Developmental Biology (II)

Below I have included some quotes from the middle chapters of the book and some links related to the topic coverage. As I already pointed out earlier, this is an excellent book on these topics.

Germ cells have three key functions: the preservation of the genetic integrity of the germline; the generation of genetic diversity; and the transmission of genetic information to the next generation. In all but the simplest animals, the cells of the germline are the only cells that can give rise to a new organism. So, unlike body cells, which eventually all die, germ cells in a sense outlive the bodies that produced them. They are, therefore, very special cells […] In order that the number of chromosomes is kept constant from generation to generation, germ cells are produced by a specialized type of cell division, called meiosis, which halves the chromosome number. Unless this reduction by meiosis occurred, the number of chromosomes would double each time the egg was fertilized. Germ cells thus contain a single copy of each chromosome and are called haploid, whereas germ-cell precursor cells and the other somatic cells of the body contain two copies and are called diploid. The halving of chromosome number at meiosis means that when egg and sperm come together at fertilization, the diploid number of chromosomes is restored. […] An important property of germ cells is that they remain pluripotent—able to give rise to all the different types of cells in the body. Nevertheless, eggs and sperm in mammals have certain genes differentially switched off during germ-cell development by a process known as genomic imprinting […] Certain genes in eggs and sperm are imprinted, so that the activity of the same gene is different depending on whether it is of maternal or paternal origin. Improper imprinting can lead to developmental abnormalities in humans. At least 80 imprinted genes have been identified in mammals, and some are involved in growth control. […] A number of developmental disorders in humans are associated with imprinted genes. Infants with Prader-Willi syndrome fail to thrive and later can become extremely obese; they also show mental retardation and mental disturbances […] Angelman syndrome results in severe motor and mental retardation. Beckwith-Wiedemann syndrome is due to a generalized disruption of imprinting on a region of chromosome 7 and leads to excessive foetal overgrowth and an increased predisposition to cancer.”

“Sperm are motile cells, typically designed for activating the egg and delivering their nucleus into the egg cytoplasm. They essentially consist of a nucleus, mitochondria to provide an energy source, and a flagellum for movement. The sperm contributes virtually nothing to the organism other than its chromosomes. In mammals, sperm mitochondria are destroyed following fertilization, and so all mitochondria in the animal are of maternal origin. […] Different organisms have different ways of ensuring fertilization by only one sperm. […] Early development is similar in both male and female mammalian embryos, with sexual differences only appearing at later stages. The development of the individual as either male or female is genetically fixed at fertilization by the chromosomal content of the egg and sperm that fuse to form the fertilized egg. […] Each sperm carries either an X or Y chromosome, while the egg has an X. The genetic sex of a mammal is thus established at the moment of conception, when the sperm introduces either an X or a Y chromosome into the egg. […] In the absence of a Y chromosome, the default development of tissues is along the female pathway. […] Unlike animals, plants do not set aside germ cells in the embryo and germ cells are only specified when a flower develops. Any meristem cell can, in principle, give rise to a germ cell of either sex, and there are no sex chromosomes. The great majority of flowering plants give rise to flowers that contain both male and female sexual organs, in which meiosis occurs. The male sexual organs are the stamens; these produce pollen, which contains the male gamete nuclei corresponding to the sperm of animals. At the centre of the flower are the female sex organs, which consist of an ovary of two carpels, which contain the ovules. Each ovule contains an egg cell.”

“The character of specialized cells such as nerve, muscle, or skin is the result of a particular pattern of gene activity that determines which proteins are synthesized. There are more than 200 clearly recognizable differentiated cell types in mammals. How these particular patterns of gene activity develop is a central question in cell differentiation. Gene expression is under a complex set of controls that include the actions of transcription factors, and chemical modification of DNA. External signals play a key role in differentiation by triggering intracellular signalling pathways that affect gene expression. […] the central feature of cell differentiation is a change in gene expression, which brings about a change in the proteins in the cells. The genes expressed in a differentiated cell include not only those for a wide range of ‘housekeeping’ proteins, such as the enzymes involved in energy metabolism, but also genes encoding cell-specific proteins that characterize a fully differentiated cell: hemoglobin in red blood cells, keratin in skin epidermal cells, and muscle-specific actin and myosin protein filaments in muscle. […] several thousand different genes are active in any given cell in the embryo at any one time, though only a small number of these may be involved in specifying cell fate or differentiation. […] Cell differentiation is known to be controlled by a wide range of external signals but it is important to remember that, while these external signals are often referred to as being ‘instructive’, they are ‘selective’, in the sense that the number of developmental options open to a cell at any given time is limited. These options are set by the cell’s internal state which, in turn, reflects its developmental history. External signals cannot, for example, convert an endodermal cell into a muscle or nerve cell. Most of the molecules that act as developmentally important signals between cells during development are proteins or peptides, and their effect is usually to induce a change in gene expression. […] The same external signals can be used again and again with different effects because the cells’ histories are different. […] At least 1,000 different transcription factors are encoded in the genomes of the fly and the nematode, and as many as 3,000 in the human genome. On average, around five different transcription factors act together at a control region […] In general, it can be assumed that activation of each gene involves a unique combination of transcription factors.”

“Stem cells involve some special features in relation to differentiation. A single stem cell can divide to produce two daughter cells, one of which remains a stem cell while the other gives rise to a lineage of differentiating cells. This occurs in our skin and gut all the time and also in the production of blood cells. It also occurs in the embryo. […] Embryonic stem (ES) cells from the inner cell mass of the early mammalian embryo when the primitive streak forms, can, in culture, differentiate into a wide variety of cell types, and have potential uses in regenerative medicine. […] it is now possible to make adult body cells into stem cells, which has important implications for regenerative medicine. […] The goal of regenerative medicine is to restore the structure and function of damaged or diseased tissues. As stem cells can proliferate and differentiate into a wide range of cell types, they are strong candidates for use in cell-replacement therapy, the restoration of tissue function by the introduction of new healthy cells. […] The generation of insulin-producing pancreatic β cells from ES cells to replace those destroyed in type 1 diabetes is a prime medical target. Treatments that direct the differentiation of ES cells towards making endoderm derivatives such as pancreatic cells have been particularly difficult to find. […] The neurodegenerative Parkinson disease is another medical target. […] To generate […] stem cells of the patient’s own tissue type would be a great advantage, and the recent development of induced pluripotent stem cells (iPS cells) offers […] exciting new opportunities. […] There is [however] risk of tumour induction in patients undergoing cell-replacement therapy with ES cells or iPS cells; undifferentiated pluripotent cells introduced into the patient could cause tumours. Only stringent selection procedures that ensure no undifferentiated cells are present in the transplanted cell population will overcome this problem. And it is not yet clear how stable differentiated ES cells and iPS cells will be in the long term.”

“In general, the success rate of cloning by body-cell nuclear transfer in mammals is low, and the reasons for this are not yet well understood. […] Most cloned mammals derived from nuclear transplantation are usually abnormal in some way. The cause of failure is incomplete reprogramming of the donor nucleus to remove all the earlier modifications. A related cause of abnormality may be that the reprogrammed genes have not gone through the normal imprinting process that occurs during germ-cell development, where different genes are silenced in the male and female parents. The abnormalities in adults that do develop from cloned embryos include early death, limb deformities and hypertension in cattle, and immune impairment in mice. All these defects are thought to be due to abnormalities of gene expression that arise from the cloning process. Studies have shown that some 5% of the genes in cloned mice are not correctly expressed and that almost half of the imprinted genes are incorrectly expressed.”

“Organ development involves large numbers of genes and, because of this complexity, general principles can be quite difficult to distinguish. Nevertheless, many of the mechanisms used in organogenesis are similar to those of earlier development, and certain signals are used again and again. Pattern formation in development in a variety of organs can be specified by position information, which is specified by a gradient in some property. […] Not surprisingly, the vascular system, including blood vessels and blood cells, is among the first organ systems to develop in vertebrate embryos, so that oxygen and nutrients can be delivered to the rapidly developing tissues. The defining cell type of the vascular system is the endothelial cell, which forms the lining of the entire circulatory system, including the heart, veins, and arteries. Blood vessels are formed by endothelial cells and these vessels are then covered by connective tissue and smooth muscle cells. Arteries and veins are defined by the direction of blood flow as well as by structural and functional differences; the cells are specified as arterial or venous before they form blood vessels but they can switch identity. […] Differentiation of the vascular cells requires the growth factor VEGF (vascular endothelial growth factor) and its receptors, and VEGF stimulates their proliferation. Expression of the Vegf gene is induced by lack of oxygen and thus an active organ using up oxygen promotes its own vascularization. New blood capillaries are formed by sprouting from pre-existing blood vessels and proliferation of cells at the tip of the sprout. […] During their development, blood vessels navigate along specific paths towards their targets […]. Many solid tumours produce VEGF and other growth factors that stimulate vascular development and so promote the tumour’s growth, and blocking new vessel formation is thus a means of reducing tumour growth. […] In humans, about 1 in 100 live-born infants has some congenital heart malformation, while in utero, heart malformation leading to death of the embryo occurs in between 5 and 10% of conceptions.”

“Separation of the digits […] is due to the programmed cell death of the cells between these digits’ cartilaginous elements. The webbed feet of ducks and other waterfowl are simply the result of less cell death between the digits. […] the death of cells between the digits is essential for separating the digits. The development of the vertebrate nervous system also involves the death of large numbers of neurons.”


Down Syndrome.
Fertilization. In vitro fertilisation. Preimplantation genetic diagnosis.
SRY gene.
X-inactivation. Dosage compensation.
Cellular differentiation.
Signal transduction. Enhancer (genetics).
Hematopoiesis. Hematopoietic stem cell transplantation. Hemoglobin. Sickle cell anemia.
Skin. Dermis. Fibroblast. Epidermis.
Skeletal muscle. Myogenesis. Myoblast.
Cloning. Dolly.
Limb development. Limb bud. Progress zone model. Apical ectodermal ridge. Polarizing region/Zone of polarizing activity. Sonic hedgehog.
Imaginal disc. Pax6. Aniridia. Neural tube.
Branching morphogenesis.
ABC model of flower development.


July 16, 2018 Posted by | Biology, Books, Botany, Cancer/oncology, Diabetes, Genetics, Medicine, Molecular biology, Ophthalmology | Leave a comment

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.”)
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.

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 (II)

Below I have added a few more observations of interest from the last half of the book. I have also bolded a few key observations and added some links along the way to make the post easier to read for people unfamiliar with these topics.

HCC [HepatoCellular Carcinoma, US] is the most common primary malignancy of the liver and globally is the fifth most common cancer [2]. […] the United States […] has seen a threefold increase between 1975 and 2007 [3]. Chronic hepatitis C virus (HCV) accounts for about half of this increase [2]. However, 15–50 % of new cases of HCC are labeled as cryptogenic or idiopathic, which suggests that other risk factors are likely playing a role [4]. NASH [Non-alcoholic steatohepatitis, US] has been proposed as the underlying cause of most cases of cryptogenic cirrhosis. […] A large proportion of cryptogenic cirrhosis […] likely represents end-stage NASH. […] In a large systematic review published in 2012, NAFLD or NASH cohorts with few or no cirrhosis cases demonstrated a minimal HCC risk with cumulative HCC mortality between 0 % and 3 % over study periods of up to two decades [8]. In contrast, consistently increased risk was observed in NASH-cirrhosis cohorts with cumulative incidence between 2.4 % over 7 years and 12.8 % over 3 years [8]. The risk of HCC was substantially lower among patients with NASH than in patients with viral hepatitis [8]. However, given the high and increasing prevalence of NAFLD, even a small increase in risk of HCC has the potential to transform into a huge case burden of HCC. […] Large population-based cohort studies from Europe have demonstrated a 1.86-fold to fourfold increase in risk of HCC among patients with diabetes [12]. Obesity, which is well established as a significant risk factor for the development of various malignancies, is associated with a 1.5-fold to fourfold increased risk for development of HCC [13]. Therefore, the excess risk of HCC in NAFLD is explained by both the increased risk for NAFLD itself with subsequent progression to NASH and the independent carcinogenic potential of diabetes and obesity [11]. […] In contrast to patients with HCC from other causes, patients with NAFLD-related HCC tend to be older and have more metabolic comorbidities but less severe liver dysfunction […] The exact mechanisms responsible for the development of HCC in NASH remain unclear.”

Patients with diabetes have an increased risk of gallstone disease, which includes gallstones, cholecystitis, or gallbladder cancer; the magnitude of the increased risk has varied across studies [22]. […] A recent systematic review and meta-analysis of studies evaluating the risk of gallstone disease estimated that a diagnosis of diabetes appears to increase the relative risk of gallstone disease by 56 % [22]. Intuitively, it would seem reasonable to attribute this to common risk factors for diabetes and gallstone disease (e.g., obesity, hyperlipidemia). However, adjustment for body mass index (BMI) in a number of studies included in the meta-analysis indicated diabetes had an independent effect on the risk of gallstone disease; it has been speculated that this is related to impaired gallbladder motility as part of diabetes-related visceral neuropathy [22]. […] A systematic review and meta-analysis suggests that both men and women with type 2 diabetes have an increased risk of gallbladder cancer (summary RR = 1.56, 95 % CI, 1.36–1.79), independent of smoking, BMI, and a history of gallstones [25]. […] While the relative risk of gallbladder cancer is increased in patients with type 2 diabetes, the absolute risk remains low […], varying from approximately 1.5 per 100,000 in North America to 25 per 100,000 in South America and Northern India [26]. […] There is a strong relationship between diabetes and hepatobiliary diseases […] Not surprisingly, autoimmune-based liver disease involving the biliary tree (i.e., primary biliary cirrhosis [PBC] and primary sclerosing cholangitis [PSC]) has been described in patients with type 1 diabetes. […] The prevalence of type 1 diabetes in patients with PSC is 4 %, and the RR of type 1 diabetes in patients with PSC was 7.95 in a large patient cohort (n = 678) [33, 34]. […] Although the relationship may not be intuitive, diabetes is intimately connected with a variety of hepatobiliary conditions […] Diabetes is often associated with more frequent adverse outcomes and should be managed aggressively.”

Impaired glucose tolerance is seen in 60 % of patients with cirrhosis [1]. Overt diabetes is seen in 20 % of patients with cirrhosis. However, it is important to note that there are two distinct types of diabetes seen with chronic liver disease. Patients can either have preexisting diabetes and later go on to develop progressive liver disease or develop diabetes as a result of cirrhosis. The latter is an entity which is sometimes referred to as “hepatogenous” diabetes. […] A recently published registry study from the UK […] demonstrated that patients with diabetes were more likely to be hospitalized with a chronic liver disease than nondiabetic patients [5]. […] type 2 diabetes was associated with an increased incidence of hospitalizations with alcoholic liver disease (RR 1.38 in men, RR 1.57 in women), nonalcoholic fatty liver disease (RR 3.03 in men, RR 5.11 in women), autoimmune liver disease (RR 1.50 in men, RR 1.25 in women), hemochromatosis (RR 1.67 in men, RR 1.60 in women), and hepatocellular carcinoma (RR 3.36 in men, RR 3.55 in women) [5, 6]. Diabetes has also been shown to affect liver disease complications. Diabetes is associated with events of hepatic decompensation such as development of ascites [7], variceal bleeding [8], and hepatic encephalopathy [9]. […] Cirrhosis is an important but under-recognized cause of mortality among patients with diabetes. In a population-based study involving nearly 7,200 patients that investigated the causes of death in patients with type 2 diabetes, chronic liver disease, and cirrhosis accounted for 4.4 % [14].”

“On average, 51 % of patients with type 1 diabetes mellitus and 35 % of patients with type 2 diabetes mellitus demonstrate pancreatic exocrine insufficiency (PEI) on fecal elastase testing where PEI is defined as fecal elastase less than 200 μg/g [17]. In a study of 1,000 patients with diabetes, including 697 with type 2 diabetes, 28.5 % of patients with type 1 and 19.9 % of patients with type 2 diabetes had severe PEI as defined by fecal elastase less than 100 μg/g [18]. […] However, there is a wide range of prevalence of PEI in these studies […] Given wide-ranging estimates, it is difficult to determine the true prevalence of PEI in patients with diabetes, especially as it translates to steatorrhea and maldigestion. […] Changes in gross and histological pancreatic morphology frequently accompany diabetes mellitus and may be a plausible link between diabetes and chronic pancreatitis. Pancreatic atrophy is often seen in autopsy studies of diabetes patients as well as with ultrasonography, computed tomography, and magnetic resonance imaging (MRI) [22–24]. Morphological changes of the pancreas in diabetes may be partially explained by the lack of trophic effect of insulin on acinar tissue. Residual exocrine function correlates well with residual beta-cell function in type 1 diabetes mellitus [25]. Yet, because not every patient with type 1 diabetes has pancreatic exocrine insufficiency, trophic action of insulin must not be the only factor. Indeed, as much of the close regulation of pancreatic exocrine function is carried out by neurohormonal mediators, diabetic neuropathy may also play a role in exocrine insufficiency in diabetics [26]. […] Though the true prevalence of PEI arising from diabetes is not definitively known, PEI leading to diabetes mellitus, termed type 3c diabetes (T3cDM) [27], appears to be less common and accounts for 5–10 % of diabetic populations [28]. A T3cDM diagnosis is made in the absence of type 1 diabetes autoimmune markers and in the setting of imaging and laboratory evidence of PEI [29]. Management of T3cDM has not been well studied, given large trials have excluded this subset of patients. […] Without dedicated clinical trials, treatment for type 3c diabetes is not standardized and commonly reflects methods used for type 2 diabetes.”

