in rodents with a clear anatomical subdivision of β-cells and other cell types. By using confocal microscopy and multi-fluorescent labeling, it was finally uncovered that human islets have not only a substantially lower percentage of β-cell population, but also a mixed — rather than compartmentalized — organization of the different cell types [297]. This cellular arrangement was demonstrated to directly alter the functional performance of human islets as opposed to rodent islets. Although it is not known whether such profound disparities in cell composition and association also exist in the PNS, it might as well be anticipated considering the many sophisticated sensory and motor activities that are unique to humans. Considerable species difference also manifest at a molecular level. […] At least 80% of human genes have a counterpart in the mouse and rat genome. However, temporal and spatial expression of these genes can vary remarkably between humans and rodents, in terms of both extent and isoform specificity.”

“Ultimately, a fundamental problem associated with resorting to rodents in DPN research is to study a human disorder that takes decades to develop and progress in organisms with a maximum lifespan of 2-3 years. […] It is […] fair to say that a full clinical spectrum of the maturity-onset DPN likely requires a length of time exceeding the longevity of rodents to present and diabetic rodent models at best only help illustrate the very early aspects of the entire disease syndrome. Since none of the early pathogenetic pathways revealed in diabetic rodents will contribute to DPN in a quantitatively and temporally uniform fashion throughout the prolonged natural history of this disease, it is not surprising that a handful of inhibitors developed against these processes have not benefited patients with relatively long-standing neuropathy. As a matter of fact, any agents targeting single biochemical insults would be too little too late to treat a chronic neurological disorder with established nerve damage and pathogenetic heterogeneity […] It is important to point out that the present review does not argue against the ability of animal models to shed light on basic molecular, cellular and physiological processes that are shared among species. Undoubtedly, animal models of diabetes have provided abundant insights into the disease biology of DPN. Nevertheless, the lack of any meaningful advance in identifying a promising pharmacological target necessitates a reexamination of the validity of current DPN models as well as to offer a plausible alternative methodology to scientific approaches and disease intervention. […] we conclude that the fundamental species differences have led to misinterpretation of rodent data and overall failure of pharmacological investment. As more is being learned, it is becoming prevailing that DPN is a chronic, heterogeneous disease unlikely to benefit from targeting specific and early pathogenetic components revealed by animal studies.”

February 13, 2018 Posted by | Books, Diabetes, Genetics, Medicine, Neurology, Pharmacology | Leave a comment

Endocrinology (part 2 – pituitary)

Below I have added some observations from the second chapter of the book, which covers the pituitary gland.

“The pituitary gland is centrally located at the base of the brain in the sella turcica within the sphenoid bone. It is attached to the hypothalamus by the pituitary stalk and a fine vascular network. […] The pituitary measures around 13mm transversely, 9mm anteroposteriorly, and 6mm vertically and weighs approximately 100mg. It increases during pregnancy to almost twice its normal size, and it decreases in the elderly. *Magnetic resonance imaging (MRI) currently provides the optimal imaging of the pituitary gland. *Computed tomography (CT) scans may still be useful in demonstrating calcification in tumours […] and hyperostosis in association with meningiomas or evidence of bone destruction. […] T1– weighted images demonstrate cerebrospinal fluid (CSF) as dark grey and brain as much whiter. This imagining is useful for demonstrating anatomy clearly. […] On T1– weighted images, pituitary adenomas are of lower signal intensity than the remainder of the normal gland. […] The presence of microadenomas may be difficult to demonstrate.”

“Hypopituitarism refers to either partial or complete deficiency of anterior and/or posterior pituitary hormones and may be due to [primary] pituitary disease or to hypothalamic pathology which interferes with the hypothalamic control of the pituitary. Causes: *Pituitary tumours. *Parapituitary tumours […] *Radiotherapy […] *Pituitary infarction (apoplexy), Sheehan’s syndrome. *Infiltration of the pituitary gland […] *infection […] *Trauma […] *Subarachnoid haemorrhage. *Isolated hypothalamic-releasing hormone deficiency, e.g. Kallmann’s syndrome […] *Genetic causes [Let’s stop here: Point is, lots of things can cause pituitary problems…] […] The clinical features depend on the type and degree of hormonal deficits, and the rate of its development, in addition to whether there is intercurrent illness. In the majority of cases, the development of hypopituitarism follows a characteristic order, which secretion of GH [growth hormone, US], then gonadotrophins being affected first, followed by TSH [Thyroid-Stimulating Hormone, US] and ACTH [Adrenocorticotropic Hormone, US] secretion at a later stage. PRL [prolactin, US] deficiency is rare, except in Sheehan’s syndrome associated with failure of lactation. ADH [antidiuretic hormone, US] deficiency is virtually unheard of with pituitary adenomas but may be seen rarely with infiltrative disorders and trauma. The majority of the clinical features are similar to those occurring when there is target gland insufficiency. […] NB Houssay phenomenon. Amelioration of diabetes mellitus in patients with hypopituitarism due to reduction in counter-regulatory hormones. […] The aims of investigation of hypopituitarism are to biochemically assess the extent of pituitary hormone deficiency and also to elucidate the cause. […] Treatment involves adequate and appropriate hormone replacement […] and management of the underlying cause.”

“Apoplexy refers to infarction of the pituitary gland due to either haemorrhage or ischaemia. It occurs most commonly in patients with pituitary adenomas, usually macroadenomas […] It is a medical emergency, and rapid hydrocortisone replacement can be lifesaving. It may present with […] sudden onset headache, vomiting, meningism, visual disturbance, and cranial nerve palsy.”

“Anterior pituitary hormone replacement therapy is usually performed by replacing the target hormone rather than the pituitary or hypothalamic hormone that is actually deficient. The exceptions to this are GH replacement […] and when fertility is desired […] [In the context of thyroid hormone replacement:] In contrast to replacement in [primary] hypothyroidism, the measurement of TSH cannot be used to assess adequacy of replacment in TSH deficiency due to hypothalamo-pituitary disease. Therefore, monitoring of treatment in order to avoid under- and over-replacement should be via both clinical assessment and by measuring free thyroid hormone concentrations […] [In the context of sex hormone replacement:] Oestrogen/testosterone administration is the usual method of replacement, but gonadotrophin therapy is required if fertility is desired […] Patients with ACTH deficiency usually need glucocorticoid replacement only and do not require mineralcorticoids, in contrast to patients with Addison’s disease. […] Monitoring of replacement [is] important to avoid over-replacement which is associated with BP, elevated glucose and insulin, and reduced bone mineral density (BMD). Under-replacement leads to the non-specific symptoms, as seen in Addison’s disease […] Conventional replacement […] may overtreat patients with partial ACTH deficiency.”

“There is now a considerable amount of evidence that there are significant and specific consequences of GH deficiency (GDH) in adults and that many of these features improve with GH replacement therapy. […] It is important to differentiate between adult and childhood onset GDH. […] the commonest cause in childhood is an isolated variable deficiency of GH-releasing hormone (GHRH) which may resolve in adult life […] It is, therefore, important to retest patients with childhood onset GHD when linear growth is completed (50% recovery of this group). Adult onset. GHD usually occurs [secondarily] to a structural pituitary or parapituitary condition or due to the effects of surgical treatment or radiotherapy. Prevalence[:] *Adult onset GHD 1/10,000 *Adult GHD due to adult and childhood onset GHD 3/10,000. Benefits of GH replacement[:] *Improved QoL and psychological well-being. *Improved exercise capacity. *↑ lean body mass and reduced fat mass. *Prolonged GH replacement therapy (>12-24 months) has been shown to increase BMD, which would be expected to reduce fracture rate. *There are, as yet, no outcome studies in terms of cardiovascular mortality. However, GH replacement does lead to a reduction (~15%) in cholesterol. GH replacement also leads to improved ventricular function and ↑ left ventricular mass. […] All patients with GHD should be considered for GH replacement therapy. […] adverse effects experienced with GH replacement usually resolve with dose reduction […] GH treatment may be associated with impairment of insulin sensitivity, and therefore markers of glycemia should be monitored. […] Contraindications to GH replacement[:] *Active malignancy. *Benign intracranial hypertension. *Pre-proliferative/proliferative retinopathy in diabetes mellitus.”

“*Pituitary adenomas are the most common pituitary disease in adults and constitute 10-15% of primary brain tumours. […] *The incidence of clinically apparent pituitary disease is 1 in 10,000. *Pituitary carcinoma is very rare (<0.1% of all tumours) and is most commonly ACTH- or prolactin-secreting. […] *Microadenoma <1cm. *Macroadenoma >1cm. [In terms of the functional status of tumours, the break-down is as follows:] *Prolactinoma 35-40%. *Non-functioning 30-35%. Growth hormone (acromegaly) 10-15%. *ACTH adenoma (Cushing’s disease) 5-10% *TSH adenoma <5%. […] Pituitary disease is associated with an increased mortality, predominantly due to vascular disease. This may be due to oversecretion of GH or ACTH, hormone deficiencies or excessive replacement (e.g. of hydrocortisone).”

“*Prolactinomas are the commonest functioning pituitary tumour. […] Malignant prolactinomas are very rare […] [Clinical features of hyperprolactinaemia:] *Galactorrhoea (up to 90%♀, <10% ♂). *Disturbed gonadal function [menstrual disturbance, infertility, reduced libido, ED in ♂] […] Hyperprolactinaemia is associated with a long-term risk of BMD. […] Hypothyroidism and chronic renal failure are causes of hyperprolactinaemia. […] Antipsychotic agents are the most likely psychotrophic agents to cause hyperprolactinaemia. […] Macroadenomas are space-occupying tumours, often associated with bony erosion and/or cavernous sinus invasion. […] *Invasion of the cavernous sinus may lead to cranial nerve palsies. *Occasionally, very invasive tumours may erode bone and present with a CSF leak or [secondary] meningitis. […] Although microprolactinomas may expand in size without treatment, the vast majority do not. […] Macroprolactinomas, however, will continue to expand and lead to pressure effects. Definite treatment of the tumour is, therefore, necessary.”

“Dopamine agonist treatment […] leads to suppression of PRL in most patients [with prolactinoma], with [secondary] effects of normalization of gonadal function and termination of galactorrhoea. Tumour shrinkage occurs at a variable rate (from 24h to 6-12 months) and extent and must be carefully monitored. Continued shrinkage may occur for years. Slow chiasmal decompression will correct visual field defects in the majority of patients, and immediate surgical decompression is not necessary. […] Cabergoline is more effective in normalization of PRL in microprolactinoma […], with fewer side effects than bromocriptine. […] Tumour enlargement following initial shrinkage on treatment is usually due to non-compliance. […] Since the introduction of dopamine agonist treatment, transsphenoidal surgery is indicated only for patients who are resistant to, or intolerant of, dopamine agonist treatment. The cure rate for macroprolactinomas treated with surgery is poor (30%), and, therefore, drug treatment is first-line in tumours of all size. […] Standard pituitary irradiation leads to slow reduction (over years) of PRL in the majority of patients. […] Radiotherapy is not indicated in the management of patients with microprolactinomas. It is useful in the treatment of macroprolactinomas once the tumour has been shrunken away from the chiasm, only if the tumour is resistant.”

“Acromegaly is the clinical condition resulting from prolonged excessive GH and hence IGF-1 secretion in adults. GH secretion is characterized by blunting of pulsatile secretion and failure of GH to become undetectable during the 24h day, unlike normal controls. […] *Prevalence 40-86 cases/million population. Annual incidence of new cases in the UK is 4/million population. *Onset is insidious, and there is, therefore, often a considerable delay between onset of clinical features and diagnosis. Most cases are diagnosed at 40-60 years. […] Pituitary gigantism [is] [t]he clinical syndrome resulting from excess GH secretion in children prior to fusion of the epiphyses. […] growth velocity without premature pubertal manifestations should arouse suspicion of pituitary gigantism. […] Causes of acromegaly[:] *Pituitary adenoma (>99% of cases). Macroadenomas 60-80%, microadenomas 20-40%. […] The clinical features arise from the effects of excess GH/IGF-1, excess PRL in some (as there is co-secretion of PRL in a minority (30%) of tumours […] and the tumour mass. [Signs and symptoms:] * sweating -> 80% of patients. *Headaches […] *Tiredness and lethargy. *Joint pains. *Change in ring or shoe size. *Facial appearance. Coarse features […] enlarged nose […] prognathism […] interdental separation. […] Enlargement of hands and feet […] [Complications:] *Hypertension (40%). *Insulin resistance and impaired glucose tolerance (40%)/diabetes mellitus (20%). *Obstructive sleep apnea – due to soft tissue swelling […] Ischaemic heart disease and cerebrovascular disease.”

“Management of acromegaly[:] The management strategy depends on the individual patient and also on the tumour size. Lowering of GH is essential in all situations […] Transsphenoidal surgery […] is usually the first line for treatment in most centres. *Reported cure rates vary: 40-91% for microadenomas and 10-48% for macroadenomas, depending on surgical expertise. […] Using the definition of post-operative cure as mean GH <2.5 micrograms/L, the reported recurrence rate is low (6% at 5 years). Radiotherapy […] is usually reserved for patients following unsuccessful transsphenoidal surgery, only occasionally is it used as [primary] therapy. […] normalization of mean GH may take several years and, during this time, adjunctive medical treatment (usually with somatostatin analogues) is required. […] Radiotherapy can induce GH deficiency which may need GH therapy. […] Somatostatin analogues lead to suppresion of GH secretion in 20-60% of patients with acromegaly. […] some patients are partial responders, and although somatostatin analogues will lead to lowering of mean GH, they do not suppress to normal despite dose escalation. These drugs may be used as [primary] therapy where the tumour does not cause mass effects or in patients who have received surgery and/or radiotherapy who have elevated mean GH. […] Dopamine agonists […] lead to lowering of GH levels but, very rarely, lead to normalization of GH or IGF-1 (<30%). They may be helpful, particularly if there is coexistent secretion of PRL, and, in these cases, there may be significant tumour shrinkage. […] GH receptor antagonists [are] [i]ndicated for somatostatin non-responders.”

“Cushing’s syndrome is an illness resulting from excess cortisol secretion, which has a high mortality if left untreated. There are several causes of hypercortisolaemia which must be differentiated, and the commonest cause is iatrogenic (oral, inhaled, or topical steroids). […] ACTH-dependent Cushing’s must be differentiated from ACTH-independent disease (usually due to an adrenal adenoma, or, rarely, carcinoma […]). Once a diagnosis of ACTH-dependent disease has been established, it is important to differentiate between pituitary-dependent (Cushing’s disease) and ectopic secretion. […] [Cushing’s disease is rare;] annual incidence approximately 2/million. The vast majority of Cushing’s syndrome is due to a pituitary ACTH-secreting corticotroph microadenoma. […] The features of Cushing’s syndrome are progressive and may be present for several years prior to diagnosis. […] *Facial appearance – round plethoric complexion, acne and hirsutism, thinning of scalp hair. *Weight gain – truncal obesity, buffalo hump […] *Skin – thin and fragile […] easy bruising […] *Proximal muscle weakness. *Mood disturbance – labile, depression, insomnia, psychosis. *Menstrual disturbance. *Low libido and impotence. […] Associated features [include:] *Hypertension (>50%) due to mineralocorticoid effects of cortisol […] *Impaired glucose tolerance/diabetes mellitus (30%). *Osteopenia and osteoporosis […] *Vascular disease […] *Susceptibility to infections. […] Cushing’s is associated with a hypercoagulable state, with increased cardiovascular thrombotic risks. […] Hypercortisolism suppresses the thyroidal, gonadal, and GH axes, leading to lowered levels of TSH and thyroid hormones as well as reduced gonadotrophins, gonadal steroids, and GH.”

“Treatment of Cushing’s disease[:] Transsphenoidal surgery [is] the first-line option in most cases. […] Pituitary radiotherapy [is] usually administered as second-line treatment, following unsuccessful transsphenoidal surgery. […] Medical treatment [is] indicated during the preoperative preparation of patients or while awaiting radiotherapy to be effective or if surgery or radiotherapy are contraindicated. *Inhibitors of steroidogenesis: metyrapone is usually used first-line, but ketoconazole should be used as first-line in children […] Disadvantage of these agents inhibiting steroidogenesis is the need to increase the dose to maintain control, as ACTH secretion will increase as cortisol concentrations decrease. […] Successful treatment (surgery or radiotherapy) of Cushing’s disease leads to cortisol deficiency and, therefore, glucocorticoid replacement therapy is essential. […] *Untreated [Cushing’s] disease leads to an approximately 30-50% mortality at 5 years, owing to vascular disease and susceptibility to infections. *Treated Cushing’s syndrome has a good prognosis […] *Although the physical features and severe psychological disorders associated with Cushing’s improve or resolve within weeks or months of successful treatment, more subtle mood disturbance may persist for longer. Adults may also have impaired cognitive function. […] it is likely that there is an cardiovascular risk. *Osteoporosis will usually resolve in children but may not improve significantly in older patients. […] *Hypertension has been shown to resolve in 80% and diabetes mellitus in up to 70%. *Recent data suggests that mortality even with successful treatment of Cushing’s is increased significantly.”

“The term incidentaloma refers to an incidentally detected lesion that is unassociated with hormonal hyper- or hyposecretion and has a benign natural history. The increasingly frequent detection of these lesions with technological improvements and more widespread use of sophisticated imaging has led to a management challenge – which, if any, lesions need investigation and/or treatment, and what is the optimal follow-up strategy (if required at all)? […] *Imaging studies using MRI demonstrate pituitary microadenomas in approximately 10% of normal volunteers. […] Clinically significant pituitary tumours are present in about 1 in 1,000 patients. […] Incidentally detected microadenomas are very unlikely (<10%) to increase in size whereas larger incidentally detected meso- and macroadenomas are more likely (40-50%) to enlarge. Thus, conservative management in selected patients may be appropriate for microadenomas which are incidentally detected […]. Macroadenomas should be treated, if possible.”

