Econstudentlog

100 Cases in Orthopaedics and Rheumatology (II)

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

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

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

A few diabetes papers of interest

i. Clinical Inertia in Type 2 Diabetes Management: Evidence From a Large, Real-World Data Set.

Despite clinical practice guidelines that recommend frequent monitoring of HbA1c (every 3 months) and aggressive escalation of antihyperglycemic therapies until glycemic targets are reached (1,2), the intensification of therapy in patients with uncontrolled type 2 diabetes (T2D) is often inappropriately delayed. The failure of clinicians to intensify therapy when clinically indicated has been termed “clinical inertia.” A recently published systematic review found that the median time to treatment intensification after an HbA1c measurement above target was longer than 1 year (range 0.3 to >7.2 years) (3). We have previously reported a rather high rate of clinical inertia in patients uncontrolled on metformin monotherapy (4). Treatment was not intensified early (within 6 months of metformin monotherapy failure) in 38%, 31%, and 28% of patients when poor glycemic control was defined as an HbA1c >7% (>53 mmol/mol), >7.5% (>58 mmol/mol), and >8% (>64 mmol/mol), respectively.

Using the electronic health record system at Cleveland Clinic (2005–2016), we identified a cohort of 7,389 patients with T2D who had an HbA1c value ≥7% (≥53 mmol/mol) (“index HbA1c”) despite having been on a stable regimen of two oral antihyperglycemic drugs (OADs) for at least 6 months prior to the index HbA1c. This HbA1c threshold would generally be expected to trigger treatment intensification based on current guidelines. Patient records were reviewed for the 6-month period following the index HbA1c, and changes in diabetes therapy were evaluated for evidence of “intensification” […] almost two-thirds of patients had no evidence of intensification in their antihyperglycemic therapy during the 6 months following the index HbA1c ≥7% (≥53 mmol/mol), suggestive of poor glycemic control. Most alarming was the finding that even among patients in the highest index HbA1c category (≥9% [≥75 mmol/mol]), therapy was not intensified in 44% of patients, and slightly more than half (53%) of those with an HbA1c between 8 and 8.9% (64 and 74 mmol/mol) did not have their therapy intensified.”

“Unfortunately, these real-world findings confirm a high prevalence of clinical inertia with regard to T2D management. The unavoidable conclusion from these data […] is that physicians are not responding quickly enough to evidence of poor glycemic control in a high percentage of patients, even in those with HbA1c levels far exceeding typical treatment targets.

ii. Gestational Diabetes Mellitus and Diet: A Systematic Review and Meta-analysis of Randomized Controlled Trials Examining the Impact of Modified Dietary Interventions on Maternal Glucose Control and Neonatal Birth Weight.

“Medical nutrition therapy is a mainstay of gestational diabetes mellitus (GDM) treatment. However, data are limited regarding the optimal diet for achieving euglycemia and improved perinatal outcomes. This study aims to investigate whether modified dietary interventions are associated with improved glycemia and/or improved birth weight outcomes in women with GDM when compared with control dietary interventions. […]

From 2,269 records screened, 18 randomized controlled trials involving 1,151 women were included. Pooled analysis demonstrated that for modified dietary interventions when compared with control subjects, there was a larger decrease in fasting and postprandial glucose (−4.07 mg/dL [95% CI −7.58, −0.57]; P = 0.02 and −7.78 mg/dL [95% CI −12.27, −3.29]; P = 0.0007, respectively) and a lower need for medication treatment (relative risk 0.65 [95% CI 0.47, 0.88]; P = 0.006). For neonatal outcomes, analysis of 16 randomized controlled trials including 841 participants showed that modified dietary interventions were associated with lower infant birth weight (−170.62 g [95% CI −333.64, −7.60]; P = 0.04) and less macrosomia (relative risk 0.49 [95% CI 0.27, 0.88]; P = 0.02). The quality of evidence for these outcomes was low to very low. Baseline differences between groups in postprandial glucose may have influenced glucose-related outcomes. […] we were unable to resolve queries regarding potential concerns for sources of bias because of lack of author response to our queries. We have addressed this by excluding these studies in the sensitivity analysis. […] after removal of the studies with the most substantial methodological concerns in the sensitivity analysis, differences in the change in fasting plasma glucose were no longer significant. Although differences in the change in postprandial glucose and birth weight persisted, they were attenuated.”