“Diabetes has been associated with an increased risk of cancer. In a Swedish population study, 24 cancer types were found to have an increased incidence among those with type 2 diabetes. Pancreatic cancer had the highest standardized incidence ratio of 2.98 (observed/expected cancer cases) compared to other cancer sites [31]. The three cell types found in the normal pancreas include acinar, ductal, and islet cells. Acinar cells comprise a majority of the organ volume (80 %), but greater than 85 % of malignant lesions arise from the ductal structures resulting in adenocarcinoma. […] According to the Surveillance, Epidemiology, and End Results (SEER) Program, pancreatic cancer is the twelfth most common cancer and the second most common gastrointestinal type behind colorectal cancer [32]. […] pancreatic cancer represents 3 % of all new cancer cases within the United States. Given the poor long-term survival rates, incidence and prevalence of the pancreatic cancer are similar. […] a majority of those with pancreatic cancer present with metastatic disease (53 %) […]. Males are affected more than females, and the median age at time of diagnosis is 71. […] Meta-analyses have demonstrated an increased risk of pancreatic cancer in those with diabetes […] [However] diabetes may be a result of pancreatic cancer as opposed to pancreatic cancer being a result of diabetes. […] Risk of pancreatic cancer does not increase as the duration of diabetes increases. Given the lack of cost-effective, noninvasive, and sensitive screening tests for pancreatic cancer, population-wide screening for pancreatic cancer in those with diabetes is prohibitive.”

June 23, 2018 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Gastroenterology | 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

Molecular biology (III)

Below I have added a few quotes and links related to the last few chapters of the book‘s coverage.

“Normal ageing results in part from exhaustion of stem cells, the cells that reside in most organs to replenish damaged tissue. As we age DNA damage accumulates and this eventually causes the cells to enter a permanent non-dividing state called senescence. This protective ploy however has its downside as it limits our lifespan. When too many stem cells are senescent the body is compromised in its capacity to renew worn-out tissue, causing the effects of ageing. This has a knock-on effect of poor intercellular communication, mitochondrial dysfunction, and loss of protein balance (proteostasis). Low levels of chronic inflammation also increase with ageing and could be the trigger for changes associated with many age-related disorders.”

“There has been a dramatic increase in ageing research using yeast and invertebrates, leading to the discovery of more ‘ageing genes’ and their pathways. These findings can be extrapolated to humans since longevity pathways are conserved between species. The major pathways known to influence ageing have a common theme, that of sensing and metabolizing nutrients. […] The field was advanced by identification of the mammalian Target Of Rapamycin, aptly named mTOR. mTOR acts as a molecular sensor that integrates growth stimuli with nutrient and oxygen availability. Small molecules such as rapamycin that reduce mTOR signalling act in a similar way to severe dietary restriction in slowing the ageing process in organisms such as yeast and worms. […] Rapamycin and its derivatives (rapalogs) have been involved in clinical trials on reducing age-related pathologies […] Another major ageing pathway is telomere maintenance. […] Telomere attrition is a hallmark of ageing and studies have established an association between shorter telomere length (TL) and the risk of various common age-related ailments […] Telomere loss is accelerated by known determinants of ill health […] The relationship between TL and cancer appears complex.”

“Cancer is not a single disease but a range of diseases caused by abnormal growth and survival of cells that have the capacity to spread. […] One of the early stages in the acquisition of an invasive phenotype is epithelial-mesenchymal transition (EMT). Epithelial cells form skin and membranes and for this they have a strict polarity (a top and a bottom) and are bound in position by close connections with adjacent cells. Mesenchymal cells on the other hand are loosely associated, have motility, and lack polarization. The transition between epithelial and mesenchymal cells is a normal process during embryogenesis and wound healing but is deregulated in cancer cells. EMT involves transcriptional reprogramming in which epithelial structural proteins are lost and mesenchymal ones acquired. This facilitates invasion of a tumour into surrounding tissues. […] Cancer is a genetic disease but mostly not inherited from the parents. Normal cells evolve to become cancer cells by acquiring successive mutations in cancer-related genes. There are two main classes of cancer genes, the proto-oncogenes and the tumour suppressor genes. The proto-oncogenes code for protein products that promote cell proliferation. […] A mutation in a proto-oncogene changes it to an ‘oncogene’ […] One gene above all others is associated with cancer suppression and that is TP53. […] approximately half of all human cancers carry a mutated TP53 and in many more, p53 is deregulated. […] p53 plays a key role in eliminating cells that have either acquired activating oncogenes or excessive genomic damage. Thus mutations in the TP53 gene allows cancer cells to survive and divide further by escaping cell death […] A mutant p53 not only lacks the tumour suppressor functions of the normal or wild type protein but in many cases it also takes on the role of an oncogene. […] Overall 5-10 per cent of cancers occur due to inherited or germ line mutations that are passed from parents to offspring. Many of these genes code for DNA repair enzymes […] The vast majority of cancer mutations are not inherited; instead they are sporadic with mutations arising in somatic cells. […] At least 15 per cent of cancers are attributable to infectious agents, examples being HPV and cervical cancer, H. pylori and gastric cancer, and also hepatitis B or C and liver cancer.”

“There are about 10 million different sites at which people can vary in their DNA sequence withing the 3 billion bases in our DNA. […] A few, but highly variable sequences or minisatellites are chosen for DNA profiling. These give a highly sensitive procedure suitable for use with small amounts of body fluids […] even shorter sequences called microsatellite repeats [are also] used. Each marker or microsatellite is a short tandem repeat (STR) of two to five base pairs of DNA sequence. A single STR will be shared by up to 20 per cent of the population but by using a dozen or so identification markers in profile, the error is miniscule. […] Microsatellites are extremely useful for analysing low-quality or degraded DNA left at a crime scene as their short sequences are usually preserved. However, DNA in specimens that have not been optimally preserved persists in exceedingly small amounts and is also highly fragmented. It is probably also riddled by contamination and chemical damage. Such sources of DNA sources of DNA are too degraded to obtain a profile using genomic STRs and in these cases mitochondrial DNA, being more abundant, is more useful than nuclear DNA for DNA profiling. […]  Mitochondrial DNA profiling is the method of choice for determining the identities of missing or unknown people when a maternally linked relative can be found. Molecular biologists can amplify hypervariable regions of mitochondrial DNA by PCR to obtain enough material for analysis. The DNA products are sequenced and single nucleotide differences are sought with a reference DNA from a maternal relative. […] It has now become possible for […] ancient DNA to reveal much more than genotype matches. […] Pigmentation characteristics can now be determined from ancient DNA since skin, hair, and eye colour are some of the easiest characteristics to predict. This is due to the limited number of base differences or SNPs required to explain most of the variability.”

“A broad range of debilitating and fatal conditions, non of which can be cured, are associated with mitochondrial DNA mutations. […] [M]itochondrial DNA mutates ten to thirty times faster than nuclear DNA […] Mitochondrial DNA mutates at a higher rate than nuclear DNA due to higher numbers of DNA molecules and reduced efficiency in controlling DNA replication errors. […] Over 100,000 copies of mitochondrial DNA are present in the cytoplasm of the human egg or oocyte. After fertilization, only maternal mitochondria survive; the small numbers of the father’s mitochondria in the zygote are targeted for destruction. Thus all mitochondrial DNA for all cell types in the resulting embryo is maternal-derived. […] Patients affected by mitochondrial disease usually have a mixture of wild type (normal) and mutant mitochondrial DNA and the disease severity depends on the ratio of the two. Importantly the actual level of mutant DNA in a mother’s heteroplas[m]y […curiously the authors throughout the coverage insist on spelling this ‘heteroplasty’, which according to google is something quite different – I decided to correct the spelling error (?) here – US] is not inherited and offspring can be better or worse off than the mother. This also causes uncertainty since the ratio of wild type to mutant mitochondria may change during development. […] Over 700 mutations in mitochondrial DNA have been found leading to myopathies, neurodegeneration, diabetes, cancer, and infertility.”


Dementia. Alzheimer’s disease. Amyloid hypothesis. Tau protein. Proteopathy. Parkinson’s disease. TP53-inducible glycolysis and apoptosis regulator (TIGAR).
Progeria. Progerin. Werner’s syndrome. Xeroderma pigmentosum. Cockayne syndrome.
Alternative lengthening of telomeres: models, mechanisms and implications (Nature).
Coats plus syndrome.
Neoplasia. Tumor angiogenesis. Inhibitor protein MDM2.
Li–Fraumeni syndrome.
Non-coding RNA networks in cancer (Nature).
Cancer stem cell. (“The reason why current cancer therapies often fail to eradicate the disease is that the CSCs survive current DNA damaging treatments and repopulate the tumour.” See also this IAS lecture which covers closely related topics – US.)
Restriction fragment length polymorphism (RFLP).
Archaic human admixture with modern humans.
El Tor strain.
DNA barcoding.
Hybrid breakdown/-inviability.
Digital PCR.
Pearson’s syndrome.
Mitochondrial replacement therapy.
Synthetic biology.
Craig Venter.
Genome editing.

June 3, 2018 Posted by | Biology, Books, Cancer/oncology, Genetics, Medicine, Molecular biology | Leave a comment

Alcohol and Aging

I’m currently reading this book. Below I have added some observations from the first five chapters. The book has 17 chapters in total, covering a wide variety of topics. I like the coverage so far. All the highlighted observations below were highlighted by me; they were not written in bold in the book.

“Alcohol consumption and alcohol-related deaths or problems have recently increased among older age groups in many developed countries […]. This increase in consumption, in combination with the ageing of populations worldwide, means that the absolute number of older people with alcohol problems is on the increase and a real danger exists that a “silent epidemic” may be evolving [2]. Although there is growing recognition of this public health problem, clinicians consistently under-detect alcohol problems and under-deliver behaviour change interventions to older people [8, 9] […] While older adults historically demonstrate much lower rates of alcohol use compared with younger adults [4, 5] and present to substance abuse treatment programs less frequently than their younger counterparts [6], substantial evidence suggests that at-risk alcohol use and alcohol use disorder (AUD) among older adults has been under-identified for decades [7, 8]. […] Individuals who have had alcohol-related problems over several decades and have survived into old age tend to be referred to as early onset drinkers. It is estimated that two-thirds of older drinkers fall into this category [2]. […] Late-onset drinking accounts for the remaining one-third of older people who use alcohol excessively [2]. Late-onset drinkers usually begin drinking in their 50s or 60s and tend to be of a higher socio-economic status than early onset drinkers with higher levels of education and income [2]. Stressful life events, such as bereavement or retirement, may trigger late-onset drinking […]. One study demonstrated that 70 % of late-onset drinkers had experienced stressful life events, compared with 25 % of early onset drinkers [17]. Those whose alcohol problems are of late onset tend to have fewer health problems and are more receptive to treatment than those with early onset problems […] Our data highlighted that losing a parent or partner was often pinpointed as an event that had prompted an escalation in alcohol use […] A recent systematic review which examined the relationship between late-life spousal bereavement and changes in routine health behaviour over 32 different studies [however] found only moderate evidence for increased alcohol consumption [41].”

“Understanding alcohol use among older adults requires a life course perspective [2] […]. Broadly speaking, to understand alcohol consumption patterns and associated risks among older adults, one must consider both biopsychosocial processes that emerge earlier in life and aging-specific processes, such as multimorbidity and retirement. […] In the population overall, older adulthood is a life stage in which overall alcohol consumption decreases, binge drinking becomes less common, and individuals give up drinking. […] data collected internationally supports the assertion that older adulthood is a period of declining drinking. […] Two forces specific to later life may be at work in decreasing levels of alcohol consumption in late life. First, the “sick-quitter” hypothesis [12, 13] suggests that changes in health during the aging process limit alcohol consumption. With declines in health, older adults decrease the quantity and frequency of their drinking leading to lower average consumption in the overall older adult population [11, 14]. Similarly, differential mortality of heavy drinkers may lead to decreases in alcohol use among cohorts of older adults; these changes in average drinking may be a function of early mortality of heavy drinkers [15]. Although alcohol use generally declines throughout the course of older adulthood, the population of older adults exhibits a great deal of variability in drinking patterns. […] longitudinal research studies have found that older men tend to consume alcohol at higher levels than women, and their consumption levels decline more slowly than women’s [6]. […] National survey data [from the UK] estimate that approximately 40–45% of older adults (65+) drank alcohol in the past year […] Numerous studies suggest that lifetime nondrinkers are more likely to be female, display greater religiosity (e.g., attend religious services), and have lower levels of education than their moderate drinking peers [20, 21]. […] Older adult nondrinkers are a heterogeneous population, and as such, lifetime nondrinkers and former drinkers should be studied separately. This is especially important when considering the issue of health and drinking because the context for abstinence may be different in these two groups [23, 24].”

“[V]ersion 5 of the DSM manual abandoned separate alcohol abuse and alcohol dependence diagnoses, and combined them into a single diagnosis: alcohol use disorder (AUD). […] The NSDUH survey estimated a past-year prevalence rate of alcohol abuse or dependence of 6.1 % among those aged 50–54 and 2.2 % among those ages 65 and older. […] AUD is the most severe manifestation of alcohol-related pathology among older adults, but most alcohol-related harm is not a function of disordered drinking [55]. […] older adults commonly take medications that interact with alcohol. A recent study of community-dwelling older adults (aged 57+) found that 41% consumed alcohol regularly and among regular alcohol consumers, 51 % used at least one alcohol interacting medication [57]. An analysis of the Irish Longitudinal Study on Ageing identified a high prevalence of alcohol use (60 %) among individuals taking alcohol interacting medications [58]. Falls are also a common health concern for older adults, and there is evidence of increased risk of falls among older adults who drink more than 14 drinks per week [59] […] a study by Holahan and colleagues [44] explored longitudinal outcomes for individuals who were moderate drinkers (below the weekly at-risk threshold) but who engaged in heavy episodic drinking (exceeded day threshold). Individuals were first surveyed between the ages of 55 and 65 and followed for 20 years. Episodic heavy drinkers were twice as likely to have died in the 20-year follow-up period compared with those who were not episodic heavy drinkers […to clarify, none of the episodic heavy drinkers in that study would qualify for a diagnosis of AUD, US] […] Alcohol use in the aging population has been defined through various thresholds of risk. Each approach brings certain advantages and problems. Using alcohol related disorders as a benchmark misses many older adults who may experience alcohol-related consequences to their health and well-being even though they do not meet criteria for disordered drinking. More conservative measures of alcohol risk may identify at-risk drinking in those for whom alcohol use may never compromise their health. […] among light to moderate drinkers, the level of risk is uncertain.

Among adults 65 years old and older in 2000–2001, just under 49.6% reported lifetime use [of tobacco] and 14% reported use in the last 12 months [30]. […] Data collected by the Centers for Disease Control in 2008 revealed that only 9% of individuals aged 65 and older reported being current smokers [42]. […] data from the 2001–2002 NESARC reveal a strong relationship between AUDs and tobacco use […] in 2012, 19.3% of adults 65 and older reported having ever used illicit drugs in their lifetime, whereas 47.6% of adults between the ages 60 and 64 reported lifetime drug use. […] In the 2005–2006 NSDUH […] 3.9% of adults aged 50–64, the bulk of the Baby Boomers at that time, reported past year marijuana use, compared to only 0.7% of those 65 years old and older [53]. Among those aged 50 and older reporting marijuana use, 49% reported using marijuana more than 30 days in the past year, with a mean of 81 days. […] The increasingly widespread, legal availability and acceptance of cannabis, for both medicinal and recreational use, may pose unique risks in an aging population. Across age groups, cannabis is known to impair short-term memory, increase one’s heart and respiratory rate, and elevate blood pressure [56]. […] For older adults, these risks may be particularly pronounced, especially for those whose cognitive or cardiovascular systems may already be compromised. […] Most researchers generally consider existing estimations of mental health and substance use disorders to be underestimations among older adults. […] Assumptions that older adults do not drink or use illicit substances should not be made.

“Although several studies in the United States and elsewhere have shown that moderate alcohol consumption is associated with reduced risk for heart disease [16–20] and that heavy intake is associated with increased risk of CVD incidence [6, 21] and all-cause mortality in various populations […], data specific to effects of alcohol in elderly populations remain scant. The few studies available, e.g., the Cardiovascular Health Study, suggest that moderate alcohol use is beneficial and may be associated with reduced Medicare costs among individuals with CVD [25]. The benefits and risks of alcohol consumption are dose dependent with a consistent cut-point for cardiovascular benefits being 1 drink per day for women and about 2 drinks per day for men [21]. These cut-points have also been observed for associations between alcohol consumption and all-cause mortality [21, 26]. Although there are many similarities in the effects of alcohol on CVD across many populations, the magnitude and significance of the association between amount of alcohol consumed and CVD risk remain inconsistent, especially within countries, regions, age, sex, race, and other population strata […] As shown in a recent review [33], a drinking pattern characterized by moderate drinking without episodes of heavy drinking may be more beneficial for CVD protection when compared to patterns that include heavy drinking episodes. […] In additional to amount of alcohol consumed per se, the pattern of alcohol consumption, commonly defined as the number of drinking days per week is also associated with CVD outcomes independent of the amount of alcohol consumed [18, 24, 34–37]. In general, a drinking pattern characterized by alcohol consumption on 4 or more days of the week is inversely associated with MI, stroke, and CVD risk factors“.

“The relation between moderate alcohol consumption and intermediate CVD markers was summarized in two recent reviews [6, 42]. Overall, moderate alcohol consumption is associated with improved concentrations of CVD risk markers, particularly HDL-C concentrations [18, 31, 43, 44]. Whether HDL-C resulting from moderate alcohol intake is functional and beneficial for cardioprotection remains unknown […] While moderate alcohol consumption shows no appreciable benefit on LDL-C, it is associated with significant improvement in insulin sensitivity […] Alcohol intake may also influence CVD markers through its effects on absorption and metabolism of nutrients in the body. This is critical especially in the elderly who may have deficiencies or insufficiencies of nutrients such as folate, vitamin B12, vitamin D, magnesium, and iron. Indeed, moderate alcohol consumption has been shown to improve status of nutrients associated with cardiovascular effects. For example, it improves iron absorption in humans [52, 53] and is associated with higher vitamin D levels in men [54]. […] heavy alcohol consumption [on the other hand] leads to deficiencies of magnesium [55], zinc, folate [56], and other nutrients and damages the intestinal lining and the liver impairing nutrient absorption and metabolism [57]. These effects of alcohol are likely to be worse in the elderly. […] chronic heavy drinking lowers magnesium [55], a nutrient needed for proper metabolism of vitamin D [58], implying that supplementation with vitamin D in heavy drinkers may not be as effective as intended. These effects of alcohol could also extend to prescription medications that are in common use among the elderly. […] Taken together, moderate alcohol seems to protect against cardiovascular disease across the whole life span but the data on older age groups are scanty. Theoretical considerations as well as emerging data on intermediate outcomes such as lipids, suggest that moderate alcohol could beneficially interact with medications such as statins to improve cardiovascular health but heavy alcohol could worsen CVD risk, especially in the elderly.”