“Non-functioning pituitary tumours […] are unassociated with clinical syndromes of anterior pituitary hormone excess. […] Non-functioning pituitary tumours (NFA) are the commonest pituitary macroadenoma. They represent around 28% of all pituitary tumours. […] 50% enlarge, if left untreated, at 5 years. […] Tumour behaviour is variable, with some tumours behaving in a very indolent, slow-growing manner and others invading the sphenoid and cavernous sinus. […] At diagnosis, approximately 50% of patients are gonadotrophin-deficient. […] The initial definitive management in virtually every case is surgical. This removes mass effects and may lead to some recovery of pituitary function in around 10%. […] The use of post-operative radiotherapy remains controversial. […] The regrowth rate at 10 years without radiotherapy approaches 45% […] administration of post-operative radiotherapy reduces this regrowth rate to <10%. […] however, there are sequelae to radiotherapy – with a significant long-term risk of hypopituitarism and a possible risk of visual deterioration and malignancy in the field of radiation. […] Unlike the case for GH- and PRL-secreting tumours, medical therapy for NFAs is usually unhelpful […] Gonadotrophinomas […] are tumours that arise from the gonadotroph cells of the pituitary gland and produce FSH, LH, or the α subunit. […] they are usually silent and unassociated with excess detectable secretion of LH and FSH […] [they] present in the same manner as other non-functioning pituitary tumours, with mass effects and hypopituitarism […] These tumours are managed as non-functioning tumours.”

“The posterior lobe of the pituitary gland arises from the forebrain and comprises up to 25% of the normal adult pituitary gland. It produces arginine vasopressin and oxytocin. […] Oxytoxin has no known role in ♂ […] In ♀, oxytoxin contracts the pregnant uterus and also causes breast duct smooth muscle contraction, leading to breast milk ejection during breastfeeding. […] However, oxytoxin deficiency has no known adverse effect on parturition or breastfeeding. […] Arginine vasopressin is the major determinant of renal water excretion and, therefore, fluid balance. It’s main action is to reduce free water clearance. […] Many substances modulate vasopressin secretion, including the catecholamines and opioids. *The main site of action of vasopressin is in the collecting duct and the thick ascending loop of Henle […] Diabetes Insipidus (DI) […] is defined as the passage of large volumes (>3L/24h) of dilute urine (osmolality <300mOsm/kg). [It may be] [d]ue to deficiency of circulating arginine vasopressin [or] [d]ue to renal resistance to vasopressin.” […lots of other causes as well – trauma, tumours, inflammation, infection, vascular, drugs, genetic conditions…]

Hyponatraemia […] Incidence *1-6% of hospital admissions Na<130mmol/L. *15-22% hospital admissions Na<135mmol/L. […] True clinically apparent hyponatraemia is associated with either excess water or salt deficiency. […] Features *Depend on the underlying cause and also on the rate of development of hyponatraemia. May develop once sodium reaches 115mmol/L or earlier if the fall is rapid. Level at 100mmol/L or less is life-threatening. *Features of excess water are mainly neurological because of brain injury […] They include confusion and headache, progressing to seizures and coma. […] SIADH [Syndrome of Inappropriate ADH, US] is a common cause of hyponatraemia. […] The elderly are more prone to SIADH, as they are unable to suppress ADH as efficiently […] ↑ risk of hyponatraemia with SSRIs. […] rapid overcorrection of hyponatraemia may cause central pontine myelinolysis (demyelination).”

“The hypothalamus releases hormones that act as releasing hormones at the anterior pituitary gland. […] The commonest syndrome to be associated with the hypothalamus is abnormal GnRH secretion, leading to reduced gonadotrophin secretion and hypogonadism. Common causes are stress, weight loss, and excessive exercise.”

January 14, 2018 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Ophthalmology, Pharmacology | Leave a comment

A few diabetes papers of interest

i. Type 2 Diabetes in the Real World: The Elusive Nature of Glycemic Control.

“Despite U.S. Food and Drug Administration (FDA) approval of over 40 new treatment options for type 2 diabetes since 2005, the latest data from the National Health and Nutrition Examination Survey show that the proportion of patients achieving glycated hemoglobin (HbA1c) <7.0% (<53 mmol/mol) remains around 50%, with a negligible decline between the periods 2003–2006 and 2011–2014. The Healthcare Effectiveness Data and Information Set reports even more alarming rates, with only about 40% and 30% of patients achieving HbA1c <7.0% (<53 mmol/mol) in the commercially insured (HMO) and Medicaid populations, respectively, again with virtually no change over the past decade. A recent retrospective cohort study using a large U.S. claims database explored why clinical outcomes are not keeping pace with the availability of new treatment options. The study found that HbA1c reductions fell far short of those reported in randomized clinical trials (RCTs), with poor medication adherence emerging as the key driver behind the disconnect. In this Perspective, we examine the implications of these findings in conjunction with other data to highlight the discrepancy between RCT findings and the real world, all pointing toward the underrealized promise of FDA-approved therapies and the critical importance of medication adherence. While poor medication adherence is not a new issue, it has yet to be effectively addressed in clinical practice — often, we suspect, because it goes unrecognized. To support the busy health care professional, innovative approaches are sorely needed.”

“To better understand the differences between usual care and clinical trial HbA1c results, multivariate regression analysis assessed the relative contributions of key biobehavioral factors, including baseline patient characteristics, drug therapy, and medication adherence (21). Significantly, the key driver was poor medication adherence, accounting for 75% of the gap […]. Adherence was defined […] as the filling of one’s diabetes prescription often enough to cover ≥80% of the time one was recommended to be taking the medication (34). By this metric, proportion of days covered (PDC) ≥80%, only 29% of patients were adherent to GLP-1 RA treatment and 37% to DPP-4 inhibitor treatment. […] These data are consistent with previous real-world studies, which have demonstrated that poor medication adherence to both oral and injectable antidiabetes agents is very common (3537). For example, a retrospective analysis [of] adults initiating oral agents in the DPP-4 inhibitor (n = 61,399), sulfonylurea (n = 134,961), and thiazolidinedione (n = 42,012) classes found that adherence rates, as measured by PDC ≥80% at the 1-year mark after the initial prescription, were below 50% for all three classes, at 47.3%, 41.2%, and 36.7%, respectively (36). Rates dropped even lower at the 2-year follow-up (36)”

“Our current ability to assess adherence and persistence is based primarily on review of pharmacy records, which may underestimate the extent of the problem. For example, using the definition of adherence of the Centers for Medicare & Medicaid Services — PDC ≥80% — a patient could miss up to 20% of days covered and still be considered adherent. In retrospective studies of persistence, the permissible gap after the last expected refill date often extends up to 90 days (39,40). Thus, a patient may have a gap of up to 90 days and still be considered persistent.

Additionally, one must also consider the issue of primary nonadherence; adherence and persistence studies typically only include patients who have completed a first refill. A recent study of e-prescription data among 75,589 insured patients found that nearly one-third of new e-prescriptions for diabetes medications were never filled (41). Finally, none of these measures take into account if the patient is actually ingesting or injecting the medication after acquiring his or her refills.”

“Acknowledging and addressing the problem of poor medication adherence is pivotal because of the well-documented dire consequences: a greater likelihood of long-term complications, more frequent hospitalizations, higher health care costs, and elevated mortality rates (4245). In patients younger than 65, hospitalization risk in one study (n = 137,277) was found to be 30% at the lowest level of adherence to antidiabetes medications (1–19%) versus 13% at the highest adherence quintile (80–100%) […]. In patients over 65, a separate study (n = 123,235) found that all-cause hospitalization risk was 37.4% in adherent cohorts (PDC ≥80%) versus 56.2% in poorly adherent cohorts (PDC <20%) (45). […] Furthermore, for every 1,000 patients who increased adherence to their antidiabetes medications by just 1%, the total medical cost savings was estimated to be $65,464 over 3 years (45). […] “for reasons that are still unclear, the N.A. [North American] patient groups tend to have lower compliance and adherence compared to global rates during large cardiovascular studies” (46,47).”

“There are many potential contributors to poor medication adherence, including depressive affect, negative treatment perceptions, lack of patient-physician trust, complexity of the medication regimen, tolerability, and cost (48). […] A recent review of interventions addressing problematic medication adherence in type 2 diabetes found that few strategies have been shown consistently to have a marked positive impact, particularly with respect to HbA1c lowering, and no single intervention was identified that could be applied successfully to all patients with type 2 diabetes (53). Additional evidence indicates that improvements resulting from the few effective interventions, such as pharmacy-based counseling or nurse-managed home telemonitoring, often wane once the programs end (54,55). We suspect that the efficacy of behavioral interventions to address medication adherence will continue to be limited until there are more focused efforts to address three common and often unappreciated patient obstacles. First, taking diabetes medications is a burdensome and often difficult activity for many of our patients. Rather than just encouraging patients to do a better job of tolerating this burden, more work is needed to make the process easier and more convenient. […] Second, poor medication adherence often represents underlying attitudinal problems that may not be a strictly behavioral issue. Specifically, negative beliefs about prescribed medications are pervasive among patients, and behavioral interventions cannot be effective unless these beliefs are addressed directly (35). […] Third, the issue of access to medications remains a primary concern. A study by Kurlander et al. (51) found that patients selectively forgo medications because of cost; however, noncost factors, such as beliefs, satisfaction with medication-related information, and depression, are also influential.”

ii. Diabetes Research and Care Through the Ages. An overview article which might be of interest especially to people who’re not much familiar with the history of diabetes research and -treatment (a topic which is also very nicely covered in Tattersall’s book). Despite including a historical review of various topics, it also includes many observations about e.g. current (and future?) practice. Some random quotes:

“Arnoldo Cantani established a new strict level of treatment (9). He isolated his patients “under lock and key, and allowed them absolutely no food but lean meat and various fats. In the less severe cases, eggs, liver, and shell-fish were permitted. For drink the patients received water, plain or carbonated, and dilute alcohol for those accustomed to liquors, the total fluid intake being limited to one and one-half to two and one-half liters per day” (6).

Bernhard Naunyn encouraged a strict carbohydrate-free diet (6,10). He locked patients in their rooms for 5 months when necessary for “sugar-freedom” (6).” […let’s just say that treatment options have changed slightly over time – US]

“The characteristics of insulin preparations include the purity of the preparation, the concentration of insulin, the species of origin, and the time course of action (onset, peak, duration) (25). From the 1930s to the early 1950s, one of the major efforts made was to develop an insulin with extended action […]. Most preparations contained 40 (U-40) or 80 (U-80) units of insulin per mL, with U-10 and U-20 eliminated in the early 1940s. U-100 was introduced in 1973 and was meant to be a standard concentration, although U-500 had been available since the early 1950s for special circumstances. Preparations were either of mixed beef and pork origin, pure beef, or pure pork. There were progressive improvements in the purity of preparations as chemical techniques improved. Prior to 1972, conventional preparations contained 8% noninsulin proteins. […] In the early 1980s, “human” insulins were introduced (26). These were made either by recombinant DNA technology in bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae) or by enzymatic conversion of pork insulin to human insulin, since pork differed by only one amino acid from human insulin. The powerful nature of recombinant DNA technology also led to the development of insulin analogs designed for specific effects. These include rapid-acting insulin analogs and basal insulin analogs.”

“Until 1996, the only oral medications available were biguanides and sulfonylureas. Since that time, there has been an explosion of new classes of oral and parenteral preparations. […] The management of type 2 diabetes (T2D) has undergone rapid change with the introduction of several new classes of glucose-lowering therapies. […] the treatment guidelines are generally clear in the context of using metformin as the first oral medication for T2D and present a menu approach with respect to the second and third glucose-lowering medication (3032). In order to facilitate this decision, the guidelines list the characteristics of each medication including side effects and cost, and the health care provider is expected to make a choice that would be most suited for patient comorbidities and health care circumstances. This can be confusing and contributes to the clinical inertia characteristic of the usual management of T2D (33).”

“Perhaps the most frustrating barrier to optimizing diabetes management is the frequent occurrence of clinical inertia (whenever the health care provider does not initiate or intensify therapy appropriately and in a timely fashion when therapeutic goals are not reached). More broadly, the failure to advance therapy in an appropriate manner can be traced to physician behaviors, patient factors, or elements of the health care system. […] Despite clear evidence from multiple studies, health care providers fail to fully appreciate that T2D is a progressive disease. T2D is associated with ongoing β-cell failure and, as a consequence, we can safely predict that for the majority of patients, glycemic control will deteriorate with time despite metformin therapy (35). Continued observation and reinforcement of the current therapeutic regimen is not likely to be effective. As an example of real-life clinical inertia for patients with T2D on monotherapy metformin and an HbA1c of 7 to <8%, it took on the average 19 months before additional glucose-lowering therapy was introduced (36). The fear of hypoglycemia and weight gain are appropriate concerns for both patient and physician, but with newer therapies these undesirable effects are significantly diminished. In addition, health care providers must appreciate that achieving early and sustained glycemic control has been demonstrated to have long-term benefits […]. Clinicians have been schooled in the notion of a stepwise approach to therapy and are reluctant to initiate combination therapy early in the course of T2D, even if the combination intervention is formulated as a fixed-dose combination. […] monotherapy metformin failure rates with a starting HbA1c >7% are ∼20% per year (35). […] To summarize the current status of T2D at this time, it should be clearly emphasized that, first and foremost, T2D is characterized by a progressive deterioration of glycemic control. A stepwise medication introduction approach results in clinical inertia and frequently fails to meet long-term treatment goals. Early/initial combination therapies that are not associated with hypoglycemia and/or weight gain have been shown to be safe and effective. The added value of reducing CV outcomes with some of these newer medications should elevate them to a more prominent place in the treatment paradigm.”

iii. Use of Adjuvant Pharmacotherapy in Type 1 Diabetes: International Comparison of 49,996 Individuals in the Prospective Diabetes Follow-up and T1D Exchange Registries.

“The majority of those with type 1 diabetes (T1D) have suboptimal glycemic control (14); therefore, use of adjunctive pharmacotherapy to improve control has been of clinical interest. While noninsulin medications approved for type 2 diabetes have been reported in T1D research and clinical practice (5), little is known about their frequency of use. The T1D Exchange (T1DX) registry in the U.S. and the Prospective Diabetes Follow-up (DPV) registry in Germany and Austria are two large consortia of diabetes centers; thus, they provide a rich data set to address this question.

For the analysis, 49,996 pediatric and adult patients with diabetes duration ≥1 year and a registry update from 1 April 2015 to 1 July 2016 were included (19,298 individuals from 73 T1DX sites and 30,698 individuals from 354 DPV sites). Adjuvant medication use (metformin, glucagon-like peptide 1 [GLP-1] receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT2] inhibitors, and other noninsulin diabetes medications including pramlintide) was extracted from participant medical records. […] Adjunctive agents, whose proposed benefits may include the ability to improve glycemic control, reduce insulin doses, promote weight loss, and suppress dysregulated postprandial glucagon secretion, have had little penetrance as part of the daily medical regimen of those in the registries studied. […] The use of any adjuvant medication was 5.4% in T1DX and 1.6% in DPV (P < 0.001). Metformin was the most commonly reported medication in both registries, with 3.5% in the T1DX and 1.3% in the DPV (P < 0.001). […] Use of adjuvant medication was associated with older age, higher BMI, and longer diabetes duration in both registries […] it is important to note that registry data did not capture the intent of adjuvant medications, which may have been to treat polycystic ovarian syndrome in women […here’s a relevant link, US].”

iv. Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study. I recently covered a closely related paper here (paper # 2) but the two papers cover different data sets so I decided it would be worth including this one in this post anyway. Some quotes:

“We previously reported results from a small pilot study comparing the prevalence of DPN in a subset of youth enrolled in the SEARCH for Diabetes in Youth (SEARCH) study and found that 8.5% of 329 youth with T1D (mean ± SD age 15.7 ± 4.3 years and diabetes duration 6.2 ± 0.9 years) and 25.7% of 70 youth with T2D (age 21.6 ± 4.1 years and diabetes duration 7.6 ± 1.8 years) had evidence of DPN (9). […this is the paper I previously covered here, US] Recently, we also reported the prevalence of microvascular and macrovascular complications in youth with T1D and T2D in the entire SEARCH cohort (10).

In the current study, we examined the cross-sectional and longitudinal risk factors for DPN. The aims were 1) to estimate prevalence of DPN in youth with T1D and T2D, overall and by age and diabetes duration, and 2) to identify risk factors (cross-sectional and longitudinal) associated with the presence of DPN in a multiethnic cohort of youth with diabetes enrolled in the SEARCH study.”

“The SEARCH Cohort Study enrolled 2,777 individuals. For this analysis, we excluded participants aged <10 years (n = 134), those with no antibody measures for etiological definition of diabetes (n = 440), and those with incomplete neuropathy assessment […] (n = 213), which reduced the analysis sample size to 1,992 […] There were 1,734 youth with T1D and 258 youth with T2D who participated in the SEARCH study and had complete data for the variables of interest. […] Seven percent of the participants with T1D and 22% of those with T2D had evidence of DPN.”

“Among youth with T1D, those with DPN were older (21 vs. 18 years, P < 0.0001), had a longer duration of diabetes (8.7 vs. 7.8 years, P < 0.0001), and had higher DBP (71 vs. 69 mmHg, P = 0.02), BMI (26 vs. 24 kg/m2, P < 0.001), and LDL-c levels (101 vs. 96 mg/dL, P = 0.01); higher triglycerides (85 vs. 74 mg/dL, P = 0.005); and lower HDL-c levels (51 vs. 55 mg/dL, P = 0.01) compared to those without DPN. The prevalence of DPN was 5% among nonsmokers vs. 10% among the current and former smokers (P = 0.001). […] Among youth with T2D, those with DPN were older (23 vs. 22 years, P = 0.01), had longer duration of diabetes (8.6 vs. 7.6 years; P = 0.002), and had lower HDL-c (40 vs. 43 mg/dL, P = 0.04) compared with those without DPN. The prevalence of DPN was higher among males than among females: 30% of males had DPN compared with 18% of females (P = 0.02). The prevalence of DPN was twofold higher in current smokers (33%) compared with nonsmokers (15%) and former smokers (17%) (P = 0.01). […] [T]he prevalence of DPN was further assessed by 5-year increment of diabetes duration in individuals with T1D or T2D […]. There was an approximately twofold increase in the prevalence of DPN with an increase in duration of diabetes from 5–10 years to >10 years for both the T1D group (5–13%) (P < 0.0001) and the T2D group (19–36%) (P = 0.02). […] in an unadjusted logistic regression model, youth with T2D were four times more likely to develop DPN compared with those with T1D, and though this association was attenuated, it remained significant independent of age, sex, height, and glycemic control (OR 2.99 [1.91; 4.67], P < 0.001)”.