“This review highlights limitations of the current literature examining dietary interventions in GDM. Most studies are too small to demonstrate significant differences in our primary outcomes. Seven studies had fewer than 50 participants and only two had more than 100 participants (n = 125 and 150). The short duration of many dietary interventions and the late gestational age at which they were started (38) may also have limited their impact on glycemic and birth weight outcomes. Furthermore, we cannot conclude if the improvements in maternal glycemia and infant birth weight are due to reduced energy intake, improved nutrient quality, or specific changes in types of carbohydrate and/or protein. […] These data suggest that dietary interventions modified above and beyond usual dietary advice for GDM have the potential to offer better maternal glycemic control and infant birth weight outcomes. However, the quality of evidence was judged as low to very low due to the limitations in the design of included studies, the inconsistency between their results, and the imprecision in their effect estimates.”

iii. Lifetime Prevalence and Prognosis of Prediabetes Without Progression to Diabetes.

Impaired fasting glucose, also termed prediabetes, is increasingly prevalent and is associated with adverse cardiovascular risk (1). The cardiovascular risks attributed to prediabetes may be driven primarily by the conversion from prediabetes to overt diabetes (2). Given limited data on outcomes among nonconverters in the community, the extent to which some individuals with prediabetes never go on to develop diabetes and yet still experience adverse cardiovascular risk remains unclear. We therefore investigated the frequency of cardiovascular versus noncardiovascular deaths in people who developed early- and late-onset prediabetes without ever progressing to diabetes.”

“We used data from the Framingham Heart Study collected on the Offspring Cohort participants aged 18–77 years at the time of initial fasting plasma glucose (FPG) assessment (1983–1987) who had serial FPG testing over subsequent examinations with continuous surveillance for outcomes including cause-specific mortality (3). As applied in prior epidemiological investigations (4), we used a case-control design focusing on the cause-specific outcome of cardiovascular death to minimize the competing risk issues that would be encountered in time-to-event analyses. To focus on outcomes associated with a given chronic glycemic state maintained over the entire lifetime, we restricted our analyses to only those participants for whom data were available over the life course and until death. […] We excluded individuals with unknown age of onset of glycemic impairment (i.e., age ≥50 years with prediabetes or diabetes at enrollment). […] We analyzed cause-specific mortality, allowing for relating time-varying exposures with lifetime risk for an event (4). We related glycemic phenotypes to cardiovascular versus noncardiovascular cause of death using a case-control design, where cases were defined as individuals who died of cardiovascular disease (death from stroke, heart failure, or other vascular event) or coronary heart disease (CHD) and controls were those who died of other causes.”

“The mean age of participants at enrollment was 42 ± 7 years (43% women). The mean age at death was 73 ± 10 years. […] In our study, approximately half of the individuals presented with glycemic impairment in their lifetime, of whom two-thirds developed prediabetes but never diabetes. In our study, these individuals had lower cardiovascular-related mortality compared with those who later developed diabetes, even if the prediabetes onset was early in life. However, individuals with early-onset prediabetes, despite lifelong avoidance of overt diabetes, had greater propensity for death due to cardiovascular or coronary versus noncardiovascular disease compared with those who maintained lifelong normal glucose status. […] Prediabetes is a heterogeneous entity. Whereas some forms of prediabetes are precursors to diabetes, other types of prediabetes never progress to diabetes but still confer increased propensity for death from a cardiovascular cause.”

iv. Learning From Past Failures of Oral Insulin Trials.

Very recently one of the largest type 1 diabetes prevention trials using daily administration of oral insulin or placebo was completed. After 9 years of study enrollment and follow-up, the randomized controlled trial failed to delay the onset of clinical type 1 diabetes, which was the primary end point. The unfortunate outcome follows the previous large-scale trial, the Diabetes Prevention Trial–Type 1 (DPT-1), which again failed to delay diabetes onset with oral insulin or low-dose subcutaneous insulin injections in a randomized controlled trial with relatives at risk for type 1 diabetes. These sobering results raise the important question, “Where does the type 1 diabetes prevention field move next?” In this Perspective, we advocate for a paradigm shift in which smaller mechanistic trials are conducted to define immune mechanisms and potentially identify treatment responders. […] Mechanistic trials will allow for better trial design and patient selection based upon molecular markers prior to large randomized controlled trials, moving toward a personalized medicine approach for the prevention of type 1 diabetes.