Alcohol is one of the main risk factors for cancer, with alcohol use attributed to up to 44% of some cancers [2, 3] and between 3.2 and 3.7 % of all cancer deaths [4, 5]. Since 1988, alcohol has been classified as a carcinogen [6]. Types of cancers linked to alcohol use include cancers of the liver, pancreas, esophagus, breast, pharynx, and larynx with most convincing evidence for alcohol-related cancers of the upper aerodigestive tract, stomach, colorectum, liver, and the lungs [2, 7]. All of these cancers have a much higher incidence and mortality rate in older adults […] For alcohol-associated cancers, 66–95% of new cases appear in those 55 years of age or older [8, 9]. For alcohol-associated cancers, other than breast cancer, 75–95 % of new cases occur in those 55 years of age or older [8, 10, 11]. […] Four countries with a decline in alcohol use (France, the UK, Sweden, and US) have […] demonstrated a stabilization or decline in the incidence and mortality rates for types of cancers closely associated with alcohol use [12]. […] The increased risk for cancer related to alcohol use is based on a combination of both quantity/frequency and duration of use, with those consuming alcohol for 20 or more years at increased risk [14]. […] consumption of alcohol at lower levels may also increase the risk for alcohol-related cancers. Nelson et al. reported that daily consumption of 1.5 drinks or greater accounted for 26–35% of alcohol-attributable deaths [5]. Thus, the evidence is growing that daily drinking, even at lower levels, increases the risk for developing cancer in later life with the conclusion that there may be no safe threshold level for alcohol consumption below which there is no risk for cancer [6, 16, 17].”

The risk for developing alcohol-related cancer is increased among those who have a history of concurrent tobacco use and at-risk alcohol use […] Among individuals who have a history of smoking two or more packs of cigarettes and consuming more than four alcoholic drinks per day, the risk of head and neck cancer is increased greater than 35-fold [22]. […] At least 75 % of head and neck cancer is associated with alcohol and tobacco use[9]. […] There are gender differences in alcohol attributable cancer deaths with over half (56–66 %) of all alcohol-attributable cancer deaths in females resulting from breast cancer [5]. […] For women, even low-risk alcohol use (5–14.9 g/day or one standard drink of alcohol or less) increases the risk of cancer, mainly breast cancer [18]. […] Alcohol use during cancer treatment can complicate the treatment regimen and lead to poor long-term outcomes. […] Alcohol use is correlated with poor survival outcomes in oncology patients. […] Another issue for patients during cancer treatment is quality of life. Alcohol consumption at higher levels […] or patients who screened positive for a possible AUD during cancer treatment experienced worse quality of life outcomes, including problems with pain, sleep, dyspnea, total distress, anxiety, coping, shortness of breath, diarrhea, poor emotional functioning, fatigue, and poor appetite [58, 59]. Current alcohol use has also been associated with higher pain scores and long-term use of opioids [48, 49].”

May 14, 2018 Posted by | Books, Cancer/oncology, Cardiology, Epidemiology, Medicine | 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.

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.”)
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

100 cases in surgery (I)

We hope this book will give a good introduction to common surgical conditions seen in everyday surgical practice. Each question has been followed up with a brief overview of the condition and its immediate management. The book should act as an essential revision aid for surgical finals and as a basis for practising surgery after qualification.

This book is far from the first book I read in this series, and the format is the same as usual: There are 100 cases included, with a variety of different organ systems and diagnoses/settings encountered. The first page of a case presents a basic history and some key findings (lab tests, x-rays, results of imaging studies) and asks you a few questions about the case; the second and sometimes third page then provides answers to the questions and some important observations of note. Cases have of course been chosen in order to illustrate a wide variety of different medical scenarios involving many different organ systems and types of complaints. All cases are ‘to some extent’ surgical in nature, but in far from all cases will surgery necessarily be the required/indicated treatment option in the specific context; sometimes non-surgical management will be preferable, sometimes (much too often, in some oncological settings..) tumours are not resectable, some of the cases deal with complications to surgical procedures, etc.

The degree with which I was familiar with the topics covered in the book was highly variable; I’ve never really read any previous medical textbooks (…more or less-) exclusively devoted to surgical topics, but I have previously in a variety of contexts read about topics such as neurosurgery, cardiovascular surgery, and the recent endocrinology text of course covered surgical topics within this field in some detail; on the other hand my knowledge of (e.g.) otorhinolaryngology is, well, …limited. Part of my motivation for having a go at this book was precisely that my knowledge of the field of surgery felt a bit too fragmented (…and, in some cases, non-existent) even if I still didn’t feel like reading, say, an 800-page handbook like this one on these topics. Despite the more modest page-count of this book I would caution against thinking this is a particularly easy/fast read; there are a lot of cases and each of them has something to teach you – and as should also be easily inferred from the quote from the preface included above, this book is probably not readable if you don’t have some medical background of one kind or another (‘read fluent medical textbook’).

Below I have added some links to topics covered in the first half of the book, as well as a few observations from the coverage.

Abdominal hernias.
Large-bowel obstruction. Small-bowel obstruction.
Perianal abscess.
Malignant melanoma. (“Factors in the history that are suggestive of malignant change in a mole[:] *Change in surface *itching *increase in size/shape/thickness *Change in colour *bleeding/ulceration *brown/pink halo […] *enlarged local lymph nodes”)
Meckel’s diverticulum.
Rectal cancer. Colorectal Cancer. (“Colorectal cancer is the second commonest cancer causing death in the UK […]. Right-sided lesions can present with iron-deficiency anaemia, weight loss or a right iliac fossa mass. Lef-sided lesions present with alteration in bowel habit, rectal bleeding, or as an emergency with obstruction or perforation.”)
Sigmoid and cecal volvulus.
Anal fissure.
Diverticular disease.
Crohn Disease Pathology. (“Increasing frequency of stool, anorexia, low-grade fever, abdominal tenderness and anaemia suggest an inflammatory bowel disease. […] The initial management of uncomplicated Crohn’s disease should be medical.”)
Ulcerative colitis. (“Long-standing ulcerative colitis carries an approximate 3 per cent risk of malignant change after 10 years”).
Acute Cholecystitis and Biliary Colic. (“The majority of episodes of acute cholecystitis settle with analgesia and antibiotics.”)
Acute pancreatitis. (“Ranson’s criteria are used to grade the severity of alcoholic pancreatitis […] Each fulfilled criterion scores a point and the total indicates the severity. […] Estimates on mortality are based on the number of points scored: 0–2 = 2 per cent; 3–4 = 15 per cent; 5–6 = 40 per cent; >7 = 100 per cent. […] The aim of treatment is to halt the progression of local inflammation into systemic inflammation, which can result in multi-organ failure. Patients will often require nursing in a high-dependency or intensive care unit. They require prompt fluid resuscitation, a urinary catheter and central venous pressure monitoring. Early enteral feeding is advocated by some specialists. If there is evidence of sepsis, the patient should receive broad-spectrum antibiotics. […] patients should be managed aggressively”)
Ascending cholangitis.
Surgical Treatment of Perforated Peptic Ulcer.
Splenic rupture. Kehr’s sign.
Barrett’s esophagus. Peptic strictures of the esophagus. (“Proton pump inhibitors are effective in reducing stricture recurrence and in the treatment of Barrett’s oesophagus. If frequent dilatations are required despite acid suppression, then surgery should be considered. […] The risk of cancer is increased by up to 30 times in patients with Barrett’s oesophagus. If Barrett’s oesophagus is found at endoscopy, then the patient should be started on lifelong acid suppression. The patient should then have endoscopic surveillance to detect dysplasia before progression to carcinoma.”)
Esophageal Cancer. (“oesophageal carcinoma […] typically affects patients between 60 and 70 years of age and has a higher incidence in males. […] Dysphagia is the most common presenting symptom and is often associated with weight loss. […] Approximately 40 per cent of patients are suitable for surgical resection.”)
Pancreatic cancer. Courvoisier’s law. (“Pancreatic cancer classically presents with painless jaundice from biliary obstruction at the head of the pancreas and is associated with a distended gallbladder. Patients with pancreatic cancer can also present with epigastric pain, radiating through to the back, and vomiting due to duodenal obstruction. Pancreatic cancer occurs in patients between 60 and 80 years of age […] Roughly three-quarters have metastases at presentation […] Only approximately 15 per cent of pancreatic malignancies are surgically resectable.”)
Chronic pancreatitis. (“Chronic pancreatitis is an irreversible inflammation causing pancreatic fibrosis and calcification. Patients usually present with chronic abdominal pain and normal or mildly elevated pancreatic enzyme levels. The pancreas may have lost its endocrine and exocrine function, leading to diabetes mellitus and steatorrhea. […] The mean age of onset is 40 years, with a male preponderance of 4:1. […] thirty per cent of cases of chronic pancreatitis are idiopathic.”)
Gastric cancer. (“Gastric carcinoma is the second commonest cause of cancer worldwide. […] The highest incidence is in Eastern Asia, with a falling incidence in Western Europe. Diet and H. pylori infection are thought to be the two most important environmental factors in the development of gastric cancer. Diets rich in pickled vegetables, salted fish and smoked meats are thought to predispose to gastric cancer. […] Gastric cancer typically presents late and is associated with a poor prognosis. […] Surgical resection is not possible in the majority of patients.”)
Fibroadenomas of the breast. (“On examination, [benign fibroadenomas] tend to be spherical, smooth and sometimes lobulated with a rubbery consistency. The differential diagnosis includes fibrocystic disease (fluctuation in size with menstrual cycle and often associated with mild tenderness), a breast cyst (smooth, well-defined consistency like fibroadenoma but a hard as opposed to a rubbery consistency) or breast carcinoma (irregular, indistinct surface and shape with hard consistency).”)
Graves’ disease. (“Patients often present with many symptoms including palpitations, anxiety, thirst, sweating, weight loss, heat intolerance and increased bowel frequency. Enhanced activity of the adrenergic system also leads to agitation and restlessness. Approximately 25–30 per cent of patients with Graves’ disease have clinical evidence of ophthalmopathy. This almost only occurs in Graves’ disease (very rarely found in hypothyroidism)”)
Ruptured abdominal aortic aneurysm: a surgical emergency with many clinical presentations.
Temporal arteritis.
Transient ischemic attack. (“A stenosis of more than 70 per cent in the internal carotid artery is an indication for carotid endarterectomy in a patient with TIAs […]. The procedure should be carried out as soon as possible and within 2 weeks of the symptoms to prevent a major stroke.”)
Acute Mesenteric Ischemia.
Acute limb ischaemia. (“Signs and symptoms of acute limb ischaemia – the six Ps: •Pain •Pulseless •Pallor •Paraesthesia •Perishingly cold •Paralysis”).
Cervical rib.
Peripheral Arterial Occlusive Disease. (“The disease will only progress in one in four patients with intermittent claudication: therefore, unless the disease is very disabling for the patient, treatment is conservative. […] Investigations should include ankle–brachial pressure index (ABPI): this is typically <0.9 in patients with claudication; however, calcified vessels (typically in patients with diabetes) may result in an erroneously normal or high ABPI. […] Regular exercise has been shown to increase the claudication distance. In the minority of cases that do require intervention (i.e. severe short distance claudication not improving with exercise), angioplasty and bypass surgery are considered.”)
Venous ulcer. Marjolin’s ulcer. (“It is important to distinguish arterial from venous ulceration, as use of compression to treat the former type of ulcer is contraindicated.”)

April 14, 2018 Posted by | Books, Cancer/oncology, Gastroenterology, Medicine | 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

Endocrinology (part 4 – reproductive endocrinology)

Some observations from chapter 4 of the book below.

“*♂. The whole process of spermatogenesis takes approximately 74 days, followed by another 12-21 days for sperm transport through the epididymis. This means that events which may affect spermatogenesis may not be apparent for up to three months, and successful induction of spermatogenesis treatment may take 2 years. *♀. From primordial follicle to primary follicle, it takes about 180 days (a continuous process). It is then another 60 days to form a preantral follicle which then proceeds to ovulation three menstrual cycles later. Only the last 2-3 weeks of this process is under gonadotrophin drive, during which time the follicle grows from 2 to 20mm.”

“Hirsutism (not a diagnosis in itself) is the presence of excess hair growth in ♀ as a result of androgen production and skin sensitivity to androgens. […] In ♀, testosterone is secreted primarily by the ovaries and adrenal glands, although a significant amount is produced by the peripheral conversion of androstenedione and DHEA. Ovarian androgen production is regulated by luteinizing hormone, whereas adrenal production is ACTH-dependent. The predominant androgens produced by the ovaries are testosterone and androstenedione, and the adrenal glands are the main source of DHEA. Circulating testosterone is mainly bound to sex hormone-binding globulin (SHBG), and it is the free testosterone which is biologically active. […] Slowly progressive hirsutism following puberty suggests a benign cause, whereas rapidly progressive hirsutism of recent onset requires further immediate investigation to rule out an androgen-secreting neoplasm. [My italics, US] […] Serum testosterone should be measured in all ♀ presenting with hirsutism. If this is <5nmol/L, then the risk of a sinister cause for her hirsutism is low.”

“Polycystic ovary syndrome (PCOS) *A heterogeneous clinical syndrome characterized by hyperandrogenism, mainly of ovarian origin, menstrual irregularity, and hyperinsulinaemia, in which other causes of androgen excess have been excluded […] *A distinction is made between polycystic ovary morphology on ultrasound (PCO which also occurs in congenital adrenal hyperplasia, acromegaly, Cushing’s syndrome, and testesterone-secreting tumours) and PCOS – the syndrome. […] PCOS is the most common endocrinopathy in ♀ of reproductive age; >95% of ♀ presenting to outpatients with hirsutism have PCOS. *The estimated prevalence of PCOS ranges from 5 to 10% on clinical criteria. Polycystic ovaries on US alone are present in 20-25% of ♀ of reproductive age. […] family history of type 2 diabetes mellitus is […] more common in ♀ with PCOS. […] Approximately 70% of ♀ with PCOS are insulin-resistant, depending on the definition. […] Type 2 diabetes mellitus is 2-4 x more common in ♀ with PCOS. […] Hyperinsulinaemia is exacerbated by obesity but can also be present in lean ♀ with PCOS. […] Insulin […] inhibits SHBG synthesis by the liver, with a consequent rise in free androgen levels. […] Symptoms often begin around puberty, after weight gain, or after stopping the oral contraceptive pill […] Oligo-/amenorrhoea [is present in] 70% […] Hirsutism [is present in] 66% […] Obesity [is present in] 50% […] *Infertility (30%). PCOS accounts for 75% of cases of anovulatory infertility. The risk of spontaneous miscarriage is also thought to be higher than the general population, mainly because of obesity. […] The aims of investigations [of PCOS] are mainly to exclude serious underlying disorders and to screen for complications, as the diagnosis is primarily clinical […] Studies have uniformly shown that weight reduction in obese ♀ with PCOS will improve insulin sensitivity and significantly reduce hyperandrogenaemia. Obese ♀ are less likely to respond to antiandrogens and infertility treatment.”

“Androgen-secreting tumours [are] [r]are tumours of the ovary or adrenal gland which may be benign or malignant, which cause virilization in ♀ through androgen production. […] Virilization […] [i]ndicates severe hyperandrogenism, is associated with clitoromegaly, and is present in 98% of ♀ with androgen-producing tumours. Not usually a feature of PCOS. […] Androgen-secreting ovarian tumours[:] *75% develop before the age of 40 years. *Account for 0.4% of all ovarian tumours; 20% are malignant. *Tumours are 5-25cm in size. The larger they are, the more likely they are to be malignant. They are rarely bilateral. […] Androgen-secreting adrenal tumours[:] *50% develop before the age of 50 years. *Larger tumours […] are more likely to be malignant. *Usually with concomitant cortisol secretion as a variant of Cushing’s syndrome. […] Symptoms and signs of Cushing’s syndrome are present in many of ♀ with adrenal tumours. […] Onset of symptoms. Usually recent onset of rapidly progressive symptoms. […] Malignant ovarian and adrenal androgen-secreting tumours are usually resistant to chemotherapy and radiotherapy. […] *Adrenal tumours. 20% 5-year survival. Most have metastatic disease at the time of surgery. *Ovarian tumours. 30% disease-free survival and 40% overall survival at 5 years. […] Benign tumours. *Prognosis excellent. *Hirsutism improves post-operatively, but clitoromegaly, male pattern balding, and deep voice may persist.”

*Oligomenorrhoea is defined as the reduction in the frequency of menses to <9 periods a year. *1° amenorrhoea is the failure of menarche by the age of 16 years. Prevalence ~0.3% *2° amenorrhoea refers to the cessation of menses for >6 months in ♀ who had previously menstruated. Prevalence ~3%. […] Although the list of causes is long […], the majority of cases of secondary amenorrhoea can be accounted for by four conditions: *Polycystic ovary syndrome. *Hypothalamic amenorrhoea. *Hyperprolactinaemia. *Ovarian failure. […] PCOS is the only common endocrine cause of amenorrhoea with normal oestrogenization – all other causes are oestrogen-deficient. Women with PCOS, therefore, are at risk of endometrial hyperplasia, and all others are at risk of osteoporosis. […] Anosmia may indicate Kallman’s syndrome. […] In routine practice, a common differential diagnosis is between mild version of PCOS and hypothalamic amenorrhoea. The distinction between these conditions may require repeated testing, as a single snapshot may not discriminate. The reason to be precise is that PCOS is oestrogen-replete and will, therefore, respond to clomiphene citrate (an antioestrogen) for fertility. HA will be oestrogen-deficient and will need HRT and ovulation induction with pulsatile GnRH or hMG [human Menopausal Gonadotropins – US]. […] […] 75% of ♀ who develop 2° amenorrhoea report hot flushes, night sweats, mood changes, fatigue, or dyspareunia; symptoms may precede the onset of menstrual disturbances.”