“The prevalence estimates for DPN found in our study for youth with T2D are similar to those in the Australian cohort (8) but lower for youth with T1D than those reported in the Danish (7) and Australian (8) cohorts. The nationwide Danish Study Group for Diabetes in Childhood reported a prevalence of 62% among 339 adolescents and youth with T1D (age 12–27 years, duration 9–25 years, and HbA1c 9.7 ± 1.7%) using the vibration perception threshold to assess DPN (7). The higher prevalence in this cohort compared with ours (62 vs. 7%) could be due to the longer duration of diabetes (9–25 vs. 5–13 years) and reliance on a single measure of neuropathy (vibration perception threshold) as opposed to our use of the MNSI, which includes vibration as well as other indicators of neuropathy. In the Australian study, Eppens et al. (8) reported abnormalities in peripheral nerve function in 27% of the 1,433 adolescents with T1D (median age 15.7 years, median diabetes duration 6.8 years, and mean HbA1c 8.5%) and 21% of the 68 adolescents with T2D (median age 15.3 years, median diabetes duration 1.3 years, and mean HbA1c 7.3%) based on thermal and vibration perception threshold. These data are thus reminiscent of the persistent inconsistencies in the definition of DPN, which are reflected in the wide range of prevalence estimates being reported.”

“The alarming rise in rates of DPN for every 5-year increase in duration, coupled with poor glycemic control and dyslipidemia, in this cohort reinforces the need for clinicians rendering care to youth with diabetes to be vigilant in screening for DPN and identifying any risk factors that could potentially be modified to alter the course of the disease (2830). The modifiable risk factors that could be targeted in this young population include better glycemic control, treatment of dyslipidemia, and smoking cessation (29,30) […]. The sharp increase in rates of DPN over time is a reminder that DPN is one of the complications of diabetes that must be a part of the routine annual screening for youth with diabetes.”

v. Diabetes and Hypertension: A Position Statement by the American Diabetes Association.

“Hypertension is common among patients with diabetes, with the prevalence depending on type and duration of diabetes, age, sex, race/ethnicity, BMI, history of glycemic control, and the presence of kidney disease, among other factors (13). Furthermore, hypertension is a strong risk factor for atherosclerotic cardiovascular disease (ASCVD), heart failure, and microvascular complications. ASCVD — defined as acute coronary syndrome, myocardial infarction (MI), angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin — is the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. Numerous studies have shown that antihypertensive therapy reduces ASCVD events, heart failure, and microvascular complications in people with diabetes (48). Large benefits are seen when multiple risk factors are addressed simultaneously (9). There is evidence that ASCVD morbidity and mortality have decreased for people with diabetes since 1990 (10,11) likely due in large part to improvements in blood pressure control (1214). This Position Statement is intended to update the assessment and treatment of hypertension among people with diabetes, including advances in care since the American Diabetes Association (ADA) last published a Position Statement on this topic in 2003 (3).”

“Hypertension is defined as a sustained blood pressure ≥140/90 mmHg. This definition is based on unambiguous data that levels above this threshold are strongly associated with ASCVD, death, disability, and microvascular complications (1,2,2427) and that antihypertensive treatment in populations with baseline blood pressure above this range reduces the risk of ASCVD events (46,28,29). The “sustained” aspect of the hypertension definition is important, as blood pressure has considerable normal variation. The criteria for diagnosing hypertension should be differentiated from blood pressure treatment targets.

Hypertension diagnosis and management can be complicated by two common conditions: masked hypertension and white-coat hypertension. Masked hypertension is defined as a normal blood pressure in the clinic or office (<140/90 mmHg) but an elevated home blood pressure of ≥135/85 mmHg (30); the lower home blood pressure threshold is based on outcome studies (31) demonstrating that lower home blood pressures correspond to higher office-based measurements. White-coat hypertension is elevated office blood pressure (≥140/90 mmHg) and normal (untreated) home blood pressure (<135/85 mmHg) (32). Identifying these conditions with home blood pressure monitoring can help prevent overtreatment of people with white-coat hypertension who are not at elevated risk of ASCVD and, in the case of masked hypertension, allow proper use of medications to reduce side effects during periods of normal pressure (33,34).”

“Diabetic autonomic neuropathy or volume depletion can cause orthostatic hypotension (35), which may be further exacerbated by antihypertensive medications. The definition of orthostatic hypotension is a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min of standing when compared with blood pressure from the sitting or supine position (36). Orthostatic hypotension is common in people with type 2 diabetes and hypertension and is associated with an increased risk of mortality and heart failure (37).

It is important to assess for symptoms of orthostatic hypotension to individualize blood pressure goals, select the most appropriate antihypertensive agents, and minimize adverse effects of antihypertensive therapy.”

“Taken together, […] meta-analyses consistently show that treating patients with baseline blood pressure ≥140 mmHg to targets <140 mmHg is beneficial, while more intensive targets may offer additional though probably less robust benefits. […] Overall, compared with people without diabetes, the relative benefits of antihypertensive treatment are similar, and absolute benefits may be greater (5,8,40). […] Multiple-drug therapy is often required to achieve blood pressure targets, particularly in the setting of diabetic kidney disease. However, the use of both ACE inhibitors and ARBs in combination is not recommended given the lack of added ASCVD benefit and increased rate of adverse events — namely, hyperkalemia, syncope, and acute kidney injury (7173). Titration of and/or addition of further blood pressure medications should be made in a timely fashion to overcome clinical inertia in achieving blood pressure targets. […] there is an absence of high-quality data available to guide blood pressure targets in type 1 diabetes. […] Of note, diastolic blood pressure, as opposed to systolic blood pressure, is a key variable predicting cardiovascular outcomes in people under age 50 years without diabetes and may be prioritized in younger adults (46,47). Though convincing data are lacking, younger adults with type 1 diabetes might more easily achieve intensive blood pressure levels and may derive substantial long-term benefit from tight blood pressure control.”

“Lifestyle management is an important component of hypertension treatment because it lowers blood pressure, enhances the effectiveness of some antihypertensive medications, promotes other aspects of metabolic and vascular health, and generally leads to few adverse effects. […] Lifestyle therapy consists of reducing excess body weight through caloric restriction, restricting sodium intake (<2,300 mg/day), increasing consumption of fruits and vegetables […] and low-fat dairy products […], avoiding excessive alcohol consumption […] (53), smoking cessation, reducing sedentary time (54), and increasing physical activity levels (55). These lifestyle strategies may also positively affect glycemic and lipid control and should be encouraged in those with even mildly elevated blood pressure.”

“Initial treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes: ACE inhibitors (65,66), angiotensin receptor blockers (ARBs) (65,66), thiazide-like diuretics (67), or dihydropyridine CCBs (68). For patients with albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g creatinine), initial treatment should include an ACE inhibitor or ARB in order to reduce the risk of progressive kidney disease […]. In the absence of albuminuria, risk of progressive kidney disease is low, and ACE inhibitors and ARBs have not been found to afford superior cardioprotection when compared with other antihypertensive agents (69). β-Blockers may be used for the treatment of coronary disease or heart failure but have not been shown to reduce mortality as blood pressure–lowering agents in the absence of these conditions (5,70).”

vi. High Illicit Drug Abuse and Suicide in Organ Donors With Type 1 Diabetes.

“Organ donors with type 1 diabetes represent a unique population for research. Through a combination of immunological, metabolic, and physiological analyses, researchers utilizing such tissues seek to understand the etiopathogenic events that result in this disorder. The Network for Pancreatic Organ Donors with Diabetes (nPOD) program collects, processes, and distributes pancreata and disease-relevant tissues to investigators throughout the world for this purpose (1). Information is also available, through medical records of organ donors, related to causes of death and psychological factors, including drug use and suicide, that impact life with type 1 diabetes.

We reviewed the terminal hospitalization records for the first 100 organ donors with type 1 diabetes in the nPOD database, noting cause, circumstance, and mechanism of death; laboratory results; and history of illicit drug use. Donors were 45% female and 79% Caucasian. Mean age at time of death was 28 years (range 4–61) with mean disease duration of 16 years (range 0.25–52).”

“Documented suicide was found in 8% of the donors, with an average age at death of 21 years and average diabetes duration of 9 years. […] Similarly, a type 1 diabetes registry from the U.K. found that 6% of subjects’ deaths were attributed to suicide (2). […] Additionally, we observed a high rate of illicit substance abuse: 32% of donors reported or tested positive for illegal substances (excluding marijuana), and multidrug use was common. Cocaine was the most frequently abused substance. Alcohol use was reported in 35% of subjects, with marijuana use in 27%. By comparison, 16% of deaths in the U.K. study were deemed related to drug misuse (2).”

“We fully recognize the implicit biases of an organ donor–based population, which may not be […’may not be’ – well, I guess that’s one way to put it! – US] directly comparable to the general population. Nevertheless, the high rate of suicide and drug use should continue to spur our energy and resources toward caring for the emotional and psychological needs of those living with type 1 diabetes. The burden of type 1 diabetes extends far beyond checking blood glucose and administering insulin.”

January 10, 2018 Posted by | Cardiology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Pharmacology, Psychiatry, Studies | Leave a comment

Random stuff

I have almost stopped posting posts like these, which has resulted in the accumulation of a very large number of links and studies which I figured I might like to blog at some point. This post is mainly an attempt to deal with the backlog – I won’t cover the material in too much detail.

i. Do Bullies Have More Sex? The answer seems to be a qualified yes. A few quotes:

“Sexual behavior during adolescence is fairly widespread in Western cultures (Zimmer-Gembeck and Helfland 2008) with nearly two thirds of youth having had sexual intercourse by the age of 19 (Finer and Philbin 2013). […] Bullying behavior may aid in intrasexual competition and intersexual selection as a strategy when competing for mates. In line with this contention, bullying has been linked to having a higher number of dating and sexual partners (Dane et al. 2017; Volk et al. 2015). This may be one reason why adolescence coincides with a peak in antisocial or aggressive behaviors, such as bullying (Volk et al. 2006). However, not all adolescents benefit from bullying. Instead, bullying may only benefit adolescents with certain personality traits who are willing and able to leverage bullying as a strategy for engaging in sexual behavior with opposite-sex peers. Therefore, we used two independent cross-sectional samples of older and younger adolescents to determine which personality traits, if any, are associated with leveraging bullying into opportunities for sexual behavior.”

“…bullying by males signal the ability to provide good genes, material resources, and protect offspring (Buss and Shackelford 1997; Volk et al. 2012) because bullying others is a way of displaying attractive qualities such as strength and dominance (Gallup et al. 2007; Reijntjes et al. 2013). As a result, this makes bullies attractive sexual partners to opposite-sex peers while simultaneously suppressing the sexual success of same-sex rivals (Gallup et al. 2011; Koh and Wong 2015; Zimmer-Gembeck et al. 2001). Females may denigrate other females, targeting their appearance and sexual promiscuity (Leenaars et al. 2008; Vaillancourt 2013), which are two qualities relating to male mate preferences. Consequently, derogating these qualities lowers a rivals’ appeal as a mate and also intimidates or coerces rivals into withdrawing from intrasexual competition (Campbell 2013; Dane et al. 2017; Fisher and Cox 2009; Vaillancourt 2013). Thus, males may use direct forms of bullying (e.g., physical, verbal) to facilitate intersexual selection (i.e., appear attractive to females), while females may use relational bullying to facilitate intrasexual competition, by making rivals appear less attractive to males.”

The study relies on the use of self-report data, which I find very problematic – so I won’t go into the results here. I’m not quite clear on how those studies mentioned in the discussion ‘have found self-report data [to be] valid under conditions of confidentiality’ – and I remain skeptical. You’ll usually want data from independent observers (e.g. teacher or peer observations) when analyzing these kinds of things. Note in the context of the self-report data problem that if there’s a strong stigma associated with being bullied (there often is, or bullying wouldn’t work as well), asking people if they have been bullied is not much better than asking people if they’re bullying others.

ii. Some topical advice that some people might soon regret not having followed, from the wonderful Things I Learn From My Patients thread:

“If you are a teenage boy experimenting with fireworks, do not empty the gunpowder from a dozen fireworks and try to mix it in your mother’s blender. But if you do decide to do that, don’t hold the lid down with your other hand and stand right over it. This will result in the traumatic amputation of several fingers, burned and skinned forearms, glass shrapnel in your face, and a couple of badly scratched corneas as a start. You will spend months in rehab and never be able to use your left hand again.”

iii. I haven’t talked about the AlphaZero-Stockfish match, but I was of course aware of it and did read a bit about that stuff. Here’s a reddit thread where one of the Stockfish programmers answers questions about the match. A few quotes:

“Which of the two is stronger under ideal conditions is, to me, neither particularly interesting (they are so different that it’s kind of like comparing the maximum speeds of a fish and a bird) nor particularly important (since there is only one of them that you and I can download and run anyway). What is super interesting is that we have two such radically different ways to create a computer chess playing entity with superhuman abilities. […] I don’t think there is anything to learn from AlphaZero that is applicable to Stockfish. They are just too different, you can’t transfer ideas from one to the other.”

“Based on the 100 games played, AlphaZero seems to be about 100 Elo points stronger under the conditions they used. The current development version of Stockfish is something like 40 Elo points stronger than the version used in Google’s experiment. There is a version of Stockfish translated to hand-written x86-64 assembly language that’s about 15 Elo points stronger still. This adds up to roughly half the Elo difference between AlphaZero and Stockfish shown in Google’s experiment.”

“It seems that Stockfish was playing with only 1 GB for transposition tables (the area of memory used to store data about the positions previously encountered in the search), which is way too little when running with 64 threads.” [I seem to recall a comp sci guy observing elsewhere that this was less than what was available to his smartphone version of Stockfish, but I didn’t bookmark that comment].

“The time control was a very artificial fixed 1 minute/move. That’s not how chess is traditionally played. Quite a lot of effort has gone into Stockfish’s time management. It’s pretty good at deciding when to move quickly, and when to spend a lot of time on a critical decision. In a fixed time per move game, it will often happen that the engine discovers that there is a problem with the move it wants to play just before the time is out. In a regular time control, it would then spend extra time analysing all alternative moves and trying to find a better one. When you force it to move after exactly one minute, it will play the move it already know is bad. There is no doubt that this will cause it to lose many games it would otherwise have drawn.”

iv. Thrombolytics for Acute Ischemic Stroke – no benefit found.

“Thrombolysis has been rigorously studied in >60,000 patients for acute thrombotic myocardial infarction, and is proven to reduce mortality. It is theorized that thrombolysis may similarly benefit ischemic stroke patients, though a much smaller number (8120) has been studied in relevant, large scale, high quality trials thus far. […] There are 12 such trials 1-12. Despite the temptation to pool these data the studies are clinically heterogeneous. […] Data from multiple trials must be clinically and statistically homogenous to be validly pooled.14 Large thrombolytic studies demonstrate wide variations in anatomic stroke regions, small- versus large-vessel occlusion, clinical severity, age, vital sign parameters, stroke scale scores, and times of administration. […] Examining each study individually is therefore, in our opinion, both more valid and more instructive. […] Two of twelve studies suggest a benefit […] In comparison, twice as many studies showed harm and these were stopped early. This early stoppage means that the number of subjects in studies demonstrating harm would have included over 2400 subjects based on originally intended enrollments. Pooled analyses are therefore missing these phantom data, which would have further eroded any aggregate benefits. In their absence, any pooled analysis is biased toward benefit. Despite this, there remain five times as many trials showing harm or no benefit (n=10) as those concluding benefit (n=2), and 6675 subjects in trials demonstrating no benefit compared to 1445 subjects in trials concluding benefit.”

“Thrombolytics for ischemic stroke may be harmful or beneficial. The answer remains elusive. We struggled therefore, debating between a ‘yellow’ or ‘red’ light for our recommendation. However, over 60,000 subjects in trials of thrombolytics for coronary thrombosis suggest a consistent beneficial effect across groups and subgroups, with no studies suggesting harm. This consistency was found despite a very small mortality benefit (2.5%), and a very narrow therapeutic window (1% major bleeding). In comparison, the variation in trial results of thrombolytics for stroke and the daunting but consistent adverse effect rate caused by ICH suggested to us that thrombolytics are dangerous unless further study exonerates their use.”

“There is a Cochrane review that pooled estimates of effect. 17 We do not endorse this choice because of clinical heterogeneity. However, we present the NNT’s from the pooled analysis for the reader’s benefit. The Cochrane review suggested a 6% reduction in disability […] with thrombolytics. This would mean that 17 were treated for every 1 avoiding an unfavorable outcome. The review also noted a 1% increase in mortality (1 in 100 patients die because of thrombolytics) and a 5% increase in nonfatal intracranial hemorrhage (1 in 20), for a total of 6% harmed (1 in 17 suffers death or brain hemorrhage).”

v. Suicide attempts in Asperger Syndrome. An interesting finding: “Over 35% of individuals with AS reported that they had attempted suicide in the past.”

Related: Suicidal ideation and suicide plans or attempts in adults with Asperger’s syndrome attending a specialist diagnostic clinic: a clinical cohort study.

“374 adults (256 men and 118 women) were diagnosed with Asperger’s syndrome in the study period. 243 (66%) of 367 respondents self-reported suicidal ideation, 127 (35%) of 365 respondents self-reported plans or attempts at suicide, and 116 (31%) of 368 respondents self-reported depression. Adults with Asperger’s syndrome were significantly more likely to report lifetime experience of suicidal ideation than were individuals from a general UK population sample (odds ratio 9·6 [95% CI 7·6–11·9], p<0·0001), people with one, two, or more medical illnesses (p<0·0001), or people with psychotic illness (p=0·019). […] Lifetime experience of depression (p=0·787), suicidal ideation (p=0·164), and suicide plans or attempts (p=0·06) did not differ significantly between men and women […] Individuals who reported suicide plans or attempts had significantly higher Autism Spectrum Quotient scores than those who did not […] Empathy Quotient scores and ages did not differ between individuals who did or did not report suicide plans or attempts (table 4). Patients with self-reported depression or suicidal ideation did not have significantly higher Autism Spectrum Quotient scores, Empathy Quotient scores, or age than did those without depression or suicidal ideation”.

The fact that people with Asperger’s are more likely to be depressed and contemplate suicide is consistent with previous observations that they’re also more likely to die from suicide – for example a paper I blogged a while back found that in that particular (large Swedish population-based cohort-) study, people with ASD were more than 7 times as likely to die from suicide than were the comparable controls.

Also related: Suicidal tendencies hard to spot in some people with autism.

This link has some great graphs and tables of suicide data from the US.

Also autism-related: Increased perception of loudness in autism. This is one of the ‘important ones’ for me personally – I am much more sound-sensitive than are most people.

vi. Early versus Delayed Invasive Intervention in Acute Coronary Syndromes.