“Before a disease can be prevented, it must be predicted. The ability to assess risk for developing type 1 diabetes (T1D) has been well documented over the last two decades (1). Using genetic markers, human leukocyte antigen (HLA) DQ and DR typing (2), islet autoantibodies (1), and assessments of glucose tolerance (intravenous or oral glucose tolerance tests) has led to accurate prediction models for T1D development (3). Prospective birth cohort studies Diabetes Autoimmunity Study in the Young (DAISY) in Colorado (4), Type 1 Diabetes Prediction and Prevention (DIPP) study in Finland (5), and BABYDIAB studies in Germany have followed genetically at-risk children for the development of islet autoimmunity and T1D disease onset (6). These studies have been instrumental in understanding the natural history of T1D and making T1D a predictable disease with the measurement of antibodies in the peripheral blood directed against insulin and proteins within β-cells […]. Having two or more islet autoantibodies confers an ∼85% risk of developing T1D within 15 years and nearly 100% over time (7). […] T1D can be predicted by measuring islet autoantibodies, and thousands of individuals including young children are being identified through screening efforts, necessitating the need for treatments to delay and prevent disease onset.”

“Antigen-specific immunotherapies hold the promise of potentially inducing tolerance by inhibiting effector T cells and inducing regulatory T cells, which can act locally at tissue-specific sites of inflammation (12). Additionally, side effects are minimal with these therapies. As such, insulin and GAD have both been used as antigen-based approaches in T1D (13). Oral insulin has been evaluated in two large randomized double-blinded placebo-controlled trials over the last two decades. First in the Diabetes Prevention Trial–Type 1 (DPT-1) and then in the TrialNet clinical trials network […] The DPT-1 enrolled relatives at increased risk for T1D having islet autoantibodies […] After 6 years of treatment, there was no delay in T1D onset. […] The TrialNet study screened, enrolled, and followed 560 at-risk relatives over 9 years from 2007 to 2016, and results have been recently published (16). Unfortunately, this trial failed to meet the primary end point of delaying or preventing diabetes onset.”

“Many factors influence the potency and efficacy of antigen-specific therapy such as dose, frequency of dosing, route of administration, and, importantly, timing in the disease process. […] Over the last two decades, most T1D clinical trial designs have randomized participants 1:1 or 2:1, drug to placebo, in a double-blind two-arm design, especially those intervention trials in new-onset T1D (18). Primary end points have been delay in T1D onset for prevention trials or stimulated C-peptide area under the curve at 12 months with new-onset trials. These designs have served the field well and provided reliable human data for efficacy. However, there are limitations including the speed at which these trials can be completed, the number of interventions evaluated, dose optimization, and evaluation of mechanistic hypotheses. Alternative clinical trial designs, such as adaptive trial designs using Bayesian statistics, can overcome some of these issues. Adaptive designs use accumulating data from the trial to modify certain aspects of the study, such as enrollment and treatment group assignments. This “learn as we go” approach relies on biomarkers to drive decisions on planned trial modifications. […] One of the significant limitations for adaptive trial designs in the T1D field, at the present time, is the lack of validated biomarkers for short-term readouts to inform trial adaptations. However, large-scale collaborative efforts are ongoing to define biomarkers of T1D-specific immune dysfunction and β-cell stress and death (9,22).”