“POI [Premature Ovarian Insufficiency] is a disorder characterized by amenorrhoea, oestrogen deficiency, and elevated gonadotrophins, developing in ♀ <40 years, as a result of loss of ovarian follicular function. […] *Incidence – 0.1% of ♀ <30 years and 1% of those <40 years. *Accounts for 10% of all cases of 2° amenorrhoea. […] POI is the result of accelerated depletion of ovarian germ cells. […] POI is usually permanent and progressive, although a remitting course is also experienced and cannot be fully predicted, so all women must know that pregnancy is possible, even though fertility treatments are not effective (often a difficult paradox to describe). Spontaneous pregnancy has been reported in 5%. […] 80% of [women with Turner’s syndrome] have POI. […] All ♀ presenting with hypergonadotrophic amenorrhoea below age 40 should be karyotyped.”

“The menopause is the permanent cessation of menstruation as a result of ovarian failure and is a retrospective diagnosis made after 12 months of amenorrhoea. The average age of at the time of the menopause is ~50 years, although smokers reach the menopause ~2 years earlier. […] Cycles gradually become increasingly anovulatory and variable in length (often shorter) from about 4 years prior to the menopause. Oligomenorrhoea often precedes permanent amenorrhoea. in 10% of ♀, menses cease abruptly, with no preceding transitional period. […] During the perimenopausal period, there is an accelerated loss of bone mineral density (BMD), rendering post-menopausal more susceptible to osteoporotic fractures. […] Post-menopausal are 2-3 x more likely to develop IHD [ischaemic heart disease] than premenopausal , even after age adjustments. The menopause is associated with an increase in risk factors for atherosclerosis, including less favourable lipid profile, insulin sensitivity, and an ↑ thrombotic tendency. […] ♀ are 2-3 x more likely to develop Alzheimer’s disease than ♂. It is suggested that oestrogen deficiency may play a role in the development of dementia. […] The aim of treatment of perimenopausal ♀ is to alleviate menopausal symptoms and optimize quality of life. The majority of women with mild symptoms require no HRT. […] There is an ↑ risk of breast cancer in HRT users which is related to the duration of use. The risk increases by 35%, following 5 years of use (over the age of 50), and falls to never-used risk 5 years after discontinuing HRT. For ♀ aged 50 not using HRT, about 45 in every 1,000 will have cancer diagnosed over the following 20 years. This number increases to 47/1,000 ♀ using HRT for 5 years, 51/1,000 using HRT for 10 years, and 57/1,000 after 15 years of use. The risk is highest in ♀ on combined HRT compared with oestradiol alone. […] Oral HRT increases the risk [of venous thromboembolism] approximately 3-fold, resulting in an extra two cases/10,000 women-years. This risk is markedly ↑ in ♀ who already have risk factors for DVT, including previous DVT, cardiovascular disease, and within 90 days of hospitalization. […] Data from >30 observational studies suggest that HRT may reduce the risk of developing CVD [cardiovascular disease] by up to 50%. However, randomized placebo-controlled trials […] have failed to show that HRT protects against IHD. Currently, HRT should not be prescribed to prevent cardiovascular disease.”

“Any chronic illness may affect testicular function, in particular chronic renal failure, liver cirrhosis, and haemochromatosis. […] 25% of  who develop mumps after puberty have associated orchitis, and 25-50% of these will develop 1° testicular failure. […] Alcohol excess will also cause 1° testicular failure. […] Cytotoxic drugs, particularly alkylating agents, are gonadotoxic. Infertility occurs in 50% of patients following chemotherapy, and a significant number of  require androgen replacement therapy because of low testosterone levels. […] Testosterone has direct anabolic effects on skeletal muscle and has been shown to increase muscle mass and strength when given to hypogonadal men. Lean body mass is also with a reduction in fat mass. […] Hypogonadism is a risk factor for osteoporosis. Testosterone inhibits bone resorption, thereby reducing bone turnover. Its administration to hypogonadal has been shown to improve bone mineral density and reduce the risk of developing osteoporosis. […] *Androgens stimulate prostatic growth, and testosterone replacement therapy may therefore induce symptoms of bladder outflow obstruction in with prostatic hypertrophy. *It is unlikely that testosterone increases the risk of developing prostrate cancer, but it may promote the growth of an existing cancer. […] Testosterone replacement therapy may cause a fall in both LDL and HDL cholesterol levels, the significance of which remains unclear. The effect of androgen replacement therapy on the risk of developing coronary artery disease is unknown.”

“Erectile dysfunction [is] [t]he consistent inability to achieve or maintain an erect penis sufficient for satisfactory sexual intercourse. Affects approximately 10% of and >50% of >70 years. […] Erectile dysfunction may […] occur as a result of several mechanisms: *Neurological damage. *Arterial insufficiency. *Venous incompetence. *Androgen deficiency. *Penile abnormalities. […] *Abrupt onset of erectile dysfunction which is intermittent is often psychogenic in origin. *Progressive and persistent dysfunction indicates an organic cause. […] Absence of morning erections suggests an organic cause of erectile dysfunction.”

“*Infertility, defined as failure of pregnancy after 1 year of unprotected regular (2 x week) sexual intercourse, affects ~10% of all couples. *Couples who fail to conceive after 1 years of regular unprotected sexual intercourse should be investigated. […] Causes[:] *♀ factors (e.g. PCOS, tubal damage) 35%. *♂ factors (idiopathic gonadal failure in 60%) 25%. *Combined factors 25%. *Unexplained infertility 15%. […] [♀] Fertility declines rapidly after the age of 36 years. […] Each episode of acute PID causes infertility in 10-15% of cases. *Trachomatis is responsible for half the cases of PID in developed countries. […] Unexplained infertility [is] [i]nfertility despite normal sexual intercourse occurring at least twice weakly, normal semen analysis, documentation of ovulation in several cycles, and normal patent tubes (by laparoscopy). […] 30-50% will become pregnant within 3 years of expectant management. If not pregnant by then, chances that spontaneous pregnancy will occur are greatly reduced, and ART should be considered. In ♀>34 years of age, then expectant management is not an option, and up to six cycles of IUI or IVF should be considered.”

February 9, 2018 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Genetics, Medicine, Pharmacology | Leave a comment

Endocrinology (part 3 – adrenal glands)

Some observations from chapter 3 below.

“The normal adrenal gland weigh 4-5g. The cortex represents 90% of the normal gland and surrounds the medulla. […] Glucocorticoid (cortisol […]) production occurs from the zona fasciculata, and adrenal androgens arise from the zona reticularis. Both of these are under the control of ACTH [see also my previous post about the book – US], which regulates both steroid synthesis and also adrenocortical growth. […] Mineralocorticoid (aldosterone […]) synthesis occurs in zona glomerulosa, predominantly under the control of the renin-angiotensin system […], although ACTH also contributes to its regulation. […] The adrenal gland […] also produces sex steroids in the form of dehydroepiandrostenedione (DHEA) and androstenedione. The synthetic pathway is under the control of ACTH. Urinary steroid profiling provides quantitative information on the biosynthetic and catabolic pathways. […] CT is the most widely used modality for imaging the adrenal glands. […] MRI can also reliably detect adrenal masses >5-10mm in diameter and, in some circumstances, provides additional information to CT […] PET can be useful in locating tumours and metastases. […] Adrenal vein sampling (AVS) […] can be useful to lateralize an adenoma or to differentiate an adenoma from bilateral hyperplasia. […] AVS is of particular value in lateralizing small aldosterone-producing adenomas that cannot easily be visualized on CT or MRI. […] The procedure should only be undertaken in patients in whom surgery is feasible and desired […] [and] should be carried out in specialist centres only; centres with <20 procedures per year have been shown to have poor success rates”.

“The majority of cases of mineralocorticoid excess are due to excess aldosterone production, […] typically associated with hypertension and hypokalemia. *Primary hyperaldosteronism is a disorder of autonomous aldosterone hypersecretion with suppressed renin levels. *Secondary hyperaldosteronism occurs when aldosterone hypersecretion occurs 2° [secondary, US] to elevated circulating renin levels. This is typical of heart failure, cirrhosis, or nephrotic syndrome but can also be due to renal artery stenosis and, occasionally, a very rare renin-producing tumour (reninoma). […] Primary hyperaldosteronism is present in around 10% of hypertensive patients. It is the most prevalent form of secondary hypertension. […] Aldosterone causes renal sodium retention and potassium loss. This results in expansion of body sodium content, leading to suppression of renal renin synthesis. The direct action of aldosterone on the distal nephron causes sodium retention and loss and hydrogen and potassium ions, resulting in a hypokalaemic alkalosis, although serum potassium […] may be normal in up to 50% of cases. Aldosterone has pathophysiological effects on a range of other tissues, causing cardiac fibrosis, vascular endothelial dysfunction, and nephrosclerosis. […] hypertension […] is often resistant to conventional therapy. […] Hypokalaemia is usually asymptomatic. […] Occasionally, the clinical syndrome of hyperaldosteronism is not associated with excess aldosterone. […] These conditions are rare.”

“Bilateral adrenal hyperplasia [make up] 60% [of cases of primary hyperaldosteronism]. […] Conn’s syndrome (aldosterone-producing adrenal adenoma) [make up] 35%. […] The pathophysiology of bilateral adrenal hyperplasia is not understood, and it is possible that it represents an extreme end of the spectrum of low renin essential hypertension. […] Aldosterone-producing carcinoma[s] [are] [r]are and usually associated with excessive secretion of other corticosteroids (cortisol, androgen, oestrogen). […] Indications [for screening include:] *Patients resistant to conventional antihypertensive medication (i.e. not controlled on three agents). *Hypertension associated with hypokalaemia […] *Hypertension developing before age of 40 years. […] Confirmation of autonomous aldosterone production is made by demonstrating failure to suppress aldosterone in face of sodium/volume loading. […] A number of tests have been described that are said to differentiate between the various subtypes of 1° [primary, US] aldosteronism […]. However, none of these are sufficiently specific to influence management decisions”.

“Laparoscopic adrenalectomy is the treatment of choice for aldosterone-secreting adenomas […] and laparoscopic adrenalectomy […] has become the procedure of choice for removal of most adrenal tumours. *Hypertension is cured in about 70%. *If it persists […], it is more amenable to medical treatment. *Overall, 50% become normotensive in 1 month and 70% within 1 year. […] Medical therapy remains an option for patients with bilateral disease and those with a solitary adrenal adenoma who are unlikely to be cured by surgery, who are unfit for operation, or who express a preference for medical management. *The mineralocorticoid receptor antagonist spironolactone […] has been used successfully for many years to treat hypertension and hypokalaemia associated with bilateral adrenal hyperplasia […] Side effects are common – particularly gynaecomastia and impotence in ♂, menstrual irregularities in ♀, and GI effects. […] Eplerenone […] is a mineralocorticoid receptor antagonist without antiandrogen effects and hence greater selectivity and less side effects than spironolactone. *Alternative drugs include the potassium-sparing diuretics amiloride and triamterene.”

“Cushing’s syndrome results from chronic excess cortisol [see also my second post in this series] […] The causes may be classified as ACTH-dependent and ACTH-independent. […] ACTH-independent Cushing’s syndrome […] is due to adrenal tumours (benign and malignant), and is responsible for 10-15% of cases of Cushing’s syndrome. […] Benign adrenocortical adenomas (ACA) are usually encapsulated and <4cm in diameter. They are usually associated with pure glucocorticoid excess. *Adrenocortical carcinomas (ACC) are usually >6cm in diameter, […] and are not infrequently associated with local invasion and metastases at the time of diagnosis. Adrenal carcinomas are characteristically associated with the excess secretion of several hormones; most frequently found is the combination of cortisol and androgen (precursors) […] ACTH-dependent Cushing’s results in bilateral adrenal hyperplasia, thus one has to firmly differentiate between ACTH-dependent and independent causes of Cushing’s before assuming bilateral adrenal hyperplasia as the primary cause of disease. […] It is important to note that, in patients with adrenal carcinoma, there may also be features related to excessive androgen production in ♀ and also a relatively more rapid time course of development of the syndrome. […] Patients with ACTH-independent Cushing’s syndrome do not suppress cortisol […] on high-dose dexamethasone testing and fail to show a rise in cortisol and ACTH following administration of CRH. […] ACTH-independent causes are adrenal in origin, and the mainstay of further investigation is adrenal imaging by CT”.

“Adrenal adenomas, which are successfully treated with surgery, have a good prognosis, and recurrence is unlikely. […] Bilateral adrenalectomy [in the context of bilateral adrenal hyperplasia] is curative. Lifelong glucocorticoid and mineralocorticoid treatment is [however] required. […] The prognosis for adrenal carcinoma is very poor despite surgery. Reports suggest a 5-year survival of 22% and median survival time of 14 months […] Treatment of adrenocortical carcinoma (ACC) should be carried out in a specialist centre, with expert surgeons, oncologists, and endocrinologists with extensive treatment in treating ACC. This improves survival.”

“Adrenal insufficiency [AI, US] is defined by the lack of cortisol, i.e. glucocorticoid deficiency, may be due to destruction of the adrenal cortex (1°, Addison’s disease and congenital adrenal hyperplasia (CAH) […] or due to disordered pituitary and hypothalamic function (2°). […] *Permanent adrenal insufficiency is found in 5 in 10,000 population. *The most frequent cause is hypothalamic-pituitary damage, which is the cause of AI in 60% of affected patients. *The remaining 40% of cases are due to primary failure of the adrenal to synthesize cortisol, almost equal prevalence of Addison’s disease (mostly of autoimmune origin, prevalence 0.9-1.4 in 10,000) and congenital adrenal hyperplasia (0.7-1.0 in 10,000). *2° adrenal insufficiency due to suppression of pituitary-hypothalamic function by exogenously administered, supraphysiological glucocorticoid doses for treatment of, for example, COPD or rheumatoid arthritis, is much more common (50-200 in 10,000 population). However, adrenal function in these patients can recover”.

“[In primary AI] [a]drenal gland destruction or dysfunction occurs due to a disease process which usually involves all three zones of the adrenal cortex, resulting in inadequate glucocorticoid, mineralocorticoid, and adrenal androgen precursor secretion. The manifestations of insufficiency do not usually appear until at least 90% of the gland has been destroyed and are usually gradual in onset […] Acute adrenal insufficiency may occur in the context of acute septicaemia […] Mineralocorticoid deficiency leads to reduced sodium retention and hyponatraemia and hypotension […] Androgen deficiency presents in ♀ with reduced axillary and pubic hair and reduced libido. (Testicular production of androgens is more important in ♂). [In secondary AI] [i]nadequate ACTH results in deficient cortisol production (and ↓ androgens in ♀). […] Mineralocorticoid secretion remains normal […] The onset is usually gradual, with partial ACTH deficiency resulting in reduced response to stress. […] Lack of stimulation of skin MC1R due to ACTH deficiency results in pale skin appearance. […] [In 1° adrenal insufficiency] hyponatraemia is present in 90% and hyperkalaemia in 65%. […] Undetectable serum cortisol is diagnostic […], but the basal cortisol is often in the normal range. A cortisol >550nmol/L precludes the diagnosis. At times of acute stress, an inappropriately low cortisol is very suggestive of the diagnosis.”

“Autoimmune adrenalitis[:] Clinical features[:] *Anorexia and weight loss (>90%). *Tiredness. *Weakness – generalized, no particular muscle groups. […] Dizziness and postural hypotension. *GI symptoms – nausea and vomiting, abdominal pain, diarrhea. *Arthralgia and myalgia. […] *Mediated by humoral and cell-mediated immune mechanisms. Autoimmune insufficiency associated with polyglandular autoimmune syndrome is more common in ♀ (70%). *Adrenal cortex antibodies are present in the majority of patients at diagnosis, and […] they are still found in approximately 70% of patients 10 years later. Up to 20% patients/year with [positive] antibodies develop adrenal insufficiency. […] *Antiadrenal antibodies are found in <2% of patients with other autoimmune endocrine disease (Hashimoto’s thyroiditis, diabetes mellitus, autoimmune hypothyroidism, hypoparathyroidism, pernicious anemia). […] antibodies to other endocrine glands are commonly found in patients with autoimmune adrenal insufficiency […] However, the presence of antibodies does not predict subsequent manifestation of organ-specific autoimmunity. […] Patients with type 1 diabetes mellitus and autoimmune thyroid disease only rarely develop autoimmune adrenal insufficiency. Approximately 60% of patients with Addison’s disease have other autoimmune or endocrine disorders. […] The adrenals are small and atrophic in chronic autoimmune adrenalitis.”

“Autoimmune polyglandular syndrome (APS) type 1[:] *Also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED). […] [C]hildhood onset. *Chronic mucocutaneous candidiasis. *Hypoparathyroidism (90%), 1° adrenal insufficiency (60%). *1° gonadal failure (41%) – usually after Addison’s diagnosis. *1° hypothyroidism. *Rarely hypopituitarism, diabetes insipidus, type 1 diabetes mellitus. […] APS type 2[:] *Adult onset. *Adrenal insufficiency (100%). 1° autoimmune thyroid disease (70%) […] Type 1 diabetes mellitus (5-20%) – often before Addison’s diagnosis. *1° gonadal failure in affected women (5-20%). […] Schmidt’s syndrome: *Addison’s disease, and *Autoimmune hypothyroidism. *Carpenter syndrome: *Addison’s disease, and *Autoimmune hypothyroidism, and/or *Type 1 diabetes mellitus.”