“Earlier trials have shown that a routine invasive strategy improves outcomes in patients with acute coronary syndromes without ST-segment elevation. However, the optimal timing of such intervention remains uncertain. […] We randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography ≤24 hours after randomization) or delayed intervention (coronary angiography ≥36 hours after randomization). The primary outcome was a composite of death, myocardial infarction, or stroke at 6 months. A prespecified secondary outcome was death, myocardial infarction, or refractory ischemia at 6 months. […] Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients.”

vii. Some wikipedia links:

Behrens–Fisher problem.
Sailing ship tactics (I figured I had to read up on this if I were to get anything out of the Aubrey-Maturin books).
Anatomical terms of muscle.
Phatic expression (“a phatic expression […] is communication which serves a social function such as small talk and social pleasantries that don’t seek or offer any information of value.”)
Three-domain system.
Beringian wolf (featured).
Subdural hygroma.
Cayley graph.
Schur polynomial.
Solar neutrino problem.
Hadamard product (matrices).
True polar wander.
Newton’s cradle.

viii. Determinant versus permanent (mathematics – technical).

ix. Some years ago I wrote a few English-language posts about some of the various statistical/demographic properties of immigrants living in Denmark, based on numbers included in a publication by Statistics Denmark. I did it by translating the observations included in that publication, which was only published in Danish. I was briefly considering doing the same thing again when the 2017 data arrived, but I decided not to do it as I recalled that it took a lot of time to write those posts back then, and it didn’t seem to me to be worth the effort – but Danish readers might be interested to have a look at the data, if they haven’t already – here’s a link to the publication Indvandrere i Danmark 2017.

x. A banter blitz session with grandmaster Peter Svidler, who recently became the first Russian ever to win the Russian Chess Championship 8 times. He’s currently shared-second in the World Rapid Championship after 10 rounds and is now in the top 10 on the live rating list in both classical and rapid – seems like he’s had a very decent year.

xi. I recently discovered Dr. Whitecoat’s blog. The patient encounters are often interesting.

December 28, 2017 Posted by | Astronomy, autism, Biology, Cardiology, Chess, Computer science, History, Mathematics, Medicine, Neurology, Physics, Psychiatry, Psychology, Random stuff, Statistics, Studies, Wikipedia, Zoology | Leave a comment

Concussion and Sequelae of Minor Head Trauma

Some related links:

PECARN Pediatric Head Injury/Trauma Algorithm.
Canadian CT Head Injury/Trauma Rule.
ACEP – Traumatic Brain Injury (Mild – Adult).
AANS – concussion.
Guidelines for the Management of Severe Traumatic Brain Injury – 4th edition.
Return-to-play guidelines.
Second-impact syndrome.
Repetitive Head Injury Syndrome (medscape).
Traumatic Brain Injury & Concussion (CDC).

December 1, 2017 Posted by | Lectures, Medicine, Neurology | Leave a comment

A few diabetes papers of interest

i. Mechanisms and Management of Diabetic Painful Distal Symmetrical Polyneuropathy.

“Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all of these will require therapy. […] Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. […] All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment.”

“The neuropathies are the most common long-term microvascular complications of diabetes and affect those with both type 1 and type 2 diabetes, with up to 50% of older type 2 diabetic patients having evidence of a distal neuropathy (1). These neuropathies are characterized by a progressive loss of nerve fibers affecting both the autonomic and somatic divisions of the nervous system. The clinical features of the diabetic neuropathies vary immensely, and only a minority are associated with pain. The major portion of this review will be dedicated to the most common painful neuropathy, chronic sensorimotor distal symmetrical polyneuropathy (DSPN). This neuropathy has major detrimental effects on its sufferers, confirming an increased risk of foot ulceration and Charcot neuroarthropathy as well as being associated with increased mortality (1).

In addition to DSPN, other rarer neuropathies may also be associated with painful symptoms including acute painful neuropathy that often follows periods of unstable glycemic control, mononeuropathies (e.g., cranial nerve palsies), radiculopathies, and entrapment neuropathies (e.g., carpal tunnel syndrome). By far the most common presentation of diabetic polyneuropathy (over 90%) is typical DSPN or chronic DSPN. […] DSPN results in insensitivity of the feet that predisposes to foot ulceration (1) and/or neuropathic pain (painful DSPN), which can be disabling. […] The onset of DSPN is usually gradual or insidious and is heralded by sensory symptoms that start in the toes and then progress proximally to involve the feet and legs in a stocking distribution. When the disease is well established in the lower limbs in more severe cases, there is upper limb involvement, with a similar progression proximally starting in the fingers. As the disease advances further, motor manifestations, such as wasting of the small muscles of the hands and limb weakness, become apparent. In some cases, there may be sensory loss that the patient may not be aware of, and the first presentation may be a foot ulcer. Approximately 50% of patients with DSPN experience neuropathic symptoms in the lower limbs including uncomfortable tingling (dysesthesia), pain (burning; shooting or “electric-shock like”; lancinating or “knife-like”; “crawling”, or aching etc., in character), evoked pain (allodynia, hyperesthesia), or unusual sensations (such as a feeling of swelling of the feet or severe coldness of the legs when clearly the lower limbs look and feel fine, odd sensations on walking likened to “walking on pebbles” or “walking on hot sand,” etc.). There may be marked pain on walking that may limit exercise and lead to weight gain. Painful DSPN is characteristically more severe at night and often interferes with normal sleep (3). It also has a major impact on the ability to function normally (both mental and physical functioning, e.g., ability to maintain work, mood, and quality of life [QoL]) (3,4). […] The unremitting nature of the pain can be distressing, resulting in mood disorders including depression and anxiety (4). The natural history of painful DSPN has not been well studied […]. However, it is generally believed that painful symptoms may persist over the years (5), occasionally becoming less prominent as the sensory loss worsens (6).”

“There have been relatively few epidemiological studies that have specifically examined the prevalence of painful DSPN, which range from 10–26% (79). In a recent study of a large cohort of diabetic patients receiving community-based health care in northwest England (n = 15,692), painful DSPN assessed using neuropathy symptom and disability scores was found in 21% (7). In one population-based study from Liverpool, U.K., the prevalence of painful DSPN assessed by a structured questionnaire and examination was estimated at 16% (8). Notably, it was found that 12.5% of these patients had never reported their symptoms to their doctor and 39% had never received treatment for their pain (8), indicating that there may be considerable underdiagnosis and undertreatment of painful neuropathic symptoms compared with other aspects of diabetes management such as statin therapy and management of hypertension. Risk factors for DSPN per se have been extensively studied, and it is clear that apart from poor glycemic control, cardiovascular risk factors play a prominent role (10): risk factors for painful DSPN are less well known.”

“A broad spectrum of presentations may occur in patients with DSPN, ranging from one extreme of the patient with very severe painful symptoms but few signs, to the other when patients may present with a foot ulcer having lost all sensation without ever having any painful or uncomfortable symptoms […] it is well recognized that the severity of symptoms may not relate to the severity of the deficit on clinical examination (1). […] Because DSPN is a diagnosis of exclusion, a careful clinical history and a peripheral neurological and vascular examination of the lower limbs are essential to exclude other causes of neuropathic pain and leg/foot pain such as peripheral vascular disease, arthritis, malignancy, alcohol abuse, spinal canal stenosis, etc. […] Patients with asymmetrical symptoms and/or signs (such as loss of an ankle jerk in one leg only), rapid progression of symptoms, or predominance of motor symptoms and signs should be carefully assessed for other causes of the findings.”

“The fact that diabetes induces neuropathy and that in a proportion of patients this is accompanied by pain despite the loss of input and numbness, suggests that marked changes occur in the processes of pain signaling in the peripheral and central nervous system. Neuropathic pain is characterized by ongoing pain together with exaggerated responses to painful and nonpainful stimuli, hyperalgesia, and allodynia. […] the changes seen suggest altered peripheral signaling and central compensatory changes perhaps driven by the loss of input. […] Very clear evidence points to the key role of changes in ion channels as a consequence of nerve damage and their roles in the disordered activity and transduction in damaged and intact fibers (50). Sodium channels depolarize neurons and generate an action potential. Following damage to peripheral nerves, the normal distribution of these channels along a nerve is disrupted by the neuroma and “ectopic” activity results from the accumulation of sodium channels at or around the site of injury. Other changes in the distribution and levels of these channels are seen and impact upon the pattern of neuronal excitability in the nerve. Inherited pain disorders arise from mutated sodium channels […] and polymorphisms in this channel impact on the level of pain in patients, indicating that inherited differences in channel function might explain some of the variability in pain between patients with DSPN (53). […] Where sodium channels act to generate action potentials, potassium channels serve as the molecular brakes of excitable cells, playing an important role in modulating neuronal hyperexcitability. The drug retigabine, a potassium channel opener acting on the channel (KV7, M-current) opener, blunts behavioral hypersensitivity in neuropathic rats (56) and also inhibits C and Aδ-mediated responses in dorsal horn neurons in both naïve and neuropathic rats (57), but has yet to reach the clinic as an analgesic”.

and C fibers terminate primarily in the superficial laminae of the dorsal horn where the large majority of neurons are nociceptive specific […]. Some of these neurons gain low threshold inputs after neuropathy and these cells project predominantly to limbic brain areas […] spinal cord neurons provide parallel outputs to the affective and sensory areas of the brain. Changes induced in these neurons by repeated noxious inputs underpin central sensitization where the resultant hyperexcitability of neurons leads to greater responses to all subsequent inputs — innocuous and noxious — expanded receptive fields and enhanced outputs to higher levels of the brain […] As a consequence of these changes in the sending of nociceptive information within the peripheral nerve and then the spinal cord, the information sent to the brain becomes amplified so that pain ratings become higher. Alongside this, the persistent input into the limbic brain areas such as the amygdala are likely to be causal in the comorbidities that patients often report due to ongoing painful inputs disrupting normal function and generating fear, depression, and sleep problems […]. Of course, many patients report that their pains are worse at night, which may be due to nocturnal changes in these central pain processing areas. […] overall, the mechanisms of pain in diabetic neuropathy extend from altered channel function in peripheral nerves through enhanced spinal processing and finally to changes in many higher centers”.

Pharmacological treatment of painful DSPN is not entirely satisfactory because currently available drugs are often ineffective and complicated by adverse events. Tricyclic compounds (TCAs) have been used as first-line agents for many years, but their use is limited by frequent side effects that may be central or anticholinergic, including dry mouth, constipation, sweating, blurred vision, sedation, and orthostatic hypotension (with the risk of falls particularly in elderly patients). […] Higher doses have been associated with an increased risk of sudden cardiac death, and caution should be taken in any patient with a history of cardiovascular disease (65). […] The selective serotonin noradrenalin reuptake inhibitors (SNRI) duloxetine and venlafaxine have been used for the management of painful DSPN (65). […] there have been several clinical trials involving pregabalin in painful DSPN, and these showed clear efficacy in management of painful DSPN (69). […] The side effects include dizziness, somnolence, peripheral edema, headache, and weight gain.”

A major deficiency in the area of the treatment of neuropathic pain in diabetes is the relative lack of comparative or combination studies. Virtually all previous trials have been of active agents against placebo, whereas there is a need for more studies that compare a given drug with an active comparator and indeed lower-dose combination treatments (64). […] The European Federation of Neurological Societies proposed that first-line treatments might comprise of TCAs, SNRIs, gabapentin, or pregabalin (71). The U.K. National Institute for Health and Care Excellence guidelines on the management of neuropathic pain in nonspecialist settings proposed that duloxetine should be the first-line treatment with amitriptyline as an alternative, and pregabalin as a second-line treatment for painful DSPN (72). […] this recommendation of duloxetine as the first-line therapy was not based on efficacy but rather cost-effectiveness. More recently, the American Academy of Neurology recommended that pregabalin is “established as effective and should be offered for relief of [painful DSPN] (Level A evidence)” (73), whereas venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids, and capsaicin were considered to be “probably effective and should be considered for treatment of painful DSPN (Level B evidence)” (63). […] this recommendation was primarily based on achievement of greater than 80% completion rate of clinical trials, which in turn may be influenced by the length of the trials. […] the International Consensus Panel on Diabetic Neuropathy recommended TCAs, duloxetine, pregabalin, and gabapentin as first-line agents having carefully reviewed all the available literature regarding the pharmacological treatment of painful DSPN (65), the final drug choice tailored to the particular patient based on demographic profile and comorbidities. […] The initial selection of a particular first-line treatment will be influenced by the assessment of contraindications, evaluation of comorbidities […], and cost (65). […] caution is advised to start at lower than recommended doses and titrate gradually.”

ii. Sex Differences in All-Cause and Cardiovascular Mortality, Hospitalization for Individuals With and Without Diabetes, and Patients With Diabetes Diagnosed Early and Late.

“A challenge with type 2 diabetes is the late diagnosis of the disease because many individuals who meet the criteria are often asymptomatic. Approximately 183 million people, or half of those who have diabetes, are unaware they have the disease (1). Furthermore, type 2 diabetes can be present for 9 to 12 years before being diagnosed and, as a result, complications are often present at the time of diagnosis (3). […] Cardiovascular disease (CVD) is the most common comorbidity associated with diabetes, and with 50% of those with diabetes dying of CVD it is the most common cause of death (1). […] Newfoundland and Labrador has the highest age-standardized prevalence of diabetes in Canada (2), and the age-standardized mortality and hospitalization rates for CVD, AMI, and stroke are some of the highest in the country (21,22). A better understanding of mortality and hospitalizations associated with diabetes for males and females is important to support diabetes prevention and management. Therefore, the objectives of this study were to compare the risk of all-cause, CVD, AMI, and stroke mortality and hospitalizations for males and females with and without diabetes and those with early and late diagnoses of diabetes. […] We conducted a population-based retrospective cohort study including 73,783 individuals aged 25 years or older in Newfoundland and Labrador, Canada (15,152 with diabetes; 9,517 with late diagnoses). […] mean age at baseline was 60.1 years (SD, 14.3 years). […] Diabetes was classified as being diagnosed “early” and “late” depending on when diabetes-related comorbidities developed. Individuals early in the disease course would not have any diabetes-related comorbidities at the time of their case dates. On the contrary, a late-diagnosed diabetes patient would have comorbidities related to diabetes at the time of diagnosis.”

“For males, 20.5% (n = 7,751) had diabetes, whereas 20.6% (n = 7,401) of females had diabetes. […] Males and females with diabetes were more likely to die, to be younger at death, to have a shorter survival time, and to be admitted to the hospital than males and females without diabetes (P < 0.01). When admitted to the hospital, individuals with diabetes stayed longer than individuals without diabetes […] Both males and females with late diagnoses were significantly older at the time of diagnosis than those with early diagnoses […]. Males and females with late diagnoses of diabetes were more likely to be deceased at the end of the study period compared with those with early diagnoses […]. Those with early diagnoses were younger at death compared with those with late diagnoses (P < 0.01); however, median survival time for both males and females with early diagnoses was significantly longer than that of those with late diagnoses (P < 0.01). During the study period, males and females with late diabetes diagnoses were more likely to be hospitalized (P < 0.01) and have a longer length of hospital stay compared with those with early diagnoses (P < 0.01).”

“[T]he hospitalization results show that an early diagnosis […] increase the risk of all-cause, CVD, and AMI hospitalizations compared with individuals without diabetes. After adjusting for covariates, males with late diabetes diagnoses had an increased risk of all-cause and CVD mortality and hospitalizations compared with males without diabetes. Similar findings were found for females. A late diabetes diagnosis was positively associated with CVD mortality (HR 6.54 [95% CI 4.80–8.91]) and CVD hospitalizations (5.22 [4.31–6.33]) for females, and the risk was significantly higher compared with their male counterparts (3.44 [2.47–4.79] and 3.33 [2.80–3.95]).”

iii. Effect of Type 1 Diabetes on Carotid Structure and Function in Adolescents and Young Adults.

I may have discussed some of the results of this study before, but a search of the blog told me that I have not covered the study itself. I thought it couldn’t hurt to add a link and a few highlights here.

“Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes. […] Participants with type 1 diabetes (N = 402) were matched to controls (N = 206) by age, sex, and race or ethnicity. Anthropometric and laboratory values, blood pressure, and IMT were measured.”

“Youth with type 1 diabetes had thicker bulb IMT, which remained significantly different after adjustment for demographics and cardiovascular risk factors. […] Because the rate of progression of IMT in healthy subjects (mean age, 40 years) in the Bogalusa Heart study was 0.017–0.020 mm/year (4), our difference of 0.016 mm suggests that our type 1 diabetic subjects had a vascular age 1 year advanced from their chronological age. […] adjustment for HbA1c ablated the case-control difference in IMT, suggesting that the thicker carotid IMT in the subjects with diabetes could be attributed to diabetes-related hyperglycemia.”

“In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, progression of IMT over the course of 6 years was faster in subjects with type 1 diabetes, yielding a thicker final IMT in cases (5). There was no difference in IMT at baseline. However, DCCT/EDIC did not image the bulb, which is likely the earliest site of thickening according to the Bogalusa Heart Study […] Our analyses reinforce the importance of imaging the carotid bulb, often the site of earliest detectible subclinical atherosclerosis in youth. The DCCT/EDIC study demonstrated that the intensive treatment group had a slower progression of IMT (5) and that mean HbA1c levels explained most of the differences in IMT progression between treatment groups (12). One longitudinal study of youth found children with type 1 diabetes who had progression of IMT over the course of 2 years had higher HbA1c (13). Our data emphasize the role of diabetes-related hyperglycemia in increasing IMT in youth with type 1 diabetes. […] In summary, our study provides novel evidence that carotid thickness is increased in youth with type 1 diabetes compared with healthy controls and that this difference is not accounted for by traditional cardiovascular risk factors. Better control of diabetes-related hyperglycemia may be needed to reduce future cardiovascular disease.”

iv. Factors Associated With Microalbuminuria in 7,549 Children and Adolescents With Type 1 Diabetes in the T1D Exchange Clinic Registry.

“Elevated urinary albumin excretion is an early sign of diabetic kidney disease (DKD). The American Diabetes Association (ADA) recommends screening for microalbuminuria (MA) annually in people with type 1 diabetes after 10 years of age and 5 years of diabetes duration, with a diagnosis of MA requiring two of three tests to be abnormal (1). Early diagnosis of MA is important because effective treatments exist to limit the progression of DKD (1). However, although reduced rates of MA have been reported over the past few decades in some (24) but not all (5,6) studies, it has been suggested that the development of proteinuria has not been prevented but, rather, has been delayed by ∼10 years and that further improvements in care are needed (7).