T1D prevention has proven much more difficult than originally thought, challenging the paradigm that T1D is a single disease. T1D is indeed a heterogeneous disease in terms of age of diagnosis, islet autoantibody profiles, and the rate of loss of residual β-cell function after clinical onset. Children have a much more rapid loss of residual insulin production (measured as C-peptide area under the curve following a mixed-meal tolerance test) after diagnosis than older adolescents and adults (23,24), indicating that childhood and adult-onset T1D are not identical. Further evidence for subtypes of T1D come from studies of human pancreata of T1D organ donors in which children (0–14 years of age) within 1 year of diagnosis had many more inflamed islets compared with older adolescents and adults aged 15–39 years old (25). Additionally, a younger age of T1D onset (<7 years) has been associated with higher numbers of CD20+ B cells within islets and fewer insulin-containing islets compared with an age of onset ≥13 years associated with fewer CD20+ islet infiltrating cells and more insulin-containing islets (26,27). This suggests a much more aggressive autoimmune process in younger children and distinct endotypes (a subtype of a condition defined by a distinct pathophysiologic mechanism), which has recently been proposed for T1D (27).”

“Safe and specific therapies capable of being used in children are needed for T1D prevention. The vast majority of drug development involves small biotechnology companies, specialty pharmaceutical firms, and large pharmaceutical companies, more so than traditional academia. A large amount of preclinical and clinical research (phase 1, 2, and 3 studies) are needed to advance a drug candidate through the development pipeline to achieve U.S. Food and Drug Administration (FDA) approval for a given disease. A recent analysis of over 4,000 drugs from 835 companies in development during 2003–2011 revealed that only 10.4% of drugs that enter clinical development at phase 1 (safety studies) advance to FDA approval (32). However, the success rate increases 50% for the lead indication of a drug, i.e., a drug specifically developed for one given disease (32). Reasons for this include strong scientific rationale and early efficacy signals such as correlating pharmacokinetic (drug levels) to pharmacodynamic (drug target effects) tests for the lead indication. Lead indications also tend to have smaller, better-defined “homogenous” patient populations than nonlead indications for the same drug. This would imply that the T1D field needs more companies developing drugs specifically for T1D, not type 2 diabetes or other autoimmune diseases with later testing to broaden a drug’s indication. […] In a similar but separate analysis, selection biomarkers were found to substantially increase the success rate of drug approvals across all phases of drug development. Using a selection biomarker as part of study inclusion criteria increased drug approval threefold from 8.4% to 25.9% when used in phase 1 trials, 28% to 46% when transitioning from a phase 2 to phase 3 efficacy trial, and 55% to 76% for a phase 3 trial to likelihood of approval (33). These striking data support the concept that enrichment of patient enrollment at the molecular level is a more successful strategy than heterogeneous enrollment in clinical intervention trials. […] Taken together, new drugs designed specifically for children at risk for T1D and a biomarker selecting patients for a treatment response may increase the likelihood for a successful prevention trial; however, experimental confirmation in clinical trials is needed.”

v. Metabolic Karma — The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture.

“Cardiovascular (CV) disease remains the major cause of mortality and is associated with significant morbidity in both type 1 and type 2 diabetes (14). Despite major improvements in the management of traditional risk factors, including hypertension, dyslipidemia, and glycemic control prevention, retardation and reversal of atherosclerosis, as manifested clinically by myocardial infarction, stroke, and peripheral vascular disease, remain a major unmet need in the population with diabetes. For example, in the Steno-2 study and in its most recent report of the follow-up phase, at least a decade after cessation of the active treatment phase, there remained a high risk of death, primarily from CV disease despite aggressive control of the traditional risk factors, in this originally microalbuminuric population with type 2 diabetes (5,6). In a meta-analysis of major CV trials where aggressive glucose lowering was instituted […] the beneficial effect of intensive glycemic control on CV disease was modest, at best (7). […] recent trials with two sodium–glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin (11,12), and two long-acting glucagon-like peptide 1 agonists, liraglutide and semaglutide (13,14), have reported CV benefits that have led in some of these trials to a decrease in CV and all-cause mortality. However, even with these recent positive CV outcomes, CV disease remains the major burden in the population with diabetes (15).”