“An adrenal incidentaloma is an adrenal mass that is discovered incidentally upon imaging […] carried out for reasons other than a suspected adrenal pathology.  […] *Autopsy studies suggest incidence prevalence of adrenal masses of 1-6% in the general population. *Imagining studies suggest that adrenal masses are present 2-3% in the general population. Incidence increases with ageing, and 8-10% of 70-year olds harbour an adrenal mass. […] It is important to determine whether the incidentally discovered adrenal mass is: *Malignant. *Functioning and associated with excess hormonal secretion.”

January 17, 2018 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Immunology, Medicine, Nephrology, 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

Endocrinology (part I – thyroid)

Handbooks like these are difficult to blog, but I decided to try anyway. The first 100 pages or so of the book deals with the thyroid gland. Some observations of interest below.

“Biosynthesis of thyroid hormones requires iodine as substrate. […] The thyroid is the only source of T4. The thyroid secretes 20% of circulating T3; the remainder is generated in extraglandular tissues by the conversion of T4 to T3 […] In the blood, T4 and T3 are almost entirely bound to plasma proteins. […] Only the free or unbound hormone is available to tissues. The metabolic state correlates more closely with the free than the total hormone concentration in the plasma. The relatively weak binding of T3 accounts for its more rapid onset and offset of action. […] The levels of thyroid hormone in the blood are tightly controlled by feedback mechanisms involved in the hypothalamo-pituitary-thyroid (HPT) axis“.

“Annual check of thyroid function [is recommended] in the annual review of diabetic patients.”

“The term thyrotoxicosis denotes the clinical, physiological, and biochemical findings that result when the tissues are exposed to excess thyroid hormone. It can arise in a variety of ways […] It is essential to establish a specific diagnosis […] The term hyperthyroidism should be used to denote only those conditions in which hyperfunction of the thyroid leads to thyrotoxicosis. […] [Thyrotoxicosis is] 10 x more common in ♀ than in ♂ in the UK. Prevalence is approximately 2% of the ♀ population. […] Subclinical hyperthyroidism is defined as low serum thyrotropin (TSH) concentration in patients with normal levels of T4 and T3. Subtle symptoms and signs of thyrotoxicosis may be present. […] There is epidemiological evidence that subclinical hyperthyroidism is a risk factor for the development of atrial fibrillation or osteoporosis.1 Meta-analyses suggest a 41% increase in all-cause mortality.2 […] Thyroid crisis [storm] represents a rare, but life-threatening, exacerbation of the manifestations of thyrotoxicosis. […] the condition is associated with a significant mortality (30-50%, depending on series) […]. Thyroid crisis develops in hyperthyroid patients who: *Have an acute infection. *Undergo thyroidal or non-thyroidal surgery or (rarely) radioiodine treatment.”

“[Symptoms and signs of hyperthyroidism (all forms):] *Hyperactivity, irritability, altered mood, insomnia. *Heat intolerance, sweating. […] *Fatigue, weakness. *Dyspnoea. *Weight loss with appetite (weight gain in 10% of patients). *Pruritus. […] *Thirst and polyuria. *Oligomenorrhoea or amenorrhoea, loss of libido, erectile dysfunction (50% of men may have sexual dysfunction). *Warm, moist skin. […] *Hair loss. *Muscle weakness and wasting. […] Manifestations of Graves’s disease (in addition to [those factors already mentioned include:]) *Diffuse goitre. *Ophthalmopathy […] A feeling of grittiness and discomfort in the eye. *Retrobulbar pressure or pain, eyelid lag or retraction. […] *Exophthalmos (proptosis) […] Optic neuropathy.”

“Two alternative regimens are practiced for Graves’s disease: dose titration and block and replace. […] The [primary] aim [of the dose titration regime] is to achieve a euthyroid state with relatively high drug doses and then to maintain euthyroidism with a low stable dose. […] This regimen has a lower rate of side effects than the block and replace regimen. The treatment is continued for 18 months, as this appears to represent the length of therapy which is generally optimal in producing the remission rate of up to 40% at 5 years after discontinuing therapy. *Relapses are most likely to occur within the first year […] Men have a higher recurrence rate than women. *Patients with multinodular goitres and thyrotoxicosis always relapse on cessation of antithyroid medication, and definite treatment with radioiodine or surgery is usually advised. […] Block and replace regimen *After achieving a euthyroid state on carbimazole alone, carbimazole at a dose of 40mg daily, together with T4 at a dose of 100 micrograms, can be prescribed. This is usually continued for 6 months. *The main advantages are fewer hospital visits for checks of thyroid function and shorter duration of treatment.”

“Radioiodine treatment[:] Indications: *Definite treatment of multinodular goitre or adenoma. *Relapsed Graves’s disease. […] *Radioactive iodine-131 is administered orally as a capsule or a drink. *There is no universal agreement regarding the optimal dose. […] The recommendation is to administer enough radioiodine to achieve euthyroidism, with the acceptance of a moderate rate of hypothyroidism, e.g. 15-20% at 2 years. […] In general, 50-70% of patients have restored normal thyroid function within 6-8 weeks of receiving radioiodine. […] The prevalence of hypothyroidism is about 50% at 10 years and continues to increase thereafter.”

“Thyrotoxicosis occurs in about 0.2% of pregnancies. […] *Diagnosis of thyrotoxicosis during pregnancy may be difficult or delayed. *Physiological changes of pregnancy are similar to those of hyperthyroidism. […] 5-7% of ♀ develop biochemical evidence of thyroid dysfunction after delivery. An incidence is seen in patients with type I diabetes mellitus (25%) […] One-third of affected ♀ with post-partum thyroiditis develop symptoms of hypothyroidism […] There is a suggestion of an risk of post-partum depression in those with hypothyroidism. […] *The use of iodides and radioiodine is contraindicated in pregnancy. *Surgery is rarely performed in pregnancy. It is reserved for patients not responding to ATDs [antithyroid drugs, US]. […] Hyperthyroid ♀ who want to conceive should attain euthyroidism before conception since uncontrolled hyperthyroidism is associated with an an risk of congenital abnormalities (stillbirth and cranial synostosis are the most serious complications).”

“Nodular thyroid disease denotes the presence of single or multiple palpable or non-palpable nodules within the thyroid gland. […] *Clinically apparent thyroid nodules are evident in ~5% of the UK population. […] Thyroid nodules always raise the concern of cancer, but <5% are cancerous. […] clinically detectable thyroid cancer is rare. It accounts for <1% of all cancer and <0.5% of cancer deaths. […] Thyroid cancers are commonest in adults aged 40-50 and rare in children [incidence of 0.2-5 per million per year] and adolescents. […] History should concentrate on: *An enlarging thyroid mass. *A previous history of radiation […] family history of thyroid cancer. *The development of hoarseness or dysphagia. *Nodules are more likely to be malignant in patients <20 or >60 years. *Thyroid nodules are more common in ♀ but more likely to be malignant in ♂. […] Physical findings suggestive of malignancy include a firm or hard, non-tender nodule, a recent history of enlargement, fixation to adjacent tissue, and the presence of regional lymphadenopathy. […] Thyroid nodules may be described as adenomas if the follicular cell differentiation is enclosed within a capsule; adenomatous when the lesions are circumscribed but not encapsulated. *The most common benign thyroid tumours are the nodules of multinodular goitres (colloid nodules) and follicular adenomas. […] Autonomously functioning thyroid adenomas (or nodules) are benign tumours that produce thyroid hormone. Clinically, they present as a single nodule that is hyperfunctioning […], sometimes causing hyperthyroidism.”

“Inflammation of the thyroid gland often leads to a transient thyrotoxicosis followed by hypothyroidism. Overt hypothyroidism caused by autoimmunity has two main forms: Hashimoto’s (goitrous) thyroiditis and atrophic thyroiditis. […] Hashimoto’s thyroiditis [is] [c]haracterized by a painless, variable-sized goitre with rubbery consistency and an irregular surface. […] Occasionally, patients present with thyrotoxicosis in association with a thyroid gland that is unusually firm […] Atrophic thyroiditis [p]robably indicates end-stage thyroid disease. These patients do not have goitre and are antibody [positive]. […] The long-term prognosis of patients with chronic thyroiditis is good because hypothyroidism can easily be corrected with T4 and the goitre is usually not of sufficient size to cause local symptoms. […] there is an association between this condition and thyroid lymphoma (rare, but risk by a factor of 70).”

“Hypothyroidism results from a variety of abnormalities that cause insufficient secretion of thyroid hormones […] The commonest cause is autoimmune thyroid disease. Myxoedema is severe hypothyroidism [which leads to] thickening of the facial features and a doughy induration of the skin. [The clinical picture of hypothyroidism:] *Insidious, non-specific onset. *Fatigue, lethargy, constipation, cold intolerance, muscle stiffness, cramps, carpal tunnel syndrome […] *Slowing of intellectual and motor activities. *↓ appetite and weight gain. *Dry skin; hair loss. […] [The term] [s]ubclinical hypothyroidism […] is used to denote raised TSH levels in the presence of normal concentrations of free thyroid hormones. *Treatment is indicated if the biochemistry is sustained in patients with a past history of radioiodine treatment for thyrotoxicosis or [positive] thyroid antibodies as, in these situations, progression to overt hypothyroidism is almost inevitable […] There is controversy over the advantages of T4 treatment in patients with [negative] thyroid antibodies and no previous radioiodine treatment. *If treatment is not given, follow-up with annual thyroid function tests is important. *There is no generally accepted consensus of when patients should receive treatment. […] *Thyroid hormone replacement with synthetic levothyroxine remains the treatment of choice in primary hypothyroidism. […] levothyroxine has a narrow therapeutic index […] Elevated TSH despite thyroxine replacement is common, most usually due to lack of compliance.”


January 8, 2018 Posted by | Books, Cancer/oncology, Diabetes, Medicine, Ophthalmology, Pharmacology | Leave a comment

Occupational Epidemiology (III)

This will be my last post about the book.

Some observations from the final chapters:

“Often there is confusion about the difference between systematic reviews and metaanalyses. A meta-analysis is a quantitative synthesis of two or more studies […] A systematic review is a synthesis of evidence on the effects of an intervention or an exposure which may also include a meta-analysis, but this is not a prerequisite. It may be that the results of the studies which have been included in a systematic review are reported in such a way that it is impossible to synthesize them quantitatively. They can then be reported in a narrative manner.10 However, a meta-analysis always requires a systematic review of the literature. […] There is a long history of debate about the value of meta-analysis for occupational cohort studies or other occupational aetiological studies. In 1994, Shapiro argued that ‘meta-analysis of published non-experimental data should be abandoned’. He reasoned that ‘relative risks of low magnitude (say, less than 2) are virtually beyond the resolving power of the epidemiological microscope because we can seldom demonstrably eliminate all sources of bias’.13 Because the pooling of studies in a meta-analysis increases statistical power, the pooled estimate may easily become significant and thus incorrectly taken as an indication of causality, even though the biases in the included studies may not have been taken into account. Others have argued that the method of meta-analysis is important but should be applied appropriately, taking into account the biases in individual studies.14 […] We believe that the synthesis of aetiological studies should be based on the same general principles as for intervention studies, and the existing methods adapted to the particular challenges of cohort and case-control studies. […] Since 2004, there is a special entity, the Cochrane Occupational Safety and Health Review Group, that is responsible for the preparing and updating of reviews of occupational safety and health interventions […]. There were over 100 systematic reviews on these topics in the Cochrane Library in 2012.”

“The believability of a systematic review’s results depends largely on the quality of the included studies. Therefore, assessing and reporting on the quality of the included studies is important. For intervention studies, randomized trials are regarded as of higher quality than observational studies, and the conduct of the study (e.g. in terms of response rate or completeness of follow-up) also influences quality. A conclusion derived from a few high-quality studies will be more reliable than when the conclusion is based on even a large number of low-quality studies. Some form of quality assessment is nowadays commonplace in intervention reviews but is still often missing in reviews of aetiological studies. […] It is tempting to use quality scores, such as the Jadad scale for RCTs34 and the Downs and Black scale for non-RCT intervention studies35 but these, in their original format, are insensitive to variation in the importance of risk areas for a given research question. The score system may give the same value to two studies (say, 10 out of 12) when one, for example, lacked blinding and the other did not randomize, thus implying that their quality is equal. This would not be a problem if randomization and blinding were equally important for all questions in all reviews, but this is not the case. For RCTs an important development in this regard has been the Cochrane risk of bias tool.36 This is a checklist of six important domains that have been shown to be important areas of bias in RCTs: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting.”

“[R]isks of bias tools developed for intervention studies cannot be used for reviews of aetiological studies without relevant modification. This is because, unlike interventions, exposures are usually more complicated to assess when we want to attribute the outcome to them alone. These scales do not cover all items that may need assessment in an aetiological study, such as confounding and information bias relating to exposures. […] Surprisingly little methodological work has been done to develop validated tools for aetiological epidemiology and most tools in use are not validated,38 […] Two separate checklists, for observational studies of incidence and prevalence and for risk factor assessment, have been developed and validated recently.40 […] Publication and other reporting bias is probably a much bigger issue for aetiological studies than for intervention studies. This is because, for clinical trials, the introduction of protocol registration, coupled with the regulatory system for new medications, has helped in assessing and preventing publication and reporting bias. No such checks exist for observational studies.”

“Most ill health that arises from occupational exposures can also arise from nonoccupational exposures, and the same type of exposure can occur in occupational and non-occupational settings. With the exception of malignant mesothelioma (which is essentially only caused by exposure to asbestos), there is no way to determine which exposure caused a particular disorder, nor where the causative exposure occurred. This means that usually it is not possible to determine the burden just by counting the number of cases. Instead, approaches to estimating this burden have been developed. There are also several ways to define burden and how best to measure it.”

“The population attributable fraction (PAF) is the proportion of cases that would not have occurred in the absence of an occupational exposure. It can be estimated by combining two measures — a risk estimate (usually relative risk (RR) or odds ratio) of the disorder of interest that is associated with exposure to the substance of concern; and an estimate of the proportion of the population exposed to the substance at work (p(E)). This approach has been used in several studies, particularly for estimating cancer burden […] There are several possible equations that can be used to calculate the PAF, depending on the available data […] PAFs cannot in general be combined by summing directly because: (1) summing PAFs for overlapping exposures (i.e. agents to which the same ‘ever exposed’ workers may have been exposed) may give an overall PAF exceeding 100%, and (2) summing disjoint (not concurrently occurring) exposures also introduces upward bias. Strategies to avoid this include partitioning exposed numbers between overlapping exposures […] or estimating only for the ‘dominant’ carcinogen with the highest risk. Where multiple exposures remain, one approach is to assume that the exposures are independent and their joint effects are multiplicative. The PAFs can then be combined to give an overall PAF for that cancer using a product sum. […] Potential sources of bias for PAFs include inappropriate choice of risk estimates, imprecision in the risk estimates and estimates of proportions exposed, inaccurate risk exposure period and latency assumptions, and a lack of separate risk estimates in some cases for women and/or cancer incidence. In addition, a key decision is the choice of which diseases and exposures are to be included.”

“The British Cancer Burden study is perhaps the most detailed study of occupationally related cancers in that it includes all those relevant carcinogens classified at the end of 2008 […] In the British study the attributable fractions ranged from less than 0.01% to 95% overall, the most important cancer sites for occupational attribution being, for men, mesothelioma (97%), sinonasal (46%), lung (21.1%), bladder (7.1%), and non-melanoma skin cancer (7.1%) and, for women, mesothelioma (83%), sinonasal (20.1%), lung (5.3%), breast (4.6%), and nasopharynx (2.5%). Occupation also contributed 2% or more overall to cancers of the larynx, oesophagus, and stomach, and soft tissue sarcoma with, in addition for men, melanoma of the eye (due to welding), and non-Hodgkin lymphoma. […] The overall results from the occupational risk factors component of the Global Burden of Disease 2010 study illustrate several important aspects of burden studies.14 Of the estimated 850 000 occupationally related deaths worldwide, the top three causes were: (1) injuries (just over a half of all deaths); (2) particulate matter, gases, and fumes leading to COPD; and (3) carcinogens. When DALYs were used as the burden measure, injuries still accounted for the highest proportion (just over one-third), but ergonomic factors leading to low back pain resulted in almost as many DALYs, and both were almost an order of magnitude higher than the DALYs from carcinogens. The difference in relative contributions of the various risk factors between deaths and DALYs arises because of the varying ages of those affected, and the differing chronicity of the resulting conditions. Both measures are valid, but they represent a different aspect of the burden arising from the hazardous exposures […]. Both the British and Global Burden of Disease studies draw attention to the important issues of: (1) multiple occupational carcinogens causing specific types of cancer, for example, the British study evaluated 21 lung carcinogens; and (2) specific carcinogens causing several different cancers, for example, IARC now defines asbestos as a group 1 or 2A carcinogen for seven cancer sites. These issues require careful consideration for burden estimation and for prioritizing risk reduction strategies. […] The long latency of many cancers means that estimates of current burden are based on exposures occurring in the past, often much higher than those existing today. […] long latency [also] means that risk reduction measures taken now will take a considerable time to be reflected in reduced disease incidence.”

“Exposures and effects are linked by dynamic processes occurring across time. These processes can often be usefully decomposed into two distinct biological relationships, each with several components: 1. The exposure-dose relationship […] 2. The dose-effect relationship […] These two component relationships are sometimes represented by two different mathematical models: a toxicokinetic model […], and a disease process model […]. Depending on the information available, these models may be relatively simple or highly complex. […] Often the various steps in the disease process do not occur at the same rate, some of these processes are ‘fast’, such as cell killing, while others are ‘slow’, such as damage repair. Frequently a few slow steps in a process become limiting to the overall rate, which sets the temporal pattern for the entire exposure-response relationship. […] It is not necessary to know the full mechanism of effects to guide selection of an exposure-response model or exposure metric. Because of the strong influence of the rate-limiting steps, often it is only necessary to have observations on the approximate time course of effects. This is true whether the effects appear to be reversible or irreversible, and whether damage progresses proportionately with each unit of exposure (actually dose) or instead occurs suddenly, and seemingly without regard to the amount of exposure, such as an asthma attack.”