Limited data exist on the frequency of a clinical diagnosis of MA in the pediatric population with type 1 diabetes in the U.S. Our aim was to use the data from the T1D Exchange clinic registry to assess factors associated with MA in 7,549 children and adolescents with type 1 diabetes.”

“The analysis cohort included 7,549 participants, with mean age of 13.8 ± 3.5 years (range 2 to 19), mean age at type 1 diabetes onset of 6.9 ± 3.9 years, and mean diabetes duration of 6.5 ± 3.7 years; 49% were female. The racial/ethnic distribution was 78% non-Hispanic white, 6% non-Hispanic black, 10% Hispanic, and 5% other. The average of all HbA1c levels (for up to the past 13 years) was 8.4 ± 1.3% (69 ± 13.7 mmol/mol) […]. MA was present in 329 of 7,549 (4.4%) participants, with a higher frequency associated with longer diabetes duration, higher mean glycosylated hemoglobin (HbA1c) level, older age, female sex, higher diastolic blood pressure (BP), and lower BMI […] increasing age [was] mainly associated with an increase in the frequency of MA when HbA1c was ≥9.5% (≥80 mmol/mol). […] MA was uncommon (<2%) among participants with HbA1c <7.5% (<58 mmol/mol). Of those with MA, only 36% were receiving ACEI/ARB treatment. […] Our results provide strong support for prior literature in emphasizing the importance of good glycemic and BP control, particularly as diabetes duration increases, in order to reduce the risk of DKD.

v. Secular Changes in the Age-Specific Prevalence of Diabetes Among U.S. Adults: 1988–2010.

“This study included 22,586 adults sampled in three periods of the National Health and Nutrition Examination Survey (1988–1994, 1999–2004, and 2005–2010). Diabetes was defined as having self-reported diagnosed diabetes or having a fasting plasma glucose level ≥126 mg/dL or HbA1c ≥6.5% (48 mmol/mol). […] The number of adults with diabetes increased by 75% from 1988–1994 to 2005–2010. After adjusting for sex, race/ethnicity, and education level, the prevalence of diabetes increased over the two decades across all age-groups. Younger adults (20–34 years of age) had the lowest absolute increase in diabetes prevalence of 1.0%, followed by middle-aged adults (35–64) at 2.7% and older adults (≥65) at 10.0% (all P < 0.001). Comparing 2005–2010 with 1988–1994, the adjusted prevalence ratios (PRs) by age-group were 2.3, 1.3, and 1.5 for younger, middle-aged, and older adults, respectively (all P < 0.05). After additional adjustment for body mass index (BMI), waist-to-height ratio (WHtR), or waist circumference (WC), the adjusted PR remained statistically significant only for adults ≥65 years of age.

CONCLUSIONS During the past two decades, the prevalence of diabetes increased across all age-groups, but adults ≥65 years of age experienced the largest increase in absolute change. Obesity, as measured by BMI, WHtR, or WC, was strongly associated with the increase in diabetes prevalence, especially in adults <65.”

The crude prevalence of diabetes changed from 8.4% (95% CI 7.7–9.1%) in 1988–1994 to 12.1% (11.3–13.1%) in 2005–2010, with a relative increase of 44.8% (28.3–61.3%) between the two survey periods. There was less change of prevalence of undiagnosed diabetes (P = 0.053). […] The estimated number (in millions) of adults with diabetes grew from 14.9 (95% CI 13.3–16.4) in 1988–1994 to 26.1 (23.8–28.3) in 2005–2010, resulting in an increase of 11.2 prevalent cases (a 75.5% [52.1–98.9%] increase). Younger adults contributed 5.5% (2.5–8.4%), middle-aged adults contributed 52.9% (43.4–62.3%), and older adults contributed 41.7% (31.9–51.4%) of the increased number of cases. In each survey time period, the number of adults with diabetes increased with age until ∼60–69 years; thereafter, it decreased […] the largest increase of cases occurred in middle-aged and older adults.”

vi. The Expression of Inflammatory Genes Is Upregulated in Peripheral Blood of Patients With Type 1 Diabetes.

“Although much effort has been devoted toward discoveries with respect to gene expression profiling in human T1D in the last decade (15), previous studies had serious limitations. Microarray-based gene expression profiling is a powerful discovery platform, but the results must be validated by an alternative technique such as real-time RT-PCR. Unfortunately, few of the previous microarray studies on T1D have been followed by a validation study. Furthermore, most previous gene expression studies had small sample sizes (<100 subjects in each group) that are not adequate for the human population given the expectation of large expression variations among individual subjects. Finally, the selection of appropriate reference genes for normalization of quantitative real-time PCR has a major impact on data quality. Most of the previous studies have used only a single reference gene for normalization. Ideally, gene transcription studies using real-time PCR should begin with the selection of an appropriate set of reference genes to obtain more reliable results (68).

We have previously carried out extensive microarray analysis and identified >100 genes with significantly differential expression between T1D patients and control subjects. Most of these genes have important immunological functions and were found to be upregulated in autoantibody-positive subjects, suggesting their potential use as predictive markers and involvement in T1D development (2). In this study, real-time RT-PCR was performed to validate a subset of the differentially expressed genes in a large sample set of 928 T1D patients and 922 control subjects. In addition to the verification of the gene expression associated with T1D, we also identified genes with significant expression changes in T1D patients with diabetes complications.

“Of the 18 genes analyzed here, eight genes […] had higher expression and three genes […] had lower expression in T1D patients compared with control subjects, indicating that genes involved in inflammation, immune regulation, and antigen processing and presentation are significantly altered in PBMCs from T1D patients. Furthermore, one adhesion molecule […] and three inflammatory genes mainly expressed by myeloid cells […] were significantly higher in T1D patients with complications (odds ratio [OR] 1.3–2.6, adjusted P value = 0.005–10−8), especially those patients with neuropathy (OR 4.8–7.9, adjusted P value <0.005). […] These findings suggest that inflammatory mediators secreted mainly by myeloid cells are implicated in T1D and its complications.

vii. Overexpression of Hemopexin in the Diabetic Eye – A new pathogenic candidate for diabetic macular edema.

“Diabetic retinopathy remains the leading cause of preventable blindness among working-age individuals in developed countries (1). Whereas proliferative diabetic retinopathy (PDR) is the commonest sight-threatening lesion in type 1 diabetes, diabetic macular edema (DME) is the primary cause of poor visual acuity in type 2 diabetes. Because of the high prevalence of type 2 diabetes, DME is the main cause of visual impairment in diabetic patients (2). When clinically significant DME appears, laser photocoagulation is currently indicated. However, the optimal period of laser treatment is frequently passed and, moreover, is not uniformly successful in halting visual decline. In addition, photocoagulation is not without side effects, with visual field loss and impairment of either adaptation or color vision being the most frequent. Intravitreal corticosteroids have been successfully used in eyes with persistent DME and loss of vision after the failure of conventional treatment. However, reinjections are commonly needed, and there are substantial adverse effects such as infection, glaucoma, and cataract formation. Intravitreal anti–vascular endothelial growth factor (VEGF) agents have also found an improvement of visual acuity and decrease of retinal thickness in DME, even in nonresponders to conventional treatment (3). However, apart from local side effects such as endophthalmitis and retinal detachment, the response to treatment of DME by VEGF blockade is not prolonged and is subject to significant variability. For all these reasons, new pharmacological treatments based on the understanding of the pathophysiological mechanisms of DME are needed.”

“Vascular leakage due to the breakdown of the blood-retinal barrier (BRB) is the main event involved in the pathogenesis of DME (4). However, little is known regarding the molecules primarily involved in this event. By means of a proteomic analysis, we have found that hemopexin was significantly increased in the vitreous fluid of patients with DME in comparison with PDR and nondiabetic control subjects (5). Hemopexin is the best characterized permeability factor in steroid-sensitive nephrotic syndrome (6,7). […] T cell–associated cytokines like tumor necrosis factor-α are able to enhance hemopexin production in mesangial cells in vitro, and this effect is prevented by corticosteroids (8). However, whether hemopexin also acts as a permeability factor in the BRB and its potential response to corticosteroids remains to be elucidated. […] the aims of the current study were 1) to compare hemopexin and hemopexin receptor (LDL receptor–related protein [LRP1]) levels in retina and in vitreous fluid from diabetic and nondiabetic patients, 2) to evaluate the effect of hemopexin on the permeability of outer and inner BRB in cell cultures, and 3) to determine whether anti-hemopexin antibodies and dexamethasone were able to prevent an eventual hemopexin-induced hyperpermeability.”

“In the current study, we […] confirmed our previous results obtained by a proteomic approach showing that hemopexin is higher in the vitreous fluid of diabetic patients with DME in comparison with diabetic patients with PDR and nondiabetic subjects. In addition, we provide the first evidence that hemopexin is overexpressed in diabetic eye. Furthermore, we have shown that hemopexin leads to the disruption of RPE [retinal pigment epithelium] cells, thus increasing permeability, and that this effect is prevented by dexamethasone. […] Our findings suggest that hemopexin can be considered a new candidate in the pathogenesis of DME and a new therapeutic target.”

viii. Relationship Between Overweight and Obesity With Hospitalization for Heart Failure in 20,985 Patients With Type 1 Diabetes.

“We studied patients with type 1 diabetes included in the Swedish National Diabetes Registry during 1998–2003, and they were followed up until hospitalization for HF, death, or 31 December 2009. Cox regression was used to estimate relative risks. […] Type 1 diabetes is defined in the NDR as receiving treatment with insulin only and onset at age 30 years or younger. These characteristics previously have been validated as accurate in 97% of cases (11). […] In a sample of 20,985 type 1 diabetic patients (mean age, 38.6 years; mean BMI, 25.0 kg/m2), 635 patients […] (3%) were admitted for a primary or secondary diagnosis of HF during a median follow-up of 9 years, with an incidence of 3.38 events per 1,000 patient-years (95% CI, 3.12–3.65). […] Cox regression adjusting for age, sex, diabetes duration, smoking, HbA1c, systolic and diastolic blood pressures, and baseline and intercurrent comorbidities (including myocardial infarction) showed a significant relationship between BMI and hospitalization for HF (P < 0.0001). In reference to patients in the BMI 20–25 kg/m2 category, hazard ratios (HRs) were as follows: HR 1.22 (95% CI, 0.83–1.78) for BMI <20 kg/m2; HR 0.94 (95% CI, 0.78–1.12) for BMI 25–30 kg/m2; HR 1.55 (95% CI, 1.20–1.99) for BMI 30–35 kg/m2; and HR 2.90 (95% CI, 1.92–4.37) for BMI ≥35 kg/m2.

CONCLUSIONS Obesity, particularly severe obesity, is strongly associated with hospitalization for HF in patients with type 1 diabetes, whereas no similar relation was present in overweight and low body weight.”

“In contrast to type 2 diabetes, obesity is not implicated as a causal factor in type 1 diabetes and maintaining normal weight is accordingly less of a focus in clinical practice of patients with type 1 diabetes. Because most patients with type 2 diabetes are overweight or obese and glucose levels can normalize in some patients after weight reduction, this is usually an important part of integrated diabetes care. Our findings indicate that given the substantial risk of cardiovascular disease in type 1 diabetic patients, it is crucial for clinicians to also address weight issues in type 1 diabetes. Because many patients are normal weight when diabetes is diagnosed, careful monitoring of weight with a view to maintaining normal weight is probably more essential than previously thought. Although overweight was not associated with an increased risk of HF, higher BMI levels probably increase the risk of future obesity. Our finding that 71% of patients with BMI >35 kg/m2 were women is potentially important, although this should be tested in other populations given that it could be a random finding. If not random, especially because the proportion was much higher than in the entire cohort (45%), then it may indicate that severe obesity is a greater problem in women than in men with type 1 diabetes.”

November 30, 2017 Posted by | Cardiology, Diabetes, Genetics, Molecular biology, Nephrology, Neurology, Ophthalmology, Pharmacology, Studies | Leave a comment

A few diabetes papers of interest

i. Thirty Years of Research on the Dawn Phenomenon: Lessons to Optimize Blood Glucose Control in Diabetes.

“More than 30 years ago in Diabetes Care, Schmidt et al. (1) defined “dawn phenomenon,” the night-to-morning elevation of blood glucose (BG) before and, to a larger extent, after breakfast in subjects with type 1 diabetes (T1D). Shortly after, a similar observation was made in type 2 diabetes (T2D) (2), and the physiology of glucose homeostasis at night was studied in normal, nondiabetic subjects (35). Ever since the first description, the dawn phenomenon has been studied extensively with at least 187 articles published as of today (6). […] what have we learned from the last 30 years of research on the dawn phenomenon? What is the appropriate definition, the identified mechanism(s), the importance (if any), and the treatment of the dawn phenomenon in T1D and T2D?”

“Physiology of glucose homeostasis in normal, nondiabetic subjects indicates that BG and plasma insulin concentrations remain remarkably flat and constant overnight, with a modest, transient increase in insulin secretion just before dawn (3,4) to restrain hepatic glucose production (4) and prevent hyperglycemia. Thus, normal subjects do not exhibit the dawn phenomenon sensu strictiori because they secrete insulin to prevent it.

In T1D, the magnitude of BG elevation at dawn first reported was impressive and largely secondary to the decrease of plasma insulin concentration overnight (1), commonly observed with evening administration of NPH or lente insulins (8) (Fig. 1). Even in early studies with intravenous insulin by the “artificial pancreas” (Biostator) (2), plasma insulin decreased overnight because of progressive inactivation of insulin in the pump (9). This artifact exaggerated the dawn phenomenon, now defined as need for insulin to limit fasting hyperglycemia (2). When the overnight waning of insulin was prevented by continuous subcutaneous insulin infusion (CSII) […] or by the long-acting insulin analogs (LA-IAs) (8), it was possible to quantify the real magnitude of the dawn phenomenon — 15–25 mg/dL BG elevation from nocturnal nadir to before breakfast […]. Nocturnal spikes of growth hormone secretion are the most likely mechanism of the dawn phenomenon in T1D (13,14). The observation from early pioneering studies in T1D (1012) that insulin sensitivity is higher after midnight until 3 a.m. as compared to the period 4–8 a.m., soon translated into use of more physiological replacement of basal insulin […] to reduce risk of nocturnal hypoglycemia while targeting fasting near-normoglycemia”.

“In T2D, identification of diurnal changes in BG goes back decades, but only quite recently fasting hyperglycemia has been attributed to a transient increase in hepatic glucose production (both glycogenolysis and gluconeogenesis) at dawn in the absence of compensatory insulin secretion (1517). Monnier et al. (7) report on the overnight (interstitial) glucose concentration (IG), as measured by continuous ambulatory IG monitoring, in three groups of 248 subjects with T2D […] Importantly, the dawn phenomenon had an impact on mean daily IG and A1C (mean increase of 0.39% [4.3 mmol/mol]), which was independent of treatment. […] Two messages from the data of Monnier et al. (7) are important. First, the dawn phenomenon is confirmed as a frequent event across the heterogeneous population of T2D independent of (oral) treatment and studied in everyday life conditions, not only in the setting of specialized clinical research units. Second, the article reaffirms that the primary target of treatment in T2D is to reestablish near-normoglycemia before and after breakfast (i.e., to treat the dawn phenomenon) to lower mean daily BG and A1C (8). […] the dawn phenomenon induces hyperglycemia not only before, but, to a larger extent, after breakfast as well (7,18). Over the years, fasting (and postbreakfast) hyperglycemia in T2D worsens as result of progressively impaired pancreatic B-cell function on the background of continued insulin resistance primarily at dawn (8,1518) and independently of age (19). Because it is an early metabolic abnormality leading over time to the vicious circle of “hyperglycemia begets hyperglycemia” by glucotoxicity and lipotoxicity, the dawn phenomenon in T2D should be treated early and appropriately before A1C continues to increase (20).”

“Oral medications do not adequately control the dawn phenomenon, even when given in combination (7,18). […] The evening replacement of basal insulin, which abolishes the dawn phenomenon by restraining hepatic glucose production and lipolysis (21), is an effective treatment as it mimics the physiology of glucose homeostasis in normal, nondiabetic subjects (4). Early use of basal insulin in T2D is an add-on option treatment after failure of metformin to control A1C <7.0% (20). However, […] it would be wise to consider initiation of basal insulin […] before — not after — A1C has increased well beyond 7.0%, as usually it is done in practice currently.”

ii. Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-up Cohort.

“Diabetic peripheral neuropathy (DPN) is among the most distressing of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life (4). Depending on the patient population and diagnostic criteria, the prevalence of DPN among adults with diabetes ranges from 30 to 70% (57). However, there are insufficient data on the prevalence and predictors of DPN among the pediatric population. Furthermore, early detection and good glycemic control have been proven to prevent or delay adverse outcomes associated with DPN (5,8,9). Near-normal control of blood glucose beginning as soon as possible after the onset of diabetes may delay the development of clinically significant nerve impairment (8,9). […] The American Diabetes Association (ADA) recommends screening for DPN in children and adolescents with type 2 diabetes at diagnosis and 5 years after diagnosis for those with type 1 diabetes, followed by annual evaluations thereafter, using simple clinical tests (10). Since subclinical signs of DPN may precede development of frank neuropathic symptoms, systematic, preemptive screening is required in order to identify DPN in its earliest stages.

There are various measures that can be used for the assessment of DPN. The Michigan Neuropathy Screening Instrument (MNSI) is a simple, sensitive, and specific tool for the screening of DPN (11). It was validated in large independent cohorts (12,13) and has been widely used in clinical trials and longitudinal cohort studies […] The aim of this pilot study was to provide preliminary estimates of the prevalence of and factors associated with DPN among children and adolescents with type 1 and type 2 diabetes.”

“A total of 399 youth (329 with type 1 and 70 with type 2 diabetes) participated in the pilot study. Youth with type 1 diabetes were younger (mean age 15.7 ± 4.3 years) and had a shorter duration of diabetes (mean duration 6.2 ± 0.9 years) compared with youth with type 2 diabetes (mean age 21.6 ± 4.1 years and mean duration 7.6 ± 1.8 years). Participants with type 2 diabetes had a higher BMI z score and waist circumference, were more likely to be smokers, and had higher blood pressure and lipid levels than youth with type 1 diabetes (all P < 0.001). A1C, however, did not significantly differ between the two groups (mean A1C 8.8 ± 1.8% [73 ± 2 mmol/mol] for type 1 diabetes and 8.5 ± 2.9% [72 ± 3 mmol/mol] for type 2 diabetes; P = 0.5) but was higher than that recommended by the ADA for this age-group (A1C ≤7.5%) (10). The prevalence of DPN (defined as the MNSIE score >2) was 8.2% among youth with type 1 diabetes and 25.7% among those with type 2 diabetes. […] Youth with DPN were older and had a longer duration of diabetes, greater central obesity (increased waist circumference), higher blood pressure, an atherogenic lipid profile (low HDL cholesterol and marginally high triglycerides), and microalbuminuria. A1C […] was not significantly different between those with and without DPN (9.0% ± 2.0 […] vs. 8.8% ± 2.1 […], P = 0.58). Although nearly 37% of youth with type 2 diabetes came from lower-income families with annual income <25,000 USD per annum (as opposed to 11% for type 1 diabetes), socioeconomic status was not significantly associated with DPN (P = 0.77).”