“This unmet need of residual CV disease in the population with diabetes remains unexplained but may occur as a result of a range of nontraditional risk factors, including low-grade inflammation and enhanced thrombogenicity as a result of the diabetic milieu (16). Furthermore, a range of injurious pathways as a result of chronic hyperglycemia previously studied in vitro in endothelial cells (17) or in models of microvascular complications may also be relevant and are a focus of this review […] [One] major factor that is likely to promote atherosclerosis in the diabetes setting is increased oxidative stress. There is not only increased generation of ROS from diverse sources but also reduced antioxidant defense in diabetes (40). […] vascular ROS accumulation is closely linked to atherosclerosis and vascular inflammation provide the impetus to consider specific antioxidant strategies as a novel therapeutic approach to decrease CV disease, particularly in the setting of diabetes.”

“One of the most important findings from numerous trials performed in subjects with type 1 and type 2 diabetes has been the identification that previous episodes of hyperglycemia can have a long-standing impact on the subsequent development of CV disease. This phenomenon known as “metabolic memory” or the “legacy effect” has been reported in numerous trials […] The underlying explanation at a molecular and/or cellular level for this phenomenon remains to be determined. Our group, as well as others, has postulated that epigenetic mechanisms may participate in conferring metabolic memory (5153). In in vitro studies initially performed in aortic endothelial cells, transient incubation of these cells in high glucose followed by subsequent return of these cells to a normoglycemic environment was associated with increased gene expression of the p65 subunit of NF-κB, NF-κB activation, and expression of NF-κB–dependent proteins, including MCP-1 and VCAM-1 (54).

In further defining a potential epigenetic mechanism that could explain the glucose-induced upregulation of genes implicated in vascular inflammation, a specific histone methylation mark was identified in the promoter region of the p65 gene (54). This histone 3 lysine 4 monomethylation (H3K4m1) occurred as a result of mobilization of the histone methyl transferase, Set7. Furthermore, knockdown of Set7 attenuated glucose-induced p65 upregulation and prevented the persistent upregulation of this gene despite these endothelial cells returning to a normoglycemic milieu (55). These findings, confirmed in animal models exposed to transient hyperglycemia (54), provide the rationale to consider Set7 as an appropriate target for end-organ protective therapies in diabetes. Although specific Set7 inhibitors are currently unavailable for clinical development, the current interest in drugs that block various enzymes, such as Set7, that influence histone methylation in diseases, such as cancer (56), could lead to agents that warrant testing in diabetes. Studies addressing other sites of histone methylation as well as other epigenetic pathways including DNA methylation and acetylation have been reported or are currently in progress (55,57,58), particularly in the context of diabetes complications. […] As in vitro and preclinical studies increase our knowledge and understanding of the pathogenesis of diabetes complications, it is likely that we will identify new molecular targets leading to better treatments to reduce the burden of macrovascular disease. Nevertheless, these new treatments will need to be considered in the context of improved management of traditional risk factors.”

vi. Perceived risk of diabetes seriously underestimates actual diabetes risk: The KORA FF4 study.

“According to the International Diabetes Federation (IDF), almost half of the people with diabetes worldwide are unaware of having the disease, and even in high-income countries, about one in three diabetes cases is not diagnosed [1,2]. In the USA, 28% of diabetes cases are undiagnosed [3]. In DEGS1, a recent population-based German survey, 22% of persons with HbA1c ≥ 6.5% were unaware of their disease [4]. Persons with undiagnosed diabetes mellitus (UDM) have a more than twofold risk of mortality compared to persons with normal glucose tolerance (NGT) [5,6]; many of them also have undiagnosed diabetes complications like retinopathy and chronic kidney disease [7,8]. […] early detection of diabetes and prediabetes is beneficial for patients, but may be delayed by patients´ being overly optimistic about their own health. Therefore, it is important to address how persons with UDM or prediabetes perceive their diabetes risk.”

“The proportion of persons who perceived their risk of having UDM at the time of the interview as “negligible”, “very low” or “low” was 87.1% (95% CI: 85.0–89.0) in NGT [normal glucose tolerance individuals], 83.9% (81.2–86.4) in prediabetes, and 74.2% (64.5–82.0) in UDM […]. The proportion of persons who perceived themselves at risk of developing diabetes in the following years ranged from 14.6% (95% CI: 12.6–16.8) in NGT to 20.6% (17.9–23.6) in prediabetes to 28.7% (20.5–38.6) in UDM […] In univariate regression models, perceiving oneself at risk of developing diabetes was associated with younger age, female sex, higher school education, obesity, self-rated poor general health, and parental diabetes […] the proportion of better educated younger persons (age ≤ 60 years) with prediabetes, who perceived themselves at risk of developing diabetes was 35%, whereas this figure was only 13% in less well educated older persons (age > 60 years).”