“In this chapter, we argue that formal disease process models have the potential to improve the sensitivity of epidemiology for detecting new and emerging occupational and environmental risks where there is limited mechanistic information. […] In our approach, these models are often used to create exposure or dose metrics, which are in turn used in epidemiological models to estimate exposure-disease associations. […] Our goal is a methodology to formulate strong tests of our exposure-disease hypotheses in which a hypothesis is developed in as much biological detail as it can be, expressed in a suitable dynamic (temporal) model, and tested by its fit with a rich data set, so that its flaws and misperceptions of reality are fully displayed. Rejecting such a fully developed biological hypothesis is more informative than either rejecting or failing to reject a generic or vaguely defined hypothesis.” For example, the hypothesis ‘truck drivers have more risk of lung cancer than non-drivers’13 is of limited usefulness for prevention […]. Hypothesizing that a particular chemical agent in truck exhaust is associated with lung cancer — whether the hypothesis is refuted or supported by data — is more likely to lead to successful prevention activities. […] we believe that the choice of models against which to compare the data should, so far as possible, be guided by explicit hypotheses about the underlying biological processes. In other words, you can get as much as possible from epidemiology by starting from well-thought-out hypotheses that are formalized as mathematical models into which the data will be placed. The disease process models can serve this purpose.2″

“The basic idea of empirical Bayes (EB) and semiBayes (SB) adjustments for multiple associations is that the observed variation of the estimated relative risks around their geometric mean is larger than the variation of the true (but unknown) relative risks. In SB adjustments, an a priori value for the extra variation is chosen which assigns a reasonable range of variation to the true relative risks and this value is then used to adjust the observed relative risks.7 The adjustment consists in shrinking outlying relative risks towards the overall mean (of the relative risks for all the different exposures being considered). The larger the individual variance of the relative risks, the stronger the shrinkage, so that the shrinkage is stronger for less reliable estimates based on small numbers. Typical applications in which SB adjustments are a useful alternative to traditional methods of adjustment for multiple comparisons are in large occupational surveillance studies, where many relative risks are estimated with few or no a priori beliefs about which associations might be causal.7″

“The advantage of [the SB adjustment] approach over classical Bonferroni corrections is that on the average it produces more valid estimates of the odds ratio for each occupation/exposure. If we do a study which involves assessing hundreds of occupations, the problem is not only that we get many ‘false positive’ results by chance. A second problem is that even the ‘true positives’ tend to have odds ratios that are too high. For example, if we have a group of occupations with true odds ratios around 1.5, then the ones that stand out in the analysis are those with the highest odds ratios (e.g. 2.5) which will be elevated partly because of real effects and partly by chance. The Bonferroni correction addresses the first problem (too many chance findings) but not the second, that the strongest odds ratios are probably too high. In contrast, SB adjustment addresses the second problem by correcting for the anticipated regression to the mean that would have occurred if the study had been repeated, and thereby on the average produces more valid odds ratio estimates for each occupation/exposure. […] most epidemiologists write their Methods and Results sections as frequentists and their Introduction and Discussion sections as Bayesians. In their Methods and Results sections, they ‘test’ their findings as if their data are the only data that exist. In the Introduction and Discussion, they discuss their findings with regard to their consistency with previous studies, as well as other issues such as biological plausibility. This creates tensions when a small study has findings which are not statistically significant but which are consistent with prior knowledge, or when a study finds statistically significant findings which are inconsistent with prior knowledge. […] In some (but not all) instances, things can be made clearer if we include Bayesian methods formally in the Methods and Results sections of our papers”.

“In epidemiology, risk is most often quantified in terms of relative risk — i.e. the ratio of the probability of an adverse outcome in someone with a specified exposure to that in someone who is unexposed, or exposed at a different specified level. […] Relative risks can be estimated from a wider range of study designs than individual attributable risks. They have the advantage that they are often stable across different groups of people (e.g. of different ages, smokers, and non-smokers) which makes them easier to estimate and quantify. Moreover, high relative risks are generally unlikely to be explained by unrecognized bias or confounding. […] However, individual attributable risks are a more relevant measure by which to quantify the impact of decisions in risk management on individuals. […] Individual attributable risk is the difference in the probability of an adverse outcome between someone with a specified exposure and someone who is unexposed, or exposed at a different specified level. It is the critical measure when considering the impact of decisions in risk management on individuals. […] Population attributable risk is the difference in the frequency of an adverse outcome between a population with a given distribution of exposures to a hazardous agent, and that in a population with no exposure, or some other specified distribution of exposures. It depends on the prevalence of exposure at different levels within the population, and on the individual attributable risk for each level of exposure. It is a measure of the impact of the agent at a population level, and is relevant to decisions in risk management for populations. […] Population attributable risks are highest when a high proportion of a population is exposed at levels which carry high individual attributable risks. On the other hand, an exposure which carries a high individual attributable risk may produce only a small population attributable risk if the prevalence of such exposure is low.”

“Hazard characterization entails quantification of risks in relation to routes, levels, and durations of exposure. […] The findings from individual studies are often used to determine a no observed adverse effect level (NOAEL), lowest observed effect level (LOEL), or benchmark dose lower 95% confidence limit (BMDL) for relevant effects […] [NOAEL] is the highest dose or exposure concentration at which there is no discernible adverse effect. […] [LOEL] is the lowest dose or exposure concentration at which a discernible effect is observed. If comparison with unexposed controls indicates adverse effects at all of the dose levels in an experiment, a NOAEL cannot be derived, but the lowest dose constitutes a LOEL, which might be used as a comparator for estimated exposures or to derive a toxicological reference value […] A BMDL is defined in relation to a specified adverse outcome that is observed in a study. Usually, this is the outcome which occurs at the lowest levels of exposure and which is considered critical to the assessment of risk. Statistical modelling is applied to the experimental data to estimate the dose or exposure concentration which produces a specified small level of effect […]. The BMDL is the lower 95% confidence limit for this estimate. As such, it depends both on the toxicity of the test chemical […], and also on the sample sizes used in the study (other things being equal, larger sample sizes will produce more precise estimates, and therefore higher BMDLs). In addition to accounting for sample size, BMDLs have the merit that they exploit all of the data points in a study, and do not depend so critically on the spacing of doses that is adopted in the experimental design (by definition a NOAEL or LOEL can only be at one of the limited number of dose levels used in the experiment). On the other hand, BMDLs can only be calculated where an adverse effect is observed. Even if there are no clear adverse effects at any dose level, a NOAEL can be derived (it will be the highest dose administered).”

December 8, 2017 Posted by | Books, Cancer/oncology, Epidemiology, Medicine, Statistics | Leave a comment

Occupational Epidemiology (II)

Some more observations from the book below.

“RD [Retinal detachment] is the separation of the neurosensory retina from the underlying retinal pigment epithelium.1 RD is often preceded by posterior vitreous detachment — the separation of the posterior vitreous from the retina as a result of vitreous degeneration and shrinkage2 — which gives rise to the sudden appearance of floaters and flashes. Late symptoms of RD may include visual field defects (shadows, curtains) or even blindness. The success rate of RD surgery has been reported to be over 90%;3 however, a loss of visual acuity is frequently reported by patients, particularly if the macula is involved.4 Since the natural history of RD can be influenced by early diagnosis, patients experiencing symptoms of posterior vitreous detachment are advised to undergo an ophthalmic examination.5 […] Studies of the incidence of RD give estimates ranging from 6.3 to 17.9 cases per 100 000 person-years.6 […] Age is a well-known risk factor for RD. In most studies the peak incidence was recorded among subjects in their seventh decade of life. A secondary peak at a younger age (20–30 years) has been identified […] attributed to RD among highly myopic patients.6 Indeed, depending on the severity,
myopia is associated with a four- to ten-fold increase in risk of RD.7 [Diabetics with retinopathy are also at increased risk of RD, US] […] While secondary prevention of RD is current practice, no effective primary prevention strategy is available at present. The idea is widespread among practitioners that RD is not preventable, probably the consequence of our historically poor understanding of the aetiology of RD. For instance, on the website of the Mayo Clinic — one of the top-ranked hospitals for ophthalmology in the US — it is possible to read that ‘There’s no way to prevent retinal detachment’.9

“Intraocular pressure […] is influenced by physical activity. Dynamic exercise causes an acute reduction in intraocular pressure, whereas physical fitness is associated with a lower baseline value.29 Conversely, a sudden rise in intraocular pressure has been reported during the Valsalva manoeuvre.30-32 […] Occupational physical activity may […] cause both short- and long-term variations in intraocular pressure. On the one hand, physically demanding jobs may contribute to decreased baseline levels by increasing physical fitness but, on the other hand, lifting tasks may cause an important acute increase in pressure. Moreover, the eye of a manual worker who performs repeated lifting tasks involving the Valsalva manoeuvre may undergo several dramatic changes in intraocular pressure within a single working shift. […] A case-control study was carried out to test the hypothesis that repeated lifting tasks involving the Valsalva manoeuvre could be a risk factor for RD. […] heavy lifting was a strong risk factor for RD (OR 4.4, 95% CI 1.6–13). Intriguingly, body mass index (BMI) also showed a clear association with RD (top quartile: OR 6.8, 95% CI 1.6–29). […] Based on their findings, the authors concluded that heavy occupational lifting (involving the Valsalva manoeuvre) may be a relevant risk factor for RD in myopics.

“The proportion of the world’s population over 60 is forecast to double from 11.6% in 2012 to 21.8% in 2050.1 […] the International Labour Organization notes that, worldwide, just 40% of the working age population has legal pension coverage, and only 26% of the working population is effectively covered by old-age pension schemes. […] in less developed regions, labour force participation in those over 65 is much higher than in more developed regions.8 […] Longer working lives increase cumulative exposures, as well as increasing the time since exposure — important when there is a long latency period between exposure and resultant disease. Further, some exposures may have a greater effect when they occur to older workers, e.g. carcinogens that are promoters rather than initiators. […] Older workers tend to have more chronic health conditions. […] Older workers have fewer injuries, but take longer to recover. […] For some ‘knowledge workers’, like physicians, even a relatively minor cognitive decline […] might compromise their competence. […]  Most past studies have treated age as merely a confounding variable and rarely, if ever, have considered it an effect modifier. […]  Jex and colleagues24 argue that conceptually we should treat age as the variable of interest so that other variables are viewed as moderating the impact of age. […] The single best improvement to epidemiological research on ageing workers is to conduct longitudinal studies, including follow-up of workers into retirement. Cross-sectional designs almost certainly incur the healthy survivor effect, since unhealthy workers may retire early.25 […] Analyses should distinguish ageing per se, genetic factors, work exposures, and lifestyle in order to understand their relative and combined effects on health.”

“Musculoskeletal disorders have long been recognized as an important source of morbidity and disability in many occupational populations.1,2 Most musculoskeletal disorders, for most people, are characterized by recurrent episodes of pain that vary in severity and in their consequences for work. Most episodes subside uneventfully within days or weeks, often without any intervention, though about half of people continue to experience some pain and functional limitations after 12 months.3,4 In working populations, musculoskeletal disorders may lead to a spell of sickness absence. Sickness absence is increasingly used as a health parameter of interest when studying the consequences of functional limitations due to disease in occupational groups. Since duration of sickness absence contributes substantially to the indirect costs of illness, interventions increasingly address return to work (RTW).5 […] The Clinical Standards Advisory Group in the United Kingdom reported RTW within 2 weeks for 75% of all low back pain (LBP) absence episodes and suggested that approximately 50% of all work days lost due to back pain in the working population are from the 85% of people who are off work for less than 7 days.6″

Any RTW curve over time can be described with a mathematical Weibull function.15 This Weibull function is characterized by a scale parameter λ and a shape parameter k. The scale parameter λ is a function of different covariates that include the intervention effect, preferably expressed as hazard ratio (HR) between the intervention group and the reference group in a Cox’s proportional hazards regression model. The shape parameter k reflects the relative increase or decrease in survival time, thus expressing how much the RTW rate will decrease with prolonged sick leave. […] a HR as measure of effect can be introduced as a covariate in the scale parameter λ in the Weibull model and the difference in areas under the curve between the intervention model and the basic model will give the improvement in sickness absence days due to the intervention. By introducing different times of starting the intervention among those workers still on sick leave, the impact of timing of enrolment can be evaluated. Subsequently, the estimated changes in total sickness absence days can be expressed in a benefit/cost ratio (BC ratio), where benefits are the costs saved due to a reduction in sickness absence and costs are the expenditures relating to the intervention.15″

“A crucial factor in understanding why interventions are effective or not is the timing of the enrolment of workers on sick leave into the intervention. The RTW pattern over time […] has important consequences for appropriate timing of the best window for effective clinical and occupational interventions. The evidence presented by Palmer and colleagues clearly suggests that [in the context of LBP] a stepped care approach is required. In the first step of rapid RTW, most workers will return to work even without specific interventions. Simple, short interventions involving effective coordination and cooperation between primary health care and the workplace will be sufficient to help the majority of workers to achieve an early RTW. In the second step, more expensive, structured interventions are reserved for those who are having difficulties returning, typically between 4 weeks and 3 months. However, to date there is little evidence on the optimal timing of such interventions for workers on sick leave due to LBP.14,15 […] the cost-benefits of a structured RTW intervention among workers on sick leave will be determined by the effectiveness of the intervention, the natural speed of RTW in the target population, the timing of the enrolment of workers into the intervention, and the costs of both the intervention and of a day of sickness absence. […] The cost-effectiveness of a RTW intervention will be determined by the effectiveness of the intervention, the costs of the intervention and of a day of sickness absence, the natural course of RTW in the target population, the timing of the enrolment of workers into the RTW intervention, and the time lag before the intervention takes effect. The latter three factors are seldom taken into consideration in systematic reviews and guidelines for management of RTW, although their impact may easily be as important  as classical measures of effectiveness, such as effect size or HR.”

“In order to obtain information of the highest quality and utility, surveillance schemes have to be designed, set up, and managed with the same methodological rigour as high-calibre prospective cohort studies. Whether surveillance schemes are voluntary or not, considerable effort has to be invested to ensure a satisfactory and sufficient denominator, the best numerator quality, and the most complete ascertainment. Although the force of statute is relied upon in some surveillance schemes, even in these the initial and continuing motivation of the reporters (usually physicians) is paramount. […] There is a surveillance ‘pyramid’ within which the patient’s own perception is at the base, the GP is at a higher level, and the clinical specialist is close to the apex. The source of the surveillance reports affects the numerator because case severity and case mix differ according to the level in the pyramid.19 Although incidence rate estimates may be expected to be lower at the higher levels in the surveillance pyramid this is not necessarily always the case. […] Although surveillance undertaken by physicians who specialize in the organ system concerned or in occupational disease (or in both aspects) may be considered to be the medical ‘gold standard’ it can suffer from a more limited patient catchment because of various referral filters. Surveillance by GPs will capture numerator cases as close to the base of the pyramid as possible, but may suffer from greater diagnostic variation than surveillance by specialists. Limiting recruitment to GPs with a special interest, and some training, in occupational medicine is a compromise between the two levels.20

“When surveillance is part of a statutory or other compulsory scheme then incident case identification is a continuous and ongoing process. However, when surveillance is voluntary, for a research objective, it may be preferable to sample over shorter, randomly selected intervals, so as to reduce the demands associated with the data collection and ‘reporting fatigue’. Evidence so far suggests that sampling over shorter time intervals results in higher incidence estimates than continuous sampling.21 […] Although reporting fatigue is an important consideration in tempering conclusions drawn from […] multilevel models, it is possible to take account of this potential bias in various ways. For example, when evaluating interventions, temporal trends in outcomes resulting from other exposures can be used to control for fatigue.23,24 The phenomenon of reporting fatigue may be characterized by an ‘excess of zeroes’ beyond what is expected of a Poisson distribution and this effect can be quantified.27 […] There are several considerations in determining incidence from surveillance data. It is possible to calculate an incidence rate based on the general population, on the population of working age, or on the total working population,19 since these denominator bases are generally readily available, but such rates are not the most useful in determining risk. Therefore, incidence rates are usually calculated in respect of specific occupations or industries.22 […] Ideally, incidence rates should be expressed in relation to quantitative estimates of exposure but most surveillance schemes would require additional data collection as special exercises to achieve this aim.” [for much more on these topics, see also M’ikanatha & Iskander’s book.]

“Estimates of lung cancer risk attributable to occupational exposures vary considerably by geographical area and depend on study design, especially on the exposure assessment method, but may account for around 5–20% of cancers among men, but less (<5%) among women;2 among workers exposed to (suspected) lung carcinogens, the percentage will be higher. […] most exposure to known lung carcinogens originates from occupational settings and will affect millions of workers worldwide.  Although it has been established that these agents are carcinogenic, only limited evidence is available about the risks encountered at much lower levels in the general population. […] One of the major challenges in community-based occupational epidemiological studies has been valid assessment of the occupational exposures experienced by the population at large. Contrary to the detailed information usually available for an industrial population (e.g. in a retrospective cohort study in a large chemical company) that often allows for quantitative exposure estimation, community-based studies […] have to rely on less precise and less valid estimates. The choice of method of exposure assessment to be applied in an epidemiological study depends on the study design, but it boils down to choosing between acquiring self-reported exposure, expert-based individual exposure assessment, or linking self-reported job histories with job-exposure matrices (JEMs) developed by experts. […] JEMs have been around for more than three decades.14 Their main distinction from either self-reported or expert-based exposure assessment methods is that exposures are no longer assigned at the individual subject level but at job or task level. As a result, JEMs make no distinction in assigned exposure between individuals performing the same job, or even between individuals performing a similar job in different companies. […] With the great majority of occupational exposures having a rather low prevalence (<10%) in the general population it is […] extremely important that JEMs are developed aiming at a highly specific exposure assessment so that only jobs with a high likelihood (prevalence) and intensity of exposure are considered to be exposed. Aiming at a high sensitivity would be disastrous because a high sensitivity would lead to an enormous number of individuals being assigned an exposure while actually being unexposed […] Combinations of the methods just described exist as well”.