“In the unadjusted logistic regression model, the odds of having DPN was nearly four times higher among those with type 2 diabetes compared with youth with type 1 diabetes (odds ratio [OR] 3.8 [95% CI 1.9–7.5, P < 0.0001). This association was attenuated, but remained significant, after adjustment for age and sex (OR 2.3 [95% CI 1.1–5.0], P = 0.03). However, this association was no longer significant (OR 2.1 [95% CI 0.3–15.9], P = 0.47) when additional covariates […] were added to the model […] The loss of the association between diabetes type and DPN with addition of covariates in the fully adjusted model could be due to power loss, given the small number of youth with DPN in the sample, or indicative of stronger associations between these covariates and DPN such that conditioning on them eliminates the observed association between DPN and diabetes type.”

“The prevalence of DPN among type 1 diabetes youth in our pilot study is lower than that reported by Eppens et al. (15) among 1,433 Australian adolescents with type 1 diabetes assessed by thermal threshold testing and VPT (prevalence of DPN 27%; median age and duration 15.7 and 6.8 years, respectively). A much higher prevalence was also reported among Danish (62.5%) and Brazilian (46%) cohorts of type 1 diabetes youth (16,17) despite a younger age (mean age among Danish children 13.7 years and Brazilian cohort 12.9 years). The prevalence of DPN among youth with type 2 diabetes (26%) found in our study is comparable to that reported among the Australian cohort (21%) (15). The wide ranges in the prevalence estimates of DPN among the young cannot solely be attributed to the inherent racial/ethnic differences in this population but could potentially be due to the differing criteria and diagnostic tests used to define and characterize DPN.”

“In our study, the duration of diabetes was significantly longer among those with DPN, but A1C values did not differ significantly between the two groups, suggesting that a longer duration with its sustained impact on peripheral nerves is an important determinant of DPN. […] Cho et al. (22) reported an increase in the prevalence of DPN from 14 to 28% over 17 years among 819 Australian adolescents with type 1 diabetes aged 11–17 years at baseline, despite improvements in care and minor improvements in A1C (8.2–8.7%). The prospective Danish Study Group of Diabetes in Childhood also found no association between DPN (assessed by VPT) and glycemic control (23).”

“In conclusion, our pilot study found evidence that the prevalence of DPN in adolescents with type 2 diabetes approaches rates reported in adults with diabetes. Several CVD risk factors such as central obesity, elevated blood pressure, dyslipidemia, and microalbuminuria, previously identified as predictors of DPN among adults with diabetes, emerged as independent predictors of DPN in this young cohort and likely accounted for the increased prevalence of DPN in youth with type 2 diabetes.

iii. Disturbed Eating Behavior and Omission of Insulin in Adolescents Receiving Intensified Insulin Treatment.

“Type 1 diabetes appears to be a risk factor for the development of disturbed eating behavior (DEB) (1,2). Estimates of the prevalence of DEB among individuals with type 1 diabetes range from 10 to 49% (3,4), depending on methodological issues such as the definition and measurement of DEB. Some studies only report the prevalence of full-threshold diagnoses of anorexia nervosa, bulimia nervosa, and eating disorders not otherwise specified, whereas others also include subclinical eating disorders (1). […] Although different terminology complicates the interpretation of prevalence rates across studies, the findings are sufficiently robust to indicate that there is a higher prevalence of DEB in type 1 diabetes compared with healthy controls. A meta-analysis reported a three-fold increase of bulimia nervosa, a two-fold increase of eating disorders not otherwise specified, and a two-fold increase of subclinical eating disorders in patients with type 1 diabetes compared with controls (2). No elevated rates of anorexia nervosa were found.”

“When DEB and type 1 diabetes co-occur, rates of morbidity and mortality are dramatically increased. A Danish study of comorbid type 1 diabetes and anorexia nervosa showed that the crude mortality rate at 10-year follow-up was 2.5% for type 1 diabetes and 6.5% for anorexia nervosa, but the rate increased to 34.8% when occurring together (the standardized mortality rates were 4.06, 8.86, and 14.5, respectively) (9). The presence of DEB in general also can severely impair metabolic control and advance the onset of long-term diabetes complications (4). Insulin reduction or omission is an efficient weight loss strategy uniquely available to patients with type 1 diabetes and has been reported in up to 37% of patients (1012). Insulin restriction is associated with poorer metabolic control, and previous research has found that self-reported insulin restriction at baseline leads to a three-fold increased risk of mortality at 11-year follow-up (10).

Few population-based studies have specifically investigated the prevalence of and relationship between DEBs and insulin restriction. The generalizability of existing research remains limited by relatively small samples and a lack of males. Further, many studies have relied on generic measures of DEBs, which may not be appropriate for use in individuals with type 1 diabetes. The Diabetes Eating Problem Survey–Revised (DEPS-R) is a newly developed and diabetes-specific screening tool for DEBs. A recent study demonstrated satisfactory psychometric properties of the Norwegian version of the DEPS-R among children and adolescents with type 1 diabetes 11–19 years of age (13). […] This study aimed to assess young patients with type 1 diabetes to assess the prevalence of DEBs and frequency of insulin omission or restriction, to compare the prevalence of DEB between males and females across different categories of weight and age, and to compare the clinical features of participants with and without DEBs and participants who restrict and do not restrict insulin. […] The final sample consisted of 770 […] children and adolescents with type 1 diabetes 11–19 years of age. There were 380 (49.4%) males and 390 (50.6%) females.”

27.7% of female and 9% of male children and adolescents with type 1 diabetes receiving intensified insulin treatment scored above the predetermined cutoff on the DEPS-R, suggesting a level of disturbed eating that warrants further attention by treatment providers. […] Significant differences emerged across age and weight categories, and notable sex-specific trends were observed. […] For the youngest (11–13 years) and underweight (BMI <18.5) categories, the proportion of DEB was <10% for both sexes […]. Among females, the prevalence of DEB increased dramatically with age to ∼33% among 14 to 16 year olds and to nearly 50% among 17 to 19 year olds. Among males, the rate remained low at 7% for 14 to 16 year olds and doubled to ∼15% for 17 to 19 year olds.

A similar sex-specific pattern was detected across weight categories. Among females, the prevalence of DEB increased steadily and significantly from 9% among the underweight category to 23% for normal weight, 42% for overweight, and 53% for the obese categories, respectively. Among males, ∼6–7% of both the underweight and normal weight groups reported DEB, with rates increasing to ∼15% for both the overweight and obese groups. […] When separated by sex, females scoring above the cutoff on the DEPS-R had significantly higher HbA1c (9.2% [SD, 1.9]) than females scoring below the cutoff (8.4% [SD, 1.3]; P < 0.001). The same trend was observed among males (9.2% [SD, 1.6] vs. 8.4% [SD, 1.3]; P < 0.01). […] A total of 31.6% of the participants reported using less insulin and 6.9% reported skipping their insulin dose entirely at least occasionally after overeating. When assessing the sexes separately, we found that 36.8% of females reported restricting and 26.2% reported skipping insulin because of overeating. The rates for males were 9.4 and 4.5%, respectively.”

“The finding that DEBs are common in young patients with type 1 diabetes is in line with previous literature (2). However, because of different assessment methods and different definitions of DEB, direct comparison with other studies is complicated, especially because this is the first study to have used the DEPS-R in a prevalence study. However, two studies using the original DEPS have reported similar results, with 37.9% (23) and 53.8% (24) of the participants reporting engaging in unhealthy weight control practices. In our study, females scored significantly higher than males, which is not surprising given previous studies demonstrating an increased risk of development of DEB in nondiabetic females compared with males. In addition, the prevalence rates increased considerably by increasing age and weight. A relationship between eating pathology and older age and higher BMI also has been demonstrated in previous research conducted in both diabetic and nondiabetic adolescent populations.”

“Consistent with existent literature (1012,27), we found a high frequency of insulin restriction. For example, Bryden et al. (11) assessed 113 males and females (aged 17–25 years) with type 1 diabetes and found that a total of 37% of the females (no males) reported a history of insulin omission or reduction for weight control purposes. Peveler et al. (12) investigated 87 females with type 1 diabetes aged 11–25 years, and 36% reported intentionally reducing or omitting their insulin doses to control their weight. Finally, Goebel-Fabbri et al. (10) examined 234 females 13–60 years of age and found that 30% reported insulin restriction. Similarly, 36.8% of the participants in our study reported reducing their insulin doses occasionally or more often after overeating.”

iv. Clinical Inertia in People With Type 2 Diabetes. A retrospective cohort study of more than 80,000 people.

“Despite good-quality evidence of tight glycemic control, particularly early in the disease trajectory (3), people with type 2 diabetes often do not reach recommended glycemic targets. Baseline characteristics in observational studies indicate that both insulin-experienced and insulin-naïve people may have mean HbA1c above the recommended target levels, reflecting the existence of patients with poor glycemic control in routine clinical care (810). […] U.K. data, based on an analysis reflecting previous NICE guidelines, show that it takes a mean of 7.7 years to initiate insulin after the start of the last OAD [oral antidiabetes drugs] (in people taking two or more OADs) and that mean HbA1c is ~10% (86 mmol/mol) at the time of insulin initiation (12). […] This failure to intensify treatment in a timely manner has been termed clinical inertia; however, data are lacking on clinical inertia in the diabetes-management pathway in a real-world primary care setting, and studies that have been carried out are, relatively speaking, small in scale (13,14). This retrospective cohort analysis investigates time to intensification of treatment in people with type 2 diabetes treated with OADs and the associated levels of glycemic control, and compares these findings with recommended treatment guidelines for diabetes.”

“We used the Clinical Practice Research Datalink (CPRD) database. This is the world’s largest computerized database, representing the primary care longitudinal records of >13 million patients from across the U.K. The CPRD is representative of the U.K. general population, with age and sex distributions comparable with those reported by the U.K. National Population Census (15). All information collected in the CPRD has been subjected to validation studies and been proven to contain consistent and high-quality data (16).”

“50,476 people taking one OAD, 25,600 people taking two OADs, and 5,677 people taking three OADs were analyzed. Mean baseline HbA1c (the most recent measurement within 6 months before starting OADs) was 8.4% (68 mmol/mol), 8.8% (73 mmol/mol), and 9.0% (75 mmol/mol) in people taking one, two, or three OADs, respectively. […] In people with HbA1c ≥7.0% (≥53 mmol/mol) taking one OAD, median time to intensification with an additional OAD was 2.9 years, whereas median time to intensification with insulin was >7.2 years. Median time to insulin intensification in people with HbA1c ≥7.0% (≥53 mmol/mol) taking two or three OADs was >7.2 and >7.1 years, respectively. In people with HbA1c ≥7.5% or ≥8.0% (≥58 or ≥64 mmol/mol) taking one OAD, median time to intensification with an additional OAD was 1.9 or 1.6 years, respectively; median time to intensification with insulin was >7.1 or >6.9 years, respectively. In those people with HbA1c ≥7.5% or ≥8.0% (≥58 or ≥64 mmol/mol) and taking two OADs, median time to insulin was >7.2 and >6.9 years, respectively; and in those people taking three OADs, median time to insulin intensification was >6.1 and >6.0 years, respectively.”

“By end of follow-up, treatment of 17.5% of people with HbA1c ≥7.0% (≥53 mmol/mol) taking three OADs was intensified with insulin, treatment of 20.6% of people with HbA1c ≥7.5% (≥58 mmol/mol) taking three OADs was intensified with insulin, and treatment of 22.0% of people with HbA1c ≥8.0% (≥64 mmol/mol) taking three OADs was intensified with insulin. There were minimal differences in the proportion of patients intensified between the groups. […] In people taking one OAD, the probability of an additional OAD or initiation of insulin was 23.9% after 1 year, increasing to 48.7% by end of follow-up; in people taking two OADs, the probability of an additional OAD or initiation of insulin was 11.4% after 1 year, increasing to 30.1% after 2 years; and in people taking three OADs, the probability of an additional OAD or initiation of insulin was 5.7% after 1 year, increasing to 12.0% by the end of follow-up […] Mean ± SD HbA1c in patients taking one OAD was 8.7 ± 1.6% in those intensified with an additional OAD (n = 14,605), 9.4 ± 2.3% (n = 1,228) in those intensified with insulin, and 8.7 ± 1.7% (n = 15,833) in those intensified with additional OAD or insulin. Mean HbA1c in patients taking two OADs was 8.8 ± 1.5% (n = 3,744), 9.8 ± 1.9% (n = 1,631), and 9.1 ± 1.7% (n = 5,405), respectively. In patients taking three OADs, mean HbA1c at intensification with insulin was 9.7 ± 1.6% (n = 514).”

This analysis shows that there is a delay in intensifying treatment in people with type 2 diabetes with suboptimal glycemic control, with patients remaining in poor glycemic control for >7 years before intensification of treatment with insulin. In patients taking one, two, or three OADs, median time from initiation of treatment to intensification with an additional OAD for any patient exceeded the maximum follow-up time of 7.2–7.3 years, dependent on subcohort. […] Despite having HbA1c levels for which diabetes guidelines recommend treatment intensification, few people appeared to undergo intensification (4,6,7). The highest proportion of people with clinical inertia was for insulin initiation in people taking three OADs. Consequently, these people experienced prolonged periods in poor glycemic control, which is detrimental to long-term outcomes.”

“Previous studies in U.K. general practice have shown similar findings. A retrospective study involving 14,824 people with type 2 diabetes from 154 general practice centers contributing to the Doctors Independent Network Database (DIN-LINK) between 1995 and 2005 observed that median time to insulin initiation for people prescribed multiple OADs was 7.7 years (95% CI 7.4–8.5 years); mean HbA1c before insulin was 9.85% (84 mmol/mol), which decreased by 1.34% (95% CI 1.24–1.44%) after therapy (12). A longitudinal observational study from health maintenance organization data in 3,891 patients with type 2 diabetes in the U.S. observed that, despite continued HbA1c levels >7% (>53 mmol/mol), people treated with sulfonylurea and metformin did not start insulin for almost 3 years (21). Another retrospective cohort study, using data from the Health Improvement Network database of 2,501 people with type 2 diabetes, estimated that only 25% of people started insulin within 1.8 years of multiple OAD failure, if followed for 5 years, and that 50% of people delayed starting insulin for almost 5 years after failure of glycemic control with multiple OADs (22). The U.K. cohort of a recent, 26-week observational study examining insulin initiation in clinical practice reported a large proportion of insulin-naïve people with HbA1c >9% (>75 mmol/mol) at baseline (64%); the mean HbA1c in the global cohort was 8.9% (74 mmol/mol) (10). Consequently, our analysis supports previous findings concerning clinical inertia in both U.K. and U.S. general practice and reflects little improvement in recent years, despite updated treatment guidelines recommending tight glycemic control.

v. Small- and Large-Fiber Neuropathy After 40 Years of Type 1 Diabetes. Associations with glycemic control and advanced protein glycation: the Oslo Study.

“How hyperglycemia may cause damage to the nervous system is not fully understood. One consequence of hyperglycemia is the generation of advanced glycation end products (AGEs) that can form nonenzymatically between glucose, lipids, and amino groups. It is believed that AGEs are involved in the pathophysiology of neuropathy. AGEs tend to affect cellular function by altering protein function (11). One of the AGEs, N-ε-(carboxymethyl)lysine (CML), has been found in excessive amounts in the human diabetic peripheral nerve (12). High levels of methylglyoxal in serum have been found to be associated with painful peripheral neuropathy (13). In recent years, differentiation of affected nerves is possible by virtue of specific function tests to distinguish which fibers are damaged in diabetic polyneuropathy: large myelinated (Aα, Aβ), small thinly myelinated (Aδ), or small nonmyelinated (C) fibers. […] Our aims were to evaluate large- and small-nerve fiber function in long-term type 1 diabetes and to search for longitudinal associations with HbA1c and the AGEs CML and methylglyoxal-derived hydroimidazolone.”

“27 persons with type 1 diabetes of 40 ± 3 years duration underwent large-nerve fiber examinations, with nerve conduction studies at baseline and years 8, 17, and 27. Small-fiber functions were assessed by quantitative sensory thresholds (QST) and intraepidermal nerve fiber density (IENFD) at year 27. HbA1c was measured prospectively through 27 years. […] Fourteen patients (52%) reported sensory symptoms. Nine patients reported symptoms of a sensory neuropathy (reduced sensibility in feet or impaired balance), while three of these patients described pain. Five patients had symptoms compatible with carpal tunnel syndrome (pain or paresthesias within the innervation territory of the median nerve […]. An additional two had no symptoms but abnormal neurological tests with absent tendon reflexes and reduced sensibility. A total of 16 (59%) of the patients had symptoms or signs of neuropathy. […] No patient with symptoms of neuropathy had normal neurophysiological findings. […] Abnormal autonomic testing was observed in 7 (26%) of the patients and occurred together with neurophysiological signs of peripheral neuropathy. […] Twenty-two (81%) had small-fiber dysfunction by QST. Heat pain thresholds in the foot were associated with hydroimidazolone and HbA1c. IENFD was abnormal in 19 (70%) and significantly lower in diabetic patients than in age-matched control subjects (4.3 ± 2.3 vs. 11.2 ± 3.5 mm, P < 0.001). IENFD correlated negatively with HbA1c over 27 years (r = −0.4, P = 0.04) and CML (r = −0.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD.”

Our study shows that small-fiber dysfunction is more prevalent than large-fiber dysfunction in diabetic neuropathy after long duration of type 1 diabetes. Although large-fiber abnormalities were less common than small-fiber abnormalities, almost 60% of the participants had their large nerves affected after 40 years with diabetes. Long-term blood glucose estimated by HbA1c measured prospectively through 27 years and AGEs predict large- and small-nerve fiber function.”

vi. Subarachnoid Hemorrhage in Type 1 Diabetes. A prospective cohort study of 4,083 patients with diabetes.

“Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular event, which is usually caused by a rupture of a cerebrovascular aneurysm. These aneurysms are mostly found in relatively large-caliber (≥1 mm) vessels and can often be considered as macrovascular lesions. The overall incidence of SAH has been reported to be 10.3 per 100,000 person-years (1), even though the variation in incidence between countries is substantial (1). Notably, the population-based incidence of SAH is 35 per 100,000 person-years in the adult (≥25 years of age) Finnish population (2). The incidence of nonaneurysmal SAH is globally unknown, but it is commonly believed that 5–15% of all SAHs are of nonaneurysmal origin. Prospective, long-term, population-based SAH risk factor studies suggest that smoking (24), high blood pressure (24), age (2,3), and female sex (2,4) are the most important risk factors for SAH, whereas diabetes (both types 1 and 2) does not appear to be associated with an increased risk of SAH (2,3).

An increased risk of cardiovascular disease is well recognized in people with diabetes. There are, however, very few studies on the risk of cerebrovascular disease in type 1 diabetes since most studies have focused on type 2 diabetes alone or together with type 1 diabetes. Cerebrovascular mortality in the 20–39-year age-group of people with type 1 diabetes is increased five- to sevenfold in comparison with the general population but accounts only for 15% of all cardiovascular deaths (5). Of the cerebrovascular deaths in patients with type 1 diabetes, 23% are due to hemorrhagic strokes (5). However, the incidence of SAH in type 1 diabetes is unknown. […] In this prospective cohort study of 4,083 patients with type 1 diabetes, we aimed to determine the incidence and characteristics of SAH.”

“52% [of participants] were men, the mean age was 37.4 ± 11.8 years, and the duration of diabetes was 21.6 ± 12.1 years at enrollment. The FinnDiane Study is a nationwide multicenter cohort study of genetic, clinical, and environmental risk factors for microvascular and macrovascular complications in type 1 diabetes. […] all type 1 diabetic patients in the FinnDiane database with follow-up data and without a history of stroke at baseline were included. […] Fifteen patients were confirmed to have an SAH, and thus the crude incidence of SAH was 40.9 (95% CI 22.9–67.4) per 100,000 person-years. Ten out of these 15 SAHs were nonaneurysmal SAHs […] The crude incidence of nonaneurysmal SAH was 27.3 (13.1–50.1) per 100,000 person-years. None of the 10 nonaneurysmal SAHs were fatal. […] Only 3 out of 10 patients did not have verified diabetic microvascular or macrovascular complications prior to the nonaneurysmal SAH event. […] Four patients with type 1 diabetes had a fatal SAH, and all these patients died within 24 h after SAH.”

The presented study results suggest that the incidence of nonaneurysmal SAH is high among patients with type 1 diabetes. […] It is of note that smoking type 1 diabetic patients had a significantly increased risk of nonaneurysmal and all-cause SAHs. Smoking also increases the risk of microvascular complications in insulin-treated diabetic patients, and these patients more often have retinal and renal microangiopathy than never-smokers (8). […] Given the high incidence of nonaneurysmal SAH in patients with type 1 diabetes and microvascular changes (i.e., diabetic retinopathy and nephropathy), the results support the hypothesis that nonaneurysmal SAH is a microvascular rather than macrovascular subtype of stroke.”

“Only one patient with type 1 diabetes had a confirmed aneurysmal SAH. Four other patients died suddenly due to an SAH. If these four patients with type 1 diabetes and a fatal SAH had an aneurysmal SAH, which, taking into account the autopsy reports and imaging findings, is very likely, aneurysmal SAH may be an exceptionally deadly event in type 1 diabetes. Population-based evidence suggests that up to 45% of people die during the first 30 days after SAH, and 18% die at emergency rooms or outside hospitals (9). […] Contrary to aneurysmal SAH, nonaneurysmal SAH is virtually always a nonfatal event (1014). This also supports the view that nonaneurysmal SAH is a disease of small intracranial vessels, i.e., a microvascular disease. Diabetic retinopathy, a chronic microvascular complication, has been associated with an increased risk of stroke in patients with diabetes (15,16). Embryonically, the retina is an outgrowth of the brain and is similar in its microvascular properties to the brain (17). Thus, it has been suggested that assessments of the retinal vasculature could be used to determine the risk of cerebrovascular diseases, such as stroke […] Most interestingly, the incidence of nonaneurysmal SAH was at least two times higher than the incidence of aneurysmal SAH in type 1 diabetic patients. In comparison, the incidence of nonaneurysmal SAH is >10 times lower than the incidence of aneurysmal SAH in the general adult population (21).”

vii. HbA1c and the Risks for All-Cause and Cardiovascular Mortality in the General Japanese Population.

Keep in mind when looking at these data that this is type 2 data. Type 1 diabetes is very rare in Japan and the rest of East Asia.

“The risk for cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. A total of 7,120 participants (2,962 men and 4,158 women; mean age 52.3 years) free of previous CVD were followed for 15 years. Adjusted hazard ratios (HRs) and 95% CIs among categories of HbA1c (<5.0%, 5.0–5.4%, 5.5–5.9%, 6.0–6.4%, and ≥6.5%) for participants without treatment for diabetes and HRs for participants with diabetes were calculated using a Cox proportional hazards model.

RESULTS During the study, there were 1,104 deaths, including 304 from CVD, 61 from coronary heart disease, and 127 from stroke (78 from cerebral infarction, 25 from cerebral hemorrhage, and 24 from unclassified stroke). Relations to HbA1c with all-cause mortality and CVD death were graded and continuous, and multivariate-adjusted HRs for CVD death in participants with HbA1c 6.0–6.4% and ≥6.5% were 2.18 (95% CI 1.22–3.87) and 2.75 (1.43–5.28), respectively, compared with participants with HbA1c <5.0%. Similar associations were observed between HbA1c and death from coronary heart disease and death from cerebral infarction.

CONCLUSIONS High HbA1c levels were associated with increased risk for all-cause mortality and death from CVD, coronary heart disease, and cerebral infarction in general East Asian populations, as in Western populations.”

November 15, 2017 Posted by | Cardiology, Diabetes, Epidemiology, Medicine, Neurology, Pharmacology, Studies | Leave a comment

A few diabetes papers of interest

i. Impact of Sex and Age at Onset of Diabetes on Mortality From Ischemic Heart Disease in Patients With Type 1 Diabetes.

“The study examined long-term IHD-specific mortality in a Finnish population-based cohort of patients with early-onset (0–14 years) and late-onset (15–29 years) T1D (n = 17,306). […] Follow-up started from the time of diagnosis of T1D and ended either at the time of death or at the end of 2011. […] ICD codes used to define patients as having T1D were 2500B–2508B, E10.0–E10.9, or O24.0. […] The median duration of diabetes was 24.4 (interquartile range 17.6–32.2) years. Over a 41-year study period totaling 433,782 person-years of follow-up, IHD accounted for 27.6% of the total 1,729 deaths. Specifically, IHD was identified as the cause of death in 478 patients, in whom IHD was the primary cause of death in 303 and a contributory cause in 175. […] Within the early-onset cohort, the average crude mortality rate in women was 33.3% lower than in men (86.3 [95% CI 65.2–112.1] vs. 128.2 [104.2–156.1] per 100,000 person-years, respectively, P = 0.02). When adjusted for duration of diabetes and the year of diabetes diagnosis, the mortality RR between women and men of 0.64 was only of borderline significance (P = 0.05) […]. In the late-onset cohort, crude mortality in women was, on average, only one-half that of men (117.2 [92.0–147.1] vs. 239.7 [210.9–271.4] per 100,000 person-years, respectively, P < 0.0001) […]. An RR of 0.43 remained highly significant after adjustment for duration of diabetes and year of diabetes diagnosis. Every year of duration of diabetes increased the risk 10–13%”

“The number of deaths from IHD in the patients with T1D were compared with the number of deaths from IHD in the background population, and the SMRs were calculated. For the total cohort (early and late onset pooled), the SMR was 7.2 (95% CI 6.4–8.0) […]. In contrast to the crude mortality rates, the SMRs were higher in women (21.6 [17.2–27.0]) than in men (5.8 [5.1–6.6]). When stratified by the age at onset of diabetes, the SMR was considerably higher in patients with early onset (16.9 [13.5–20.9]) than in those with late onset (5.9 [5.2–6.8]). In both the late- and the early-onset cohorts, there was a striking difference in the SMRs between women and men, and this was especially evident in the early-onset cohort where the SMR for women was 52.8 (36.3–74.5) compared with 12.1 (9.2–15.8) for men. This higher risk of death from IHD compared with the background population was evident in all women, regardless of age. However, the most pronounced effect was seen in women in the early-onset cohort <40 years of age, who were 83 times more likely to die of IHD than the age-matched women in the background population. This compares with a 37 times higher risk of death from IHD in women aged >40 years. The corresponding SMRs for men aged <40 and ≥40 years were 19.4 and 8.5, respectively.”

“Overall, the 40-year cumulative mortality for IHD was 8.8% (95% CI 7.9–9.7%) in all patients […] The 40-year cumulative IHD mortality in the early-onset cohort was 6.3% (4.8–7.8%) for men and 4.5% (3.1–5.9%) for women (P = 0.009 by log-rank test) […]. In the late-onset cohort, the corresponding cumulative mortality rates were 16.6% (14.3–18.7%) in men and 8.5% (6.5–10.4%) in women (P < 0.0001 by log-rank test)”

“The major findings of the current study are that women with early-onset T1D are exceptionally vulnerable to dying from IHD, which is especially evident in those receiving a T1D diagnosis during the prepubertal and pubertal years. Crude mortality rates were similar for women compared with men, highlighting the loss of cardioprotection in women. […] Although men of all ages have greater crude mortality rates than women regardless of the age at onset of T1D, the current study shows that mortality from IHD attributable to diabetes is much more pronounced in women than in men. […] it is conceivable that one of the underlying reasons for the loss of female sex as a protective factor against the development of CVD in the setting of diabetes may be the loss of ovarian hormones. Indeed, women with T1D have been shown to have reduced levels of plasma estradiol compared with age-matched nondiabetic women (23) possibly because of idiopathic ovarian failure or dysregulation of the hypothalamic-pituitary-ovarian axis.”

“One of the novelties of the present study is that the risk of death from IHD highly depends on the age at onset of T1D. The data show that the SMR was considerably higher in early-onset (0–14 years) than in late-onset (15–29 years) T1D in both sexes. […] the risk of dying from IHD is high in both women and men receiving a diagnosis of T1D at a young age.

ii. Microalbuminuria as a Risk Predictor in Diabetes: The Continuing Saga.

“The term “microalbuminuria” (MA) originated in 1964 when Professor Harry Keen first used it to signify a small amount of albumin in the urine of patients with type 1 diabetes (1). […] Whereas early research focused on the relevance of MA as a risk factor for diabetic kidney disease, research over the past 2 decades has shifted to examine whether MA is a true risk factor. To appreciate fully the contribution of MA to overall cardiorenal risk, it is important to distinguish between a risk factor and risk marker. A risk marker is a variable that identifies a pathophysiological state, such as inflammation or infection, and is not necessarily involved, directly or causally, in the genesis of a specified outcome (e.g., association of a cardiovascular [CV] event with fever, high-sensitivity C-reactive protein [hs-CRP], or MA). Conversely, a risk factor is involved clearly and consistently with the cause of a specified event (e.g., a CV event associated with persistently elevated blood pressure or elevated levels of LDL). Both a risk marker and a risk factor can predict an adverse outcome, but only one lies within the causal pathway of a disease. Moreover, a reduction (or alteration in a beneficial direction) of a risk factor (i.e., achievement of blood pressure goal) generally translates into a reduction of adverse outcomes, such as CV events; this is not necessarily true for a risk marker.”

“The data sources included in this article were all PubMed-referenced articles in English-language peer-reviewed journals since 1964. Studies selected had to have a minimum follow-up of 1 year; include at least 100 participants; be either a randomized trial, a systematic review, a meta-analysis, or a large observational cohort study in patients with any type of diabetes; or be trials of high CV risk that included at least 50% of patients with diabetes. All studies had to assess changes in MA tied to CV or CKD outcomes and not purely reflect changes in MA related to blood pressure, unless they were mechanistic studies. On the basis of these inclusion criteria, 31 studies qualified and provide the data used for this review.”

“Early studies in patients with diabetes supported the concept that as MA increases to higher levels, the risk of CKD progression and CV risk also increases […]. Moreover, evidence from epidemiological studies in patients with diabetes suggested that the magnitude of urine albumin excretion should be viewed as a continuum of CV risk, with the lower the albumin excretion, the lower the CV risk (15,16). However, MA values can vary daily up to 100% (11). These large biological variations are a result of a variety of conditions, with a central core tied to inflammation associated with factors ranging from increased blood pressure variability, high blood glucose levels, high LDL cholesterol, and high uric acid levels to high sodium ingestion, smoking, and exercise (17) […]. Additionally, any febrile illness, regardless of etiology, will increase urine albumin excretion (18). Taken together, these data support the concept that MA is highly variable and that values over a short time period (i.e., 3–6 months) are meaningless in predicting any CV or kidney disease outcome.”

“Initial studies to understand the mechanisms of MA examined changes in glomerular membrane permeability as a key determinant in patients with diabetes […]. Many factors affect the genesis and level of MA, most of which are linked to inflammatory conditions […]. A good evidence base, however, supports the concept that MA directly reflects the amount of inflammation and vascular “leakiness” present in patients with diabetes (16,18,19).

More recent studies have found a number of other factors that affect glomerular permeability by modifying cytokines that affect permeability. Increased amounts of glycated albumin reduce glomerular nephrin and increase vascular endothelial growth factor (20). Additionally, increases in sodium intake (21) as well as intraglomerular pressure secondary to high protein intake or poorly controlled blood pressure (22,23) increase glomerular permeability in diabetes and, hence, MA levels.

In individuals with diabetes, albumin is glycated and associated with the generation of reactive oxygen species. In addition, many other factors such as advanced glycation end products, reactive oxygen species, and other cellular toxins contribute to vascular injury. Once such injury occurs, the effect of pressor hormones, such as angiotensin II, is magnified, resulting in a faster progression of vascular injury. The end result is direct injury to the vascular smooth muscle cells, endothelial cells, and visceral epithelial cells (podocytes) of the glomerular capillary wall membrane as well as to the proximal tubular cells and podocyte basement membrane of the nephron (20,24,25). All these contribute to the development of MA. […] better glycemic control is associated with far lower levels of inflammatory markers (31).”

“MA is accepted as a CV risk marker for myocardial infarction and stroke, regardless of diabetes status. […] there is good evidence in those with type 2 diabetes that the presence of MA >100 mg/day is associated with higher CV events and greater likelihood of kidney disease development (6). Evidence for this association comes from many studies and meta-analyses […] a meta-analysis by Perkovic et al. (37) demonstrated a dose-response relationship between the level of albuminuria and CV risk. In this meta-analysis, individuals with MA were at 50% greater risk of coronary heart disease (risk ratio 1.47 [95% CI 1.30–1.66]) than those without. Those with macroalbuminuria (i.e., >300 mg/day) had more than a twofold risk for coronary heart disease (risk ratio 2.17 [95% CI 1.87–2.52]) (37). Despite these data indicating a higher CV risk in patients with MA regardless of diabetes status and other CV risk factors, there is no consensus that the addition of MA to conventional CV risk stratification for the general population (e.g., Framingham or Reynolds scoring systems) is of any clinical value, and that includes patients with diabetes (38).”

“Given that MA was evaluated in a post hoc manner in almost all interventional studies, it is likely that the reduction in MA simply reflects the effects of either renin-angiotensin system (RAS) blockade on endothelial function or significant blood pressure reduction rather than the MA itself being implicated as a CV disease risk factor (18). […] associations of lowering MA with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) does not prove a direct benefit on CV event lowering associated with MA reduction in diabetes. […] Four long-term, appropriately powered trials demonstrated an inverse relationship between reductions in MA and primary event rates for CV events […]. Taken together, these studies support the concept that MA is a risk marker in diabetes and is consistent with data of other inflammatory markers, such as hs-CRP [here’s a relevant link – US], such that the higher the level, the higher the risk (15,39,42). The importance of MA as a CV risk marker is exemplified further by another meta-analysis that showed that MA has a similar magnitude of CV risk as hs-CRP and is a better predictor of CV events (43). Thus, the data supporting MA as a risk marker for CV events are relatively consistent, clearly indicate that an association exists, and help to identify the presence of underlying inflammatory states, regardless of etiology.”

“In people with early stage nephropathy (i.e., stage 2 or 3a [GFR 45–89 mL/min/1.73 m2]) and MA, there is no clear benefit on slowing GFR decline by reducing MA with drugs that block the RAS independent of lowering blood pressure (16). This is exemplified by many trials […]. Thus, blood pressure lowering is the key goal for all patients with early stage nephropathy associated with normoalbuminuria or MA. […] When albuminuria levels are in the very high or macroalbuminuria range (i.e., >300 mg/day), it is accepted that the patient has CKD and is likely to progress ultimately to ESRD, unless they die of a CV event (39,52). However, only one prospective randomized trial evaluated the role of early intervention to reduce blood pressure with an ACE inhibitor versus a calcium channel blocker in CKD progression by assessing change in MA and creatinine clearance in people with type 2 diabetes (Appropriate Blood Pressure Control in Diabetes [ABCD] trial) (23). After >7 years of follow-up, there was no relationship between changes in MA and CKD progression. Moreover, there was regression to the mean of MA.”

“Many observational studies used development of MA as indicating the presence of early stage CKD. Early studies by the individual groups of Mogensen and Parving demonstrated a relationship between increases in MA and progression to nephropathy in type 1 diabetes. These groups also showed that use of ACE inhibitors, blood pressure reduction, and glucose control reduced MA (9,58,59). However, more recent studies in both type 1 and type 2 diabetes demonstrated that only a subgroup of patients progress from MA to >300 mg/day albuminuria, and this subgroup accounts for those destined to progress to ESRD (29,32,6063). Thus, the presence of MA alone is not predictive of CKD progression. […] some patients with type 2 diabetes progress to ESRD without ever having developed albuminuria levels of ≥300 mg/day (67). […] Taken together, data from outcome trials, meta-analyses, and observations demonstrate that MA [Micro-Albuminuria] alone is not synonymous with the presence of clearly defined CKD [Chronic Kidney Disease] in diabetes, although it is used as part of the criteria for the diagnosis of CKD in the most recent CKD classification and staging (71). Note that only a subgroup of ∼25–30% of people with diabetes who also have MA will likely progress to more advanced stages of CKD. Predictors of progression to ESRD, apart from family history, and many years of poor glycemic and blood pressure control are still not well defined. Although there are some genetic markers, such as CUBN and APOL1, their use in practice is not well established.”