The present study shows that three out of four persons with UDM [undiagnosed diabetes mellitus] believed that the probability of having undetected diabetes was low or very low. In persons with prediabetes, more than 70% believed that they were not at risk of developing diabetes in the next years. People with prediabetes were more inclined to perceive themselves at risk of diabetes if their self-rated general health was poor, their mother or father had diabetes, they were obese, they were female, their educational level was high, and if they were younger. […] People with undiagnosed diabetes or prediabetes considerably underestimate their probability of having or developing diabetes. […] perceived diabetes risk was lower in men, lower educated and older persons. […] Our results showed that people with low and intermediate education strongly underestimate their risk of diabetes and may qualify as target groups for detection of UDM and prediabetes.”

“The present results were in line with results from the Dutch Hoorn Study [18,19]. Adriaanse et al. reported that among persons with UDM, only 28.3% perceived their likeliness of having diabetes to be at least 10% [18], and among persons with high risk of diabetes (predicted from a symptom risk questionnaire), the median perceived likeliness of having diabetes was 10.8% [19]. Again, perceived risk did not fully reflect the actual risk profiles. For BMI, there was barely any association with perceived risk of diabetes in the Dutch study [19].”

July 2, 2018 Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Immunology, Medicine, Molecular biology, Pharmacology, Studies | Leave a comment

Blood (II)

Below I have added some quotes from the chapters of the book I did not cover in my first post, as well as some supplementary links.

Haemoglobin is of crucial biological importance; it is also easy to obtain safely in large quantities from donated blood. These properties have resulted in its becoming the most studied protein in human history. Haemoglobin played a key role in the history of our understanding of all proteins, and indeed the science of biochemistry itself. […] Oxygen transport defines the primary biological function of blood. […] Oxygen gas consists of two atoms of oxygen bound together to form a symmetrical molecule. However, oxygen cannot be transported in the plasma alone. This is because water is very poor at dissolving oxygen. Haemoglobin’s primary function is to increase this solubility; it does this by binding the oxygen gas on to the iron in its haem group. Every haem can bind one oxygen molecule, increasing the amount of oxygen able to dissolve in the blood.”

“An iron atom can exist in a number of different forms depending on how many electrons it has in its atomic orbitals. In its ferrous (iron II) state iron can bind oxygen readily. The haemoglobin protein has therefore evolved to stabilize its haem iron cofactor in this ferrous state. The result is that over fifty times as much oxygen is stored inside the confines of the red blood cell compared to outside in the watery plasma. However, using iron to bind oxygen comes at a cost. Iron (II) can readily lose one of its electrons to the bound oxygen, a process called ‘oxidation’. So the same form of iron that can bind oxygen avidly (ferrous) also readily reacts with that same oxygen forming an unreactive iron III state, called ‘ferric’. […] The complex structure of the protein haemoglobin is required to protect the ferrous iron from oxidizing. The haem iron is held in a precise configuration within the protein. Specific amino acids are ideally positioned to stabilize the iron–oxygen bond and prevent it from oxidizing. […] the iron stays ferrous despite the presence of the nearby oxygen. Having evolved over many hundreds of millions of years, this stability is very difficult for chemists to mimic in the laboratory. This is one reason why, desirable as it might be in terms of cost and convenience, it is not currently possible to replace blood transfusions with a simple small chemical iron oxygen carrier.”