“Community-based studies, by definition, address a wider range of types of exposure and a much wider range of encountered exposure levels (e.g. relatively high exposures in primary production but often lower in downstream use, or among indirectly exposed individuals). A limitation of single community-based studies is often the relatively low number of exposed individuals. Pooling across studies might therefore be beneficial. […] Pooling projects need careful planning and coordination, because the original studies were conducted for different purposes, at different time periods, using different questionnaires. This heterogeneity is sometimes perceived as a disadvantage but also implies variations that can be studied and thereby provide important insights. Every pooling project has its own dynamics but there are several general challenges that most pooling projects confront. Creating common variables for all studies can stretch from simple re-naming of variables […] or recoding of units […] to the re-categorization of national educational systems […] into years of formal education. Another challenge is to harmonize the different classification systems of, for example, diseases (e.g. International Classification of Disease (ICD)-9 versus ICD-10), occupations […], and industries […]. This requires experts in these respective fields as well as considerable time and money. Harmonization of data may mean losing some information; for example, ISCO-68 contains more detail than ISCO-88, which makes it possible to recode ISCO-68 to ISCO-88 with only a little loss of detail, but it is not possible to recode ISCO-88 to ISCO-68 without losing one or two digits in the job code. […] Making the most of the data may imply that not all studies will qualify for all analyses. For example, if a study did not collect data regarding lung cancer cell type, it can contribute to the overall analyses but not to the cell type-specific analyses. It is important to remember that the quality of the original data is critical; poor data do not become better by pooling.”

December 6, 2017 Posted by | Books, Cancer/oncology, Demographics, Epidemiology, Health Economics, Medicine, Ophthalmology, Statistics | Leave a comment


A few quotes from the book and some related links below. Here’s my very short goodreads review of the book.


“The main naturally occurring radionuclides of primordial origin are uranium-235, uranium-238, thorium-232, their decay products, and potassium-40. The average abundance of uranium, thorium, and potassium in the terrestrial crust is 2.6 parts per million, 10 parts per million, and 1% respectively. Uranium and thorium produce other radionuclides via neutron- and alpha-induced reactions, particularly deeply underground, where uranium and thorium have a high concentration. […] A weak source of natural radioactivity derives from nuclear reactions of primary and secondary cosmic rays with the atmosphere and the lithosphere, respectively. […] Accretion of extraterrestrial material, intensively exposed to cosmic rays in space, represents a minute contribution to the total inventory of radionuclides in the terrestrial environment. […] Natural radioactivity is [thus] mainly produced by uranium, thorium, and potassium. The total heat content of the Earth, which derives from this radioactivity, is 12.6 × 1024 MJ (one megajoule = 1 million joules), with the crust’s heat content standing at 5.4 × 1021 MJ. For comparison, this is significantly more than the 6.4 × 1013 MJ globally consumed for electricity generation during 2011. This energy is dissipated, either gradually or abruptly, towards the external layers of the planet, but only a small fraction can be utilized. The amount of energy available depends on the Earth’s geological dynamics, which regulates the transfer of heat to the surface of our planet. The total power dissipated by the Earth is 42 TW (one TW = 1 trillion watts): 8 TW from the crust, 32.3 TW from the mantle, 1.7 TW from the core. This amount of power is small compared to the 174,000 TW arriving to the Earth from the Sun.”

“Charged particles such as protons, beta and alpha particles, or heavier ions that bombard human tissue dissipate their energy locally, interacting with the atoms via the electromagnetic force. This interaction ejects electrons from the atoms, creating a track of electron–ion pairs, or ionization track. The energy that ions lose per unit path, as they move through matter, increases with the square of their charge and decreases linearly with their energy […] The energy deposited in the tissues and organs of your body by ionizing radiation is defined absorbed dose and is measured in gray. The dose of one gray corresponds to the energy of one joule deposited in one kilogram of tissue. The biological damage wrought by a given amount of energy deposited depends on the kind of ionizing radiation involved. The equivalent dose, measured in sievert, is the product of the dose and a factor w related to the effective damage induced into the living matter by the deposit of energy by specific rays or particles. For X-rays, gamma rays, and beta particles, a gray corresponds to a sievert; for neutrons, a dose of one gray corresponds to an equivalent dose of 5 to 20 sievert, and the factor w is equal to 5–20 (depending on the neutron energy). For protons and alpha particles, w is equal to 5 and 20, respectively. There is also another weighting factor taking into account the radiosensitivity of different organs and tissues of the body, to evaluate the so-called effective dose. Sometimes the dose is still quoted in rem, the old unit, with 100 rem corresponding to one sievert.”

“Neutrons emitted during fission reactions have a relatively high velocity. When still in Rome, Fermi had discovered that fast neutrons needed to be slowed down to increase the probability of their reaction with uranium. The fission reaction occurs with uranium-235. Uranium-238, the most common isotope of the element, merely absorbs the slow neutrons. Neutrons slow down when they are scattered by nuclei with a similar mass. The process is analogous to the interaction between two billiard balls in a head-on collision, in which the incoming ball stops and transfers all its kinetic energy to the second one. ‘Moderators’, such as graphite and water, can be used to slow neutrons down. […] When Fermi calculated whether a chain reaction could be sustained in a homogeneous mixture of uranium and graphite, he got a negative answer. That was because most neutrons produced by the fission of uranium-235 were absorbed by uranium-238 before inducing further fissions. The right approach, as suggested by Szilárd, was to use separated blocks of uranium and graphite. Fast neutrons produced by the splitting of uranium-235 in the uranium block would slow down, in the graphite block, and then produce fission again in the next uranium block. […] A minimum mass – the critical mass – is required to sustain the chain reaction; furthermore, the material must have a certain geometry. The fissile nuclides, capable of sustaining a chain reaction of nuclear fission with low-energy neutrons, are uranium-235 […], uranium-233, and plutonium-239. The last two don’t occur in nature but can be produced artificially by irradiating with neutrons thorium-232 and uranium-238, respectively – via a reaction called neutron capture. Uranium-238 (99.27%) is fissionable, but not fissile. In a nuclear weapon, the chain reaction occurs very rapidly, releasing the energy in a burst.”

“The basic components of nuclear power reactors, fuel, moderator, and control rods, are the same as in the first system built by Fermi, but the design of today’s reactors includes additional components such as a pressure vessel, containing the reactor core and the moderator, a containment vessel, and redundant and diverse safety systems. Recent technological advances in material developments, electronics, and information technology have further improved their reliability and performance. […] The moderator to slow down fast neutrons is sometimes still the graphite used by Fermi, but water, including ‘heavy water’ – in which the water molecule has a deuterium atom instead of a hydrogen atom – is more widely used. Control rods contain a neutron-absorbing material, such as boron or a combination of indium, silver, and cadmium. To remove the heat generated in the reactor core, a coolant – either a liquid or a gas – is circulating through the reactor core, transferring the heat to a heat exchanger or directly to a turbine. Water can be used as both coolant and moderator. In the case of boiling water reactors (BWRs), the steam is produced in the pressure vessel. In the case of pressurized water reactors (PWRs), the steam generator, which is the secondary side of the heat exchanger, uses the heat produced by the nuclear reactor to make steam for the turbines. The containment vessel is a one-metre-thick concrete and steel structure that shields the reactor.”

“Nuclear energy contributed 2,518 TWh of the world’s electricity in 2011, about 14% of the global supply. As of February 2012, there are 435 nuclear power plants operating in 31 countries worldwide, corresponding to a total installed capacity of 368,267 MW (electrical). There are 63 power plants under construction in 13 countries, with a capacity of 61,032 MW (electrical).”

“Since the first nuclear fusion, more than 60 years ago, many have argued that we need at least 30 years to develop a working fusion reactor, and this figure has stayed the same throughout those years.”

“[I]onizing radiation is […] used to improve many properties of food and other agricultural products. For example, gamma rays and electron beams are used to sterilize seeds, flour, and spices. They can also inhibit sprouting and destroy pathogenic bacteria in meat and fish, increasing the shelf life of food. […] More than 60 countries allow the irradiation of more than 50 kinds of foodstuffs, with 500,000 tons of food irradiated every year. About 200 cobalt-60 sources and more than 10 electron accelerators are dedicated to food irradiation worldwide. […] With the help of radiation, breeders can increase genetic diversity to make the selection process faster. The spontaneous mutation rate (number of mutations per gene, for each generation) is in the range 10-8–10-5. Radiation can increase this mutation rate to 10-5–10-2. […] Long-lived cosmogenic radionuclides provide unique methods to evaluate the ‘age’ of groundwaters, defined as the mean subsurface residence time after the isolation of the water from the atmosphere. […] Scientists can date groundwater more than a million years old, through chlorine-36, produced in the atmosphere by cosmic-ray reactions with argon.”

“Radionuclide imaging was developed in the 1950s using special systems to detect the emitted gamma rays. The gamma-ray detectors, called gamma cameras, use flat crystal planes, coupled to photomultiplier tubes, which send the digitized signals to a computer for image reconstruction. Images show the distribution of the radioactive tracer in the organs and tissues of interest. This method is based on the introduction of low-level radioactive chemicals into the body. […] More than 100 diagnostic tests based on radiopharmaceuticals are used to examine bones and organs such as lungs, intestines, thyroids, kidneys, the liver, and gallbladder. They exploit the fact that our organs preferentially absorb different chemical compounds. […] Many radiopharmaceuticals are based on technetium-99m (an excited state of technetium-99 – the ‘m’ stands for ‘metastable’ […]). This radionuclide is used for the imaging and functional examination of the heart, brain, thyroid, liver, and other organs. Technetium-99m is extracted from molybdenum-99, which has a much longer half-life and is therefore more transportable. It is used in 80% of the procedures, amounting to about 40,000 per day, carried out in nuclear medicine. Other radiopharmaceuticals include short-lived gamma-emitters such as cobalt-57, cobalt-58, gallium-67, indium-111, iodine-123, and thallium-201. […] Methods routinely used in medicine, such as X-ray radiography and CAT, are increasingly used in industrial applications, particularly in non-destructive testing of containers, pipes, and walls, to locate defects in welds and other critical parts of the structure.”

“Today, cancer treatment with radiation is generally based on the use of external radiation beams that can target the tumour in the body. Cancer cells are particularly sensitive to damage by ionizing radiation and their growth can be controlled or, in some cases, stopped. High-energy X-rays produced by a linear accelerator […] are used in most cancer therapy centres, replacing the gamma rays produced from cobalt-60. The LINAC produces photons of variable energy bombarding a target with a beam of electrons accelerated by microwaves. The beam of photons can be modified to conform to the shape of the tumour, which is irradiated from different angles. The main problem with X-rays and gamma rays is that the dose they deposit in the human tissue decreases exponentially with depth. A considerable fraction of the dose is delivered to the surrounding tissues before the radiation hits the tumour, increasing the risk of secondary tumours. Hence, deep-seated tumours must be bombarded from many directions to receive the right dose, while minimizing the unwanted dose to the healthy tissues. […] The problem of delivering the needed dose to a deep tumour with high precision can be solved using collimated beams of high-energy ions, such as protons and carbon. […] Contrary to X-rays and gamma rays, all ions of a given energy have a certain range, delivering most of the dose after they have slowed down, just before stopping. The ion energy can be tuned to deliver most of the dose to the tumour, minimizing the impact on healthy tissues. The ion beam, which does not broaden during the penetration, can follow the shape of the tumour with millimetre precision. Ions with higher atomic number, such as carbon, have a stronger biological effect on the tumour cells, so the dose can be reduced. Ion therapy facilities are [however] still very expensive – in the range of hundreds of millions of pounds – and difficult to operate.”

“About 50 million years ago, a global cooling trend took our planet from the tropical conditions at the beginning of the Tertiary to the ice ages of the Quaternary, when the Arctic ice cap developed. The temperature decrease was accompanied by a decrease in atmospheric CO2 from 2,000 to 300 parts per million. The cooling was probably caused by a reduced greenhouse effect and also by changes in ocean circulation due to plate tectonics. The drop in temperature was not constant as there were some brief periods of sudden warming. Ocean deep-water temperatures dropped from 12°C, 50 million years ago, to 6°C, 30 million years ago, according to archives in deep-sea sediments (today, deep-sea waters are about 2°C). […] During the last 2 million years, the mean duration of the glacial periods was about 26,000 years, while that of the warm periods – interglacials – was about 27,000 years. Between 2.6 and 1.1 million years ago, a full cycle of glacial advance and retreat lasted about 41,000 years. During the past 1.2 million years, this cycle has lasted 100,000 years. Stable and radioactive isotopes play a crucial role in the reconstruction of the climatic history of our planet”.


CUORE (Cryogenic Underground Observatory for Rare Events).
Lawrence Livermore National Laboratory.
Marie Curie. Pierre Curie. Henri Becquerel. Wilhelm Röntgen. Joseph Thomson. Ernest Rutherford. Hans Geiger. Ernest Marsden. Niels Bohr.
Ruhmkorff coil.
Pitchblende (uraninite).
Polonium. Becquerel.
Alpha decay. Beta decay. Gamma radiation.
Plum pudding model.
Robert Boyle. John Dalton. Dmitri Mendeleev. Frederick Soddy. James Chadwick. Enrico Fermi. Lise Meitner. Otto Frisch.
Periodic Table.
Exponential decay. Decay chain.
Particle accelerator. Cockcroft-Walton generator. Van de Graaff generator.
Barn (unit).
Nuclear fission.
Manhattan Project.
Chernobyl disaster. Fukushima Daiichi nuclear disaster.
Electron volt.
Thermoluminescent dosimeter.
Silicon diode detector.
Enhanced geothermal system.
Chicago Pile Number 1. Experimental Breeder Reactor 1. Obninsk Nuclear Power Plant.
Natural nuclear fission reactor.
Gas-cooled reactor.
Generation I reactors. Generation II reactor. Generation III reactor. Generation IV reactor.
Nuclear fuel cycle.
Accelerator-driven subcritical reactor.
Thorium-based nuclear power.
Small, sealed, transportable, autonomous reactor.
Fusion power. P-p (proton-proton) chain reaction. CNO cycle. Tokamak. ITER (International Thermonuclear Experimental Reactor).
Sterile insect technique.
Phase-contrast X-ray imaging. Computed tomography (CT). SPECT (Single-photon emission computed tomography). PET (positron emission tomography).
Boron neutron capture therapy.
Radiocarbon dating. Bomb pulse.
Radioactive tracer.
Radithor. The Radiendocrinator.
Radioisotope heater unit. Radioisotope thermoelectric generator. Seebeck effect.
Accelerator mass spectrometry.
Atomic bombings of Hiroshima and Nagasaki. Treaty on the Non-Proliferation of Nuclear Weapons. IAEA.
Nuclear terrorism.
Swiss light source. Synchrotron.
Chronology of the universe. Stellar evolution. S-process. R-process. Red giant. Supernova. White dwarf.
Victor Hess. Domenico Pacini. Cosmic ray.
Allende meteorite.
Age of the Earth. History of Earth. Geomagnetic reversal. Uranium-lead dating. Clair Cameron Patterson.
Glacials and interglacials.
Taung child. Lucy. Ardi. Ardipithecus kadabba. Acheulean tools. Java Man. Ötzi.
Argon-argon dating. Fission track dating.

November 28, 2017 Posted by | Archaeology, Astronomy, Biology, Books, Cancer/oncology, Chemistry, Engineering, Geology, History, Medicine, Physics | Leave a comment

A few diabetes papers of interest

i. Glycated Hemoglobin and All-Cause and Cause-Specific Mortality in Singaporean Chinese Without Diagnosed Diabetes: The Singapore Chinese Health Study.

“Previous studies have reported that elevated levels of HbA1c below the diabetes threshold (<6.5%) are associated with an increased risk for cardiovascular morbidity and mortality (312). Yet, this research base is not comprehensive, and data from Chinese populations are scant, especially in those without diabetes. This gap in the literature is important since Southeast Asian populations are experiencing epidemic rates of type 2 diabetes and related comorbidities with a substantial global health impact (1316).

Overall, there are few cohort studies that have examined the etiologic association between HbA1c levels and all-cause and cause-specific mortality. There is even lesser insight on the nature of the relationship between HbA1c and significant clinical outcomes in Southeast Asian populations. Therefore, we examined the association between HbA1c and all-cause and cause-specific mortality in the Singapore Chinese Health Study (SCHS).”

“The design of the SCHS has been previously summarized (17). Briefly, the cohort was drawn from men and women, aged 45–74 years, who belonged to one of the major dialect groups (Hokkien or Cantonese) of Chinese in Singapore. […] Between April 1993 and December 1998, 63,257 individuals completed an in-person interview that included questions on usual diet, demographics, height and weight, use of tobacco, usual physical activity, menstrual and reproductive history (women only), medical history including history of diabetes diagnosis by a physician, and family history of cancer. […] At the follow-up interview (F1), which occurred in 1999–2004, subjects were asked to update their baseline interview information. […] The study population derived from 28,346 participants of the total 54,243 who were alive and participated at F1, who provided consent at F1 to collect subsequent blood samples (a consent rate of ∼65%). The participants for this study were a random selection of individuals from the full study population who did not report a history of diabetes or CVD at the baseline or follow-up interview and reported no history of cancer.”

“During 74,890 person-years of follow-up, there were 888 total deaths, of which 249 were due to CVD, 388 were due to cancer, and 169 were recorded as respiratory mortality. […] There was a positive association between HbA1c and age, BMI, and prevalence of self-reported hypertension, while an inverse association was observed between educational attainment and HbA1c. […] The crude mortality rate was 1,186 deaths per 100,000 person-years. The age- and sex-standardized mortality rates for all-cause, CVD, and cerebrovascular each showed a J-shaped pattern according to HbA1c level. The CHD and cancer mortality rates were higher for HbA1c ≥6.5% (≥48 mmol/mol) and otherwise displayed no apparent pattern. […] There was no association between any level of HbA1c and respiratory causes of death.”