“In the context of the data presented in this article, MA should be viewed as a risk marker associated with an increase in CV risk and for kidney disease, but its presence alone does not indicate established kidney disease, especially if the eGFR is well above 60 mL/min/1.73 m2. Increases in MA, with blood pressure and other CV risk factors controlled, are likely but not proven to portend a poor prognosis for CKD progression over time. Achieving target blood pressure (<140/80 mmHg) and target HbA1c (<7%) should be priorities in treating patients with MA. Recent guidelines from both the American Diabetes Association and the National Kidney Foundation provide a strong recommendation for using agents that block the RAS, such as ACE inhibitors and ARBs, as part of the regimen for those with albuminuria levels >300 mg/day but not MA (73). […] maximal antialbuminuric effects will [however] not be achieved with these agents unless a low-sodium diet is strictly followed.”

iii. The SEARCH for Diabetes in Youth Study: Rationale, Findings, and Future Directions.

“The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support from the National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U.S. and represents the largest, most diverse study of diabetes among U.S. youth. An active registry of youth diagnosed with diabetes at age <20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. […] This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions.”

“SEARCH includes a registry and a cohort study […]. The registry study identifies incident cases each year since 2002 through the present with ∼5.5 million children <20 years of age (∼6% of the U.S. population <20 years) under surveillance annually. Approximately 3.5 million children <20 years of age were under surveillance in 2001 at the six SEARCH recruitment centers, with approximately the same number at the five centers under surveillance in 2009.”

“The prevalence of all types of diabetes was 1.8/1,000 youth in 2001 and was 2.2/1,000 youth in 2009, which translated to at least 154,000 children/youth in the U.S. with diabetes in 2001 (5) and at least 192,000 in 2009 (6). Overall, between 2001 and 2009, prevalence of type 1 diabetes in youth increased by 21.1% (95% CI 15.6–27.0), with similar increases for boys and girls and in most racial/ethnic and age groups (2) […]. The prevalence of type 2 diabetes also increased significantly over the same time period by 30.5% (95% CI 17.3–45.1), with increases observed in both sexes, 10–14- and 15–19-year-olds, and among Hispanic and non-Hispanic white and African American youth (2). These data on changes in type 2 are consistent with smaller U.S. studies (711).”

“The incidence of diabetes […] in 2002 to 2003 was 24.6/100,000/year (12), representing ∼15,000 new patients every year with type 1 diabetes and 3,700 with type 2 diabetes, increasing to 18,436 newly diagnosed type 1 and 5,089 with type 2 diabetes in 2008 to 2009 (13). Among non-Hispanic white youth, the incidence of type 1 diabetes increased by 2.7% (95% CI 1.2–4.3) annually between 2002 and 2009. Significant increases were observed among all age groups except the youngest age group (0–4 years) (14). […] The underlying factors responsible for this increase have not yet been identified.”

Over 50% of youth are hospitalized at diabetes onset, and ∼30% of children newly diagnosed with diabetes present with diabetic ketoacidosis (DKA) (19). Prevalence of DKA at diagnosis was three times higher among youth with type 1 diabetes (29.4%) compared with youth with type 2 diabetes (9.7%) and was lowest in Asian/Pacific Islanders (16.2%) and highest among Hispanics (27.0%).”

“A significant proportion of youth with diabetes, particularly those with type 2 diabetes, have very poor glycemic control […]: 17% of youth with type 1 diabetes and 27% of youth with type 2 diabetes had A1C levels ≥9.5% (≥80 mmol/mol). Minority youth were significantly more likely to have higher A1C levels compared with non-Hispanic white youth, regardless of diabetes type. […] Optimal care is an important component of successful long-term management for youth with diabetes. While there are high levels of adherence for some diabetes care indicators such as blood pressure checks (95%), urinary protein tests (83%), and lipid assessments (88%), approximately one-third of youth had no documentation of eye or A1C values at appropriate intervals and therefore were not meeting the American Diabetes Association (ADA)-recommended screening for diabetic control and complications (40). Participants ≥18 years old, particularly those with type 2 diabetes, and minority youth with type 1 diabetes had fewer tests of all kinds performed. […] Despite current treatment options, the prevalence of poor glycemic control is high, particularly among minority youth. Our initial findings suggest that a substantial number of youth with diabetes will develop serious, debilitating complications early in life, which is likely to have significant implications for their quality of life, as well as economic and health care implications.”

“Because recognition of the broader spectrum of diabetes in children and adolescents is recent, there are no gold-standard definitions for differentiating the types of diabetes in this population, either for research or clinical purposes or for public health surveillance. The ADA classification of diabetes as type 1 and type 2 does not include operational definitions for the specific etiologic markers of diabetes type, such as types and numbers of diabetes autoantibodies or measures of insulin resistance, hallmarks of type 1 and 2 diabetes, respectively (43). Moreover, obese adolescents with a clinical phenotype suggestive of type 2 diabetes can present with ketoacidosis (44) or have evidence of autoimmunity (45).”

“Using the ADA framework (43), we operationalized definitions of two main etiologic markers, autoimmunity and insulin sensitivity, to identify four etiologic subgroups based on the presence or absence of markers. Autoimmunity was based on presence of one or more diabetes autoantibodies (GAD65 and IA2). Insulin sensitivity was estimated using clinical variables (A1C, triglyceride level, and waist circumference) from a formula that was highly associated with estimated insulin sensitivity measured using a euglycemic-hyperinsulinemic clamp among youth with type 1 and 2 and normal control subjects (46). Participants were categorized as insulin resistant […] and insulin sensitive (47). Using this approach, 54.5% of SEARCH cases were classified as typical type 1 (autoimmune, insulin-sensitive) diabetes, while 15.9% were classified as typical type 2 (nonautoimmune, insulin-resistant) diabetes. Cases that were classified as autoimmune and insulin-resistant likely represent individuals with type 1 autoimmune diabetes and concomitant obesity, a phenotype becoming more prevalent as a result of the recent increase in the frequency of obesity, but is unlikely to be a distinct etiologic entity.”

“Ten percent of SEARCH participants had no evidence of either autoimmunity or insulin resistance and thus require additional testing, including additional measurements of diabetes-related autoantibodies (only two antibodies were measured in SEARCH) as well as testing for monogenic forms of diabetes to clarify etiology. Among antibody-negative youth, 8% of those tested had a mutation in one or more of the hepatocyte nuclear factor-1α (HNF-1α), glucokinase, and HNF-4α genes, an estimated monogenic diabetes population prevalence of at least 1.2% (48).”

iv. Does the Prevailing Hypothesis That Small-Fiber Dysfunction Precedes Large-Fiber Dysfunction Apply to Type 1 Diabetic Patients?

The short answer is ‘yes, it does’. Some observations from the paper:

“Diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes, affecting 28–55% of patients (1). A prospective Finnish study found evidence of probable or definite neuropathy in 8.3% of diabetic patients at the time of diagnosis, 16.7% after 5 years, and 41.9% after 10 years (2). Diabetes-related peripheral neuropathy results in serious morbidity, including chronic neuropathic pain, leg weakness and falls, sensory loss and foot ulceration, and amputation (3). Health care costs associated with diabetic neuropathy were estimated at $10.9 billion in the U.S. in 2003 (4). However, despite the high prevalence of diabetes and DSP, and the important public health implications, there is a lack of serum- or tissue-based biomarkers to diagnose and follow patients with DSP longitudinally. Moreover, numerous attempts at treatment have yielded negative results.”

“DSP is known to cause injury to both large-diameter, myelinated (Aα and Aβ) fibers and small-diameter, unmyelinated nerve (Aδ and C) fibers; however, the sequence of nerve fiber damage remains uncertain. While earlier reports seemed to indicate simultaneous loss of small- and large-diameter nerve fibers, with preserved small/large ratios (5), more recent studies have suggested the presence of early involvement of small-diameter Aδ and C fibers (611). Some suggest a temporal relationship of small-fiber impairment preceding that of large fibers. For example, impairment in the density of the small intraepidermal nerve fibers in symptomatic patients with impaired glucose tolerance (prediabetes) have been observed in the face of normal large-fiber function, as assessed by nerve conduction studies (NCSs) (9,10). In addition, surveys of patients with DSP have demonstrated an overwhelming predominance of sensory and autonomic symptoms, as compared with motor weakness. Again, this has been interpreted as indicative of preferential small-fiber dysfunction (12). Though longitudinal studies are limited, such studies have lead to the current prevailing hypothesis for the natural history of DSP that measures of small-fiber morphology and function decline prior to those of large fibers. One implication of this hypothesis is that small-fiber testing could serve as an earlier, subclinical primary end point in clinical trials investigating interventions for DSP (13).

The hypothesis described above has been investigated exclusively in type 2 diabetic or prediabetic patients. Through the study of a cohort of healthy volunteers and type 1 diabetic subjects […], we had the opportunity to evaluate in cross-sectional analysis the relationship between measures of large-fiber function and small-fiber structure and function. Under the hypothesis that small-fiber abnormalities precede large-fiber dysfunction in the natural history of DSP, we sought to determine if: 1) the majority of subjects who meet criteria for large-fiber dysfunction have concurrent evidence of small-fiber dysfunction and 2) the subset of patients without DSP includes a spectrum with normal small-fiber tests (indicating lack of initiation of nerve injury) as well as abnormal small-fiber tests (indicating incipient DSP).”

“Overall, 57 of 131 (43.5%) type 1 diabetic patients met DSP criteria, and 74 of 131 (56.5%) did not meet DSP criteria. Abnormality of CCM [link] was present in 30 of 57 (52.6%) DSP patients and 6 of 74 (8.1%) type 1 diabetic patients without DSP. Abnormality of CDT [Cooling Detection Thresholds, relevant link] was present in 47 of 56 (83.9%) DSP patients and 17 of 73 (23.3%) without DSP. Abnormality of LDIflare [laser Doppler imaging of heat-evoked flare] was present in 30 of 57 (52.6%) DSP patients and 20 of 72 (27.8%) without DSP. Abnormality of HRV [Heart Rate Variability] was present in 18 of 45 (40.0%) DSP patients and 6 of 70 (8.6%) without DSP. […] sensitivity analysis […] revealed that abnormality of any one of the four small-fiber measures was present in 55 of 57 (96.5%) DSP patients […] and 39 of 74 (52.7%) type 1 diabetic patients without DSP. Similarly, abnormality of any two of the four small-fiber measures was present in 43 of 57 (75.4%) DSP patients […] and 9 of 74 (12.2%) without DSP. Finally, abnormality of either CDT or CCM (with these two tests selected based on their high reliability) was noted in 53 of 57 (93.0%) DSP patients and 21 of 74 (28.4%) patients without DSP […] When DSP was defined based on symptoms and signs plus abnormal sural SNAP [sensory nerve action potential] amplitude or conduction velocity, there were 68 of 131 patients who met DSP criteria and 63 of 131 who did not. Abnormality of any one of the four small-fiber measures was present in 63 of 68 (92.6%) DSP patients and 31 of 63 (49.2%) type 1 diabetic patients without DSP. […] Finally, if DSP was defined based on clinical symptoms and signs alone, with TCNS ≥5, there were 68 of 131 patients who met DSP criteria and 63 of 131 who did not. Abnormality of any one of the four small-fiber measures was present in 62 of 68 (91.2%) DSP patients and 32 of 63 (50.8%) type 1 diabetic patients without DSP.”

“Qualitative analysis of contingency tables shows that the majority of patients with DSP have concurrent evidence of small-fiber dysfunction, and patients without DSP include a spectrum with normal small-fiber tests (indicating lack of initiation of nerve injury) as well as abnormal small-fiber tests. Evidence of isolated large-fiber injury was much less frequent […]. These findings suggest that small-fiber damage may herald the onset of DSP in type 1 diabetes. In addition, the above findings remained true when alternative definitions of DSP were explored in a sensitivity analysis. […] The second important finding was the linear relationships noted between small-fiber structure and function tests (CDT, CNFL, LDIflare, and HRV) […] and the number of NCS abnormalities (a marker of large-fiber function). This might indicate that once the process of large-fiber nerve injury in DSP has begun, damage to large and small nerve fibers occurs simultaneously.”

v. Long-Term Complications and Mortality in Young-Onset Diabetes.

“Records from the Royal Prince Alfred Hospital Diabetes Clinical Database, established in 1986, were matched with the Australian National Death Index to establish mortality outcomes for all subjects until June 2011. Clinical and mortality outcomes in 354 patients with T2DM, age of onset between 15 and 30 years (T2DM15–30), were compared with T1DM in several ways but primarily with 470 patients with T1DM with a similar age of onset (T1DM15–30) to minimize the confounding effect of age on outcome.

RESULTS For a median observation period of 21.4 (interquartile range 14–30.7) and 23.4 (15.7–32.4) years for the T2DM and T1DM cohorts, respectively, 71 of 824 patients (8.6%) died. A significant mortality excess was noted in T2DM15–30 (11 vs. 6.8%, P = 0.03), with an increased hazard for death (hazard ratio 2.0 [95% CI 1.2–3.2], P = 0.003). Death for T2DM15–30 occurred after a significantly shorter disease duration (26.9 [18.1–36.0] vs. 36.5 [24.4–45.4] years, P = 0.01) and at a relatively young age. There were more cardiovascular deaths in T2DM15–30 (50 vs. 30%, P < 0.05). Despite equivalent glycemic control and shorter disease duration, the prevalence of albuminuria and less favorable cardiovascular risk factors were greater in the T2DM15–30 cohort, even soon after diabetes onset. Neuropathy scores and macrovascular complications were also increased in T2DM15–30 (P < 0.0001).

CONCLUSIONS Young-onset T2DM is the more lethal phenotype of diabetes and is associated with a greater mortality, more diabetes complications, and unfavorable cardiovascular disease risk factors when compared with T1DM.

“Only a few previous studies have looked at comparative mortality in T1DM and T2DM onset in patients <30 years of age. In a Swedish study of patients with diabetes aged 15–34 years compared with a general population, the standardized mortality ratio was higher for the T2DM than for the T1DM cohort (2.9 vs. 1.8) (17). […] Recently, Dart et al. (19) examined survival in youth aged 1–18 years with T2DM versus T1DM. Kaplan-Meier analysis revealed a statistically significant lower survival probability for the youth with T2DM, although the number at risk was low after 10 year’s duration. Taken together, these findings are in keeping with the present observations and are supportive evidence for a higher mortality in young-onset T2DM than in T1DM. The majority of deaths appear to be from cardiovascular causes and significantly more so for young T2DM.”

“Although the age of onset of T1DM diabetes is usually in little doubt because of a more abrupt presentation, it is possible that the age of onset of T2DM was in fact earlier than recognized. With a previously published method for estimating time delay until diagnosis of T2DM (26) by plotting the prevalence of retinopathy against duration and extrapolating to a point of zero retinopathy, we found that there is no difference in the slope and intercept of this relationship between the T2DM and the T1DM cohorts […] delay in diagnosis is unlikely to be an explanation for the differences in observed outcome.”

vi. Cardiovascular Risk Factors Are Associated With Increased Arterial Stiffness in Youth With Type 1 Diabetes.

“Increased arterial stiffness independently predicts all-cause and CVD mortality (3), and higher pulse pressure predicts CVD mortality, incidence, and end-stage renal disease development among adults with type 1 diabetes (1,4,5). Several reports have shown that youth and adults with type 1 diabetes have elevated arterial stiffness, though the mechanisms are largely unknown (6). The etiology of advanced atherosclerosis in type 1 diabetes is likely multifactorial, involving metabolic, behavioral, and diabetes-specific cardiovascular (CV) risk factors. Aging, high blood pressure (BP), obesity, the metabolic syndrome (MetS), and type 2 diabetes are the main contributors of sustained increased arterial stiffness in adults (7,8). However, the natural history, the age-related progression, and the possible determinants of increased arterial stiffness in youth with type 1 diabetes have not been studied systematically. […] There are currently no data examining the impact of CV risk factors and their clustering in youth with type 1 diabetes on subsequent CVD morbidity and mortality […]. Thus, the aims of this report were: 1) to describe the progression of arterial stiffness, as measured by pulse wave velocity (PWV), over time, among youth with type 1 diabetes, and 2) to explore the association of CV risk factors and their clustering as MetS with PWV in this cohort.”

“Youth were age 14.5 years (SD 2.8) and had an average disease duration of 4.8 (3.8) years at baseline, 46.3% were female, and 87.6% were of NHW race/ethnicity. At baseline, 10.0% had high BP, 10.9% had a large waist circumference, 11.6% had HDL-c ≤40 mg/dL, 10.9% had a TG level ≥110 mg/dL, and 7.0% had at least two of the above CV risk factors (MetS). In addition, 10.3% had LDL-c ≥130 mg/dL, 72.0% had an HbA1c ≥7.5% (58 mmol/mol), and 9.2% had ACR ≥30 μg/mL. Follow-up measures were obtained on average at age 19.2 years, when the average duration of diabetes was 10.1 (3.9) years.”

“Over an average follow-up period of ∼5 years, there was a statistically significant increase of 0.7 m/s in PWV (from 5.2 to 5.9 m/s), representing an annual increase of 2.8% or 0.145 m/s. […] Based on our data, if this rate of change is stable over time, the estimated average PWV by the time these youth enter their third decade of life will be 11.3 m/s, which was shown to be associated with a threefold increased hazard for major CV events (26). There are no similar studies in youth to compare these findings. In adults, the rate of change in PWV was 0.081 m/s/year in nondiabetic normotensive patients, although it was higher in hypertensive adults (0.147 m/s/year) (7). We also showed that the presence of central adiposity and elevated BP at baseline, as well as clustering of at least two CV risk factors, was associated with significantly worse PWV over time, although these baseline factors did not significantly influence the rate of change in PWV over this period of time. Changes in CV risk factors, specifically increases in central adiposity, LDL-c levels, and worsening glucose control, were independently associated with worse PWV over time. […] Our inability to detect a difference in the rate of change in PWV in our youth with MetS (vs. those without MetS) may be due to several factors, including a combination of a relatively small sample size, short period of follow-up, and young age of the cohort (thus with lower baseline PWV levels).”

 

November 8, 2017 Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Medicine, Nephrology, Neurology, Studies | Leave a comment