“Given the success of the haem iron and globin combination in haemoglobin, it is no surprise that organisms have used this basic biochemical architecture for a variety of purposes throughout evolution, not just oxygen transport in blood. One example is the protein myoglobin. This protein resides inside animal cells; in the human it is found in the heart and skeletal muscle. […] Myoglobin has multiple functions. Its primary role is as an aid to oxygen diffusion. Whereas haemoglobin transports oxygen from the lung to the cell, myoglobin transports it once it is inside the cell. As oxygen is so poorly soluble in water, having a chain of molecules inside the cell that can bind and release oxygen rapidly significantly decreases the time it takes the gas to get from the blood capillary to the part of the cell—the mitochondria—where it is needed. […] Myoglobin can also act as an emergency oxygen backup store. In humans this is trivial and of questionable importance. Not so in diving mammals such as whales and dolphins that have as much as thirty times the myoglobin content of the terrestrial equivalent; indeed those mammals that dive for the longest duration have the most myoglobin. […] The third known function of myoglobin is to protect the muscle cells from damage by nitric oxide gas.”

“The heart is the organ that pumps blood around the body. If the heart stops functioning, blood does not flow. The driving force for this flow is the pressure difference between the arterial blood leaving the heart and the returning venous blood. The decreasing pressure in the venous side explains the need for unidirectional valves within veins to prevent the blood flowing in the wrong direction. Without them the return of the blood through the veins to the heart would be too slow, especially when standing up, when the venous pressure struggles to overcome gravity. […] normal [blood pressure] ranges rise slowly with age. […] high resistance in the arterial circulation at higher blood pressures [places] additional strain on the left ventricle. If the heart is weak, it may fail to achieve the extra force required to pump against this resistance, resulting in heart failure. […] in everyday life, a low blood pressure is rarely of concern. Indeed, it can be a sign of fitness as elite athletes have a much lower resting blood pressure than the rest of the population. […] the effect of exercise training is to thicken the muscles in the walls of the heart and enlarge the chambers. This enables more blood to be pumped per beat during intense exercise. The consequence of this extra efficiency is that when an athlete is resting—and therefore needs no more oxygen than a more sedentary person—the heart rate and blood pressure are lower than average. Most people’s experience of hypotension will be reflected by dizzy spells and lack of balance, especially when moving quickly to an upright position. This is because more blood pools in the legs when you stand up, meaning there is less blood for the heart to pump. The immediate effect should be for the heart to beat faster to restore the pressure. If there is a delay, the decrease in pressure can decrease the blood flow to the brain and cause dizziness; in extreme cases this can lead to fainting.”

“If hypertension is persistent, patients are most likely to be treated with drugs that target specific pathways that the body uses to control blood pressure. For example angiotensin is a protein that can trigger secretion of the hormone aldosterone from the adrenal gland. In its active form angiotensin can directly constrict blood vessels, while aldosterone enhances salt and water retention, so raising blood volume. Both these effects increase blood pressure. Angiotensin is converted into its active form by an enzyme called ‘Angiotensin Converting Enzyme’ (ACE). An ACE inhibitor drug prevents this activity, keeping angiotensin in its inactive form; this will therefore drop the patient’s blood pressure. […] The metal calcium controls many processes in the body. Its entry into muscle cells triggers muscle contraction. Preventing this entry can therefore reduce the force of contraction of the heart and the ability of arteries to constrict. Both of these will have the effect of decreasing blood pressure. Calcium enters muscle cells via specific protein-based channels. Drugs that block these channels (calcium channel blockers) are therefore highly effective at treating hypertension.”

Autoregulation is a homeostatic process designed to ensure that blood flow remains constant [in settings where constancy is desirable]. However, there are many occasions when an organism actively requires a change in blood flow. It is relatively easy to imagine what these are. In the short term, blood supplies oxygen and nutrients. When these are used up rapidly, or their supply becomes limited, the response will be to increase blood flow. The most obvious example is the twenty-fold increase in oxygen and glucose consumption that occurs in skeletal muscle during exercise when compared to rest. If there were no accompanying increase in blood flow to the muscle the oxygen supply would soon run out. […] There are hundreds of molecules known that have the ability to increase or decrease blood flow […] The surface of all blood vessels is lined by a thin layer of cells, the ‘endothelium’. Endothelial cells form a barrier between the blood and the surrounding tissue, controlling access of materials into and out of the blood. For example white blood cells can enter or leave the circulation via interacting with the endothelium; this is the route by which neutrophils migrate from the blood to the site of tissue damage or bacterial/viral attack as part of the innate immune response. However, the endothelium is not just a selective barrier. It also plays an active role in blood physiology