“Chinese men and women with no history of cancer, reported diabetes, or CVD with an HbA1c level ≥6.5% (≥48 mmol/mol) were at a significant increased risk of mortality during follow-up relative to their peers with an HbA1c of 5.4–5.6% (36–38 mmol/mol). No other range of HbA1c was significantly associated with risk of mortality during follow-up, and in secondary analyses, when the HbA1c level ≥6.5% (≥48 mmol/mol) was divided into four categories, this increased risk was observed in all four categories; thus, these data represent a clear threshold association between HbA1c and mortality in this population. These results are consistent with previous prospective cohort studies identifying chronically high HbA1c, outside of diabetes, to be associated with increased risk for all-cause and CVD-related mortality (312,22).”

“Hyperglycemia is a known risk factor for CVD, not limited to individuals with diabetes. This may be in part due to the vascular damage caused by oxidative stress in periods of hypo- and hyperglycemia (23,24). For individuals with impaired fasting glucose and impaired glucose tolerance, increased oxidative stress and endothelial dysfunction are present before the onset of diabetes (25). The association between chronically high levels of HbA1c and development of and death from cancer is not as well defined (9,2630). Abnormal metabolism may play a role in cancer development and death. This is important, considering cancer is the leading cause of death in Singapore for adults 15–59 years of age (31). Increased risk for cancer mortality was found in individuals with impaired glucose tolerance (30). […] Hyperinsulinemia and IGF-I are associated with increased cancer risk, possibly through mitogenic effects and tumor formation (27,28,37). This is the basis for the insulin-cancer hypothesis. Simply put, chronic levels of hyperinsulinemia reduce the production of IGF binding proteins 1 and 2. The absence of these proteins results in excess bioactive IGF-I, supporting tumor development (38). Chronic hyperglycemia, indicating high levels of insulin and IGF-I, may explain inhibition of cell apoptosis, increased cell proliferation, and increased cancer risk (39).”

ii. The Cross-sectional and Longitudinal Associations of Diabetic Retinopathy With Cognitive Function and Brain MRI Findings: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial.

“Brain imaging studies suggest that type 2 diabetes–related microvascular disease may affect the central nervous system in addition to its effects on other organs, such as the eye and kidney. Histopathological evidence indicates that microvascular disease in the brain can lead to white matter lesions (WMLs) visible with MRI of the brain (1), and risk for them is often increased by type 2 diabetes (26). Type 2 diabetes also has recently been associated with lower brain volume, particularly gray matter volume (79).

The association between diabetic retinopathy and changes in brain tissue is of particular interest because retinal and cerebral small vessels have similar anatomy, physiology, and embryology (10). […] the preponderance of evidence suggests diabetic retinopathy is associated with increased WML burden (3,1214), although variation exists. While cross-sectional studies support a correlation between diabetic retinopathy and WMLs (2,3,6,15), diabetic retinopathy and brain atrophy (16), diabetic retinopathy and psychomotor speed (17,18), and psychomotor speed and WMLs (5,19,20), longitudinal evidence demonstrating the assumed sequence of disease development, for example, vascular damage of eye and brain followed by cognitive decline, is lacking.

Using Action to Control Cardiovascular Risk in Diabetes (ACCORD) data, in which a subset of participants received longitudinal measurements of diabetic retinopathy, cognition, and MRI variables, we analyzed the 1) cross-sectional associations between diabetic retinopathy and evidence of brain microvascular disease and 2) determined whether baseline presence or severity of diabetic retinopathy predicts 20- or 40-month changes in cognitive performance or brain microvascular disease.”

“The ACCORD trial (21) was a multicenter randomized trial examining the effects of intensive glycemic control, blood pressure, and lipids on cardiovascular disease events. The 10,251 ACCORD participants were aged 40–79 years, had poorly controlled type 2 diabetes (HbA1c > 7.5% [58.5 mmol/mol]), and had or were at high risk for cardiovascular disease. […] The ACCORD-Eye sample comprised 3,472 participants who did not report previous vitrectomy or photocoagulation surgery for proliferative diabetic retinopathy at baseline […] ACCORD-MIND included a subset of 2,977 ACCORD participants who completed a 30-min cognitive testing battery, 614 of whom also had useable scans from the MRI substudy (23,24). […] ACCORD-MIND had visits at three time points: baseline, 20 months, and 40 months. MRI of the brain was completed at baseline and the 40-month time point.”

“Baseline diabetic retinopathy was associated with more rapid 40-month declines in DSST and MMSE [Mini-Mental State Examination] when adjusting for demographics and lifestyle factors in model 1 […]. Moreover, increasing severity of diabetic retinopathy was associated with increased amounts of decline in DSST [Digit Symbol Substitution Test] performance (−1.30, −1.76, and −2.81 for no, mild, and moderate/severe NPDR, respectively; P = 0.003) […Be careful about how to interpret that p-value – see below, US] . The associations remained virtually unchanged after further adjusting for vascular and diabetes risk factors, depression, and visual acuity using model 2.”

“This longitudinal study provides new evidence that diabetic retinopathy is associated with future cognitive decline in persons with type 2 diabetes and confirms the finding from the Edinburgh Type 2 Diabetes Study derived from cross-sectional data that lifetime cognitive decline is associated with diabetic retinopathy (32). We found that the presence of diabetic retinopathy, independent of visual acuity, predicts greater declines in global cognitive function measured with the MMSE and that the magnitude of decline in processing speed measured with the DSST increased with increasing severity of baseline diabetic retinopathy. The association with psychomotor speed is consistent with prior cross-sectional findings in community-based samples of middle-aged (18) and older adults (17), as well as prospective studies of a community-based sample of middle-aged adults (33) and patients with type 1 diabetes (34) showing that retinopathy with different etiologies predicted a subsequent decline in psychomotor speed. This study extends these findings to patients with type 2 diabetes.”

“we tested a number of different associations but did not correct P values for multiple testing” [Aargh!, US.]

iii. Incidence of Remission in Adults With Type 2 Diabetes: The Diabetes & Aging Study.

(Note to self before moving on to the paper: these people identified type 1 diabetes by self-report or diabetes onset at <30 years of age, treated with insulin only and never treated with oral agents).

“It is widely believed that type 2 diabetes is a chronic progressive condition, which at best can be controlled, but never cured (1), and that once treatment with glucose-lowering medication is initiated, it is required indefinitely and is intensified over time (2,3). However, a growing body of evidence from clinical trials and case-control studies (46) has reported the remission of type 2 diabetes in certain populations, most notably individuals who received bariatric surgery. […] Despite the clinical relevance and importance of remission, little is known about the incidence of remission in community settings (11,12). Studies to date have focused largely on remission after gastric bypass or relied on data from clinical trials, which have limited generalizability. Therefore, we conducted a retrospective cohort study to describe the incidence rates and variables associated with remission among adults with type 2 diabetes who received usual care, excluding bariatric surgery, in a large, ethnically diverse population. […] 122,781 individuals met our study criteria, yielding 709,005 person-years of total follow-up time.”

“Our definitions of remission were based on the 2009 ADA consensus statement (10). “Partial remission” of diabetes was defined as having two or more consecutive subdiabetic HbA1c measurements, all of which were in the range of 5.7–6.4% [39–46 mmol/mol] over a period of at least 12 months. “Complete remission” was defined as having two or more consecutive normoglycemic HbA1c measurements, all of which were <5.7% [<39 mmol/mol] over a period of at least 12 months. “Prolonged remission” was defined as having two or more consecutive normoglycemic HbA1c measurements, all of which were <5.7% [<39 mmol/mol] over a period of at least 60 months. Each definition of remission requires the absence of pharmacologic treatment during the defined observation period.”

“The average age of participants was 62 years, 47.1% were female, and 51.6% were nonwhite […]. The mean (SD) interval between HbA1c tests in the remission group was 256 days (139 days). The mean interval (SD) between HbA1c tests among patients not in the remission group was 212 days (118 days). The median time since the diagnosis of diabetes in our cohort was 5.9 years, and the average baseline HbA1c level was 7.4% [57 mmol/mol]. The 18,684 individuals (15.2%) in the subset with new-onset diabetes, defined as ≤2 years since diagnosis, were younger, were more likely to have their diabetes controlled by diet, and had fewer comorbidities […] The incidence densities of partial, complete, and prolonged remission in the full cohort were 2.8 (95% CI 2.6–2.9), 0.24 (95% CI 0.20–0.28), and 0.04 (95% CI 0.01–0.06) cases per 1,000 person-years, respectively […] The 7-year cumulative incidences of partial, complete, and prolonged remission were 1.5% (95% CI 1.4–1.5%), 0.14% (95% CI 0.12–0.16%), and 0.01% (95% CI 0.003–0.02%), respectively. The 7-year cumulative incidence of any remission decreased with longer time since diagnosis from a high of 4.6% (95% CI 4.3–4.9%) for individuals diagnosed with diabetes in the past 2 years to a low of 0.4% (95% CI 0.3–0.5%) in those diagnosed >10 years ago. The 7-year cumulative incidence of any remission was much lower for individuals using insulin (0.05%; 95% CI 0.03–0.1%) or oral agents (0.3%; 95% CI 0.2–0.3%) at baseline compared with diabetes patients not using medication at baseline (12%; 95% CI 12–13%).”

“In this large cohort of insured adults with type 2 diabetes not treated with bariatric surgery, we found that 1.5% of individuals with recent evidence of clinical diabetes achieved at least partial remission over a 7-year period. If these results were generalized to the 25.6 million U.S. adults living with type 2 diabetes in 2010 (25), they would suggest that 384,000 adults could experience remission over the next 7 years. However, the rate of prolonged remission was extremely rare (0.007%), translating into only 1,800 adults in the U.S. experiencing remission lasting at least 5 years. To provide context, 1.7% of the cohort died, while only 0.8% experienced any level of remission, during the calendar year 2006. Thus, the chances of dying were higher than the chances of any remission. […] Although remission of type 2 diabetes is uncommon, it does occur in patients who have not undergone surgical interventions. […] Our analysis shows that remission is rare and variable. The likelihood of remission is more common among individuals with early-onset diabetes and those not treated with glucose-lowering medications at the point of diabetes diagnosis. Although rare, remission can also occur in individuals with more severe diabetes and those previously treated with insulin.”

iv. Blood pressure control for diabetic retinopathy (Cochrane review).

“Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Simultaneous blood pressure control has been advocated for the same purpose, but findings reported from individual studies have supported varying conclusions regarding the ocular benefit of interventions on blood pressure. […] The primary aim of this review was to summarize the existing evidence regarding the effect of interventions to control or reduce blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs. A secondary aim was to compare classes of anti-hypertensive medications with respect to the same outcomes.”

“We included 15 RCTs, conducted primarily in North America and Europe, that had enrolled 4157 type 1 and 9512 type 2 diabetic participants, ranging from 16 to 2130 participants in individual trials. […] Study designs, populations, interventions, and lengths of follow-up (range one to nine years) varied among the included trials. Overall, the quality of the evidence for individual outcomes was low to moderate.”

“The evidence from these trials supported a benefit of more intensive blood pressure control intervention with respect to 4- to 5-year incidence of diabetic retinopathy (estimated risk ratio (RR) 0.80; 95% confidence interval (CI) 0.71 to 0.92) and the combined outcome of incidence and progression (estimated RR 0.78; 95% CI 0.63 to 0.97). The available evidence provided less support for a benefit with respect to 4- to 5-year progression of diabetic retinopathy (point estimate was closer to 1 than point estimates for incidence and combined incidence and progression, and the CI overlapped 1; estimated RR 0.88; 95% CI 0.73 to 1.05). The available evidence regarding progression to proliferative diabetic retinopathy or clinically significant macular edema or moderate to severe loss of best-corrected visual acuity did not support a benefit of intervention on blood pressure: estimated RRs and 95% CIs 0.95 (0.83 to 1.09) and 1.06 (0.85 to 1.33), respectively, after 4 to 5 years of follow-up. Findings within subgroups of trial participants (type 1 and type 2 diabetics; participants with normal blood pressure levels at baseline and those with elevated levels) were similar to overall findings.”

“The available evidence supports a beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to 4 to 5 years. However, the lack of evidence to support such intervention to slow progression of diabetic retinopathy or to prevent other outcomes considered in this review, along with the relatively modest support for the beneficial effect on incidence, weakens the conclusion regarding an overall benefit of intervening on blood pressure solely to prevent diabetic retinopathy.”

v. Early Atherosclerosis Relates to Urinary Albumin Excretion and Cardiovascular Risk Factors in Adolescents With Type 1 Diabetes: Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT).

“Children with type 1 diabetes are at greatly increased risk for the development of both renal and cardiovascular disease in later life (1,2). Evidence is accumulating that these two complications may have a common pathophysiology, with endothelial dysfunction a key early event.

Microalbuminuria is a recognized marker of endothelial damage (3) and predicts progression to proteinuria and diabetic nephropathy, as well as to atherosclerosis (4) and increased cardiovascular risk (5). It is, however, rare in adolescents with type 1 diabetes who more often have higher urinary albumin excretion rates within the normal range, which are associated with later progression to microalbuminuria and proteinuria (6).”

“The Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT) (10) is designed to examine the impact of minor differences in albumin excretion in adolescents on the initiation and progression of cardiovascular and renal disease. The primary cardiovascular end point in AdDIT is carotid intima-media thickness (cIMT). Subclinical atherosclerosis can be detected noninvasively using high-resolution ultrasound to measure the intima-media thickness (IMT) of the carotid arteries, which predicts cardiovascular morbidity and mortality (11,12). […] The primary aim of this study was to examine the relationship of increased urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes with structural arterial wall changes. We hypothesized that even minor increases in albumin excretion would be associated with early atherosclerosis but that this would be detectable only in the abdominal aorta. […] A total of 406 adolescents, aged 10–16 years, with type 1 diabetes for more than 1 year, recruited in five centers across Australia, were enrolled in this cross-sectional study”.

“Structural changes in the aorta and carotid arteries could be detected in >50% of adolescents with type 1 diabetes […] The difference in aIMT [aortic intima-media thickness] between type 1 diabetic patients and age- and sex-matched control subjects was equivalent to that seen with a 5- to 6-year age increase in the type 1 diabetic patients. […] Aortic IMT was […] able to better differentiate adolescents with type 1 diabetes from control subjects than was carotid wall changes. Aortic IMT enabled detection of the very early wall changes that are present with even small differences in urinary albumin excretion. This not only supports the concept of early intervention but provides a link between renal and cardiovascular disease.

The independent relationship between aIMT and urinary albumin excretion extends our knowledge of the pathogenesis of cardiovascular and renal disease in type 1 diabetes by showing that the first signs of the development of cardiovascular disease and diabetic nephropathy are related. The concept that microalbuminuria is a marker of a generalized endothelial damage, as well as a marker of renal disease, has been recognized for >20 years (3,20,21). Endothelial dysfunction is the first critical step in the development of atherosclerosis (22). Early rises in urinary albumin excretion precede the development of microalbuminuria and proteinuria (23). It follows that the first structural changes of atherosclerosis could relate to the first biochemical changes of diabetic nephropathy. To our knowledge, this is the first study to provide evidence of this.”

“In conclusion, atherosclerosis is detectable from early adolescence in type 1 diabetes. Its early independent associations are male sex, age, systolic blood pressure, LDL cholesterol, and, importantly, urinary albumin excretion. […] Early rises in urinary albumin excretion during adolescence not only are important for determining risk of progression to microalbuminuria and diabetic nephropathy but also may alert the clinician to increased risk of cardiovascular disease.”

vi. Impact of Islet Autoimmunity on the Progressive β-Cell Functional Decline in Type 2 Diabetes.

“Historically, type 2 diabetes (T2D) has not been considered to be immune mediated. However, many notable discoveries in recent years have provided evidence to support the concept of immune system involvement in T2D pathophysiology (15). Immune cells have been identified in the pancreases of phenotypic T2D patients (35). Moreover, treatment with interleukin-1 receptor agonist improves β-cell function in T2D patients (68). These studies suggest that β-cell damage/destruction mediated by the immune system may be a component of T2D pathophysiology.

Although the β-cell damage and destruction in autoimmune diabetes is most likely T-cell mediated (T), immune markers of autoimmune diabetes have primarily centered on the presence of circulating autoantibodies (Abs) to various islet antigens (915). Abs commonly positive in type 1 diabetes (T1D), especially GAD antibody (GADA) and islet cell Abs (ICA), have been shown to be more common in patients with T2D than in nondiabetic control populations, and the presence of multiple islet Abs, such as GADA, ICA, and tyrosine phosphatase-2 (insulinoma-associated protein 2 [IA-2]), have been demonstrated to be associated with an earlier need for insulin treatment in adult T2D patients (14,1620).”

“In this study, we observed development of islet autoimmunity, measured by islet Abs and islet-specific T-cell responses, in 61% of the phenotypic T2D patients. We also observed a significant association between positive islet-reactive T-cell responses and a more rapid decline in β-cell function as assessed by FCP and glucagon-SCP responses. […] The results of this pilot study led us to hypothesize that islet autoimmunity is present or will develop in a large portion of phenotypic T2D patients and that the development of islet autoimmunity is associated with a more rapid decline in β-cell function. Moreover, the prevalence of islet autoimmunity in most previous studies is grossly underestimated because these studies have not tested for islet-reactive T cells in T2D patients but have based the presence of autoimmunity on antibody testing alone […] The results of this pilot study suggest important changes to our understanding of T2D pathogenesis by demonstrating that the prevalence of islet autoimmune development is not only more prevalent in T2D patients than previously estimated but may also play an important role in β-cell dysfunction in the T2D disease process.”

September 18, 2017 Posted by | Cancer/oncology, Cardiology, Diabetes, Epidemiology, Immunology, Medicine, Nephrology, Neurology, Ophthalmology, Studies | Leave a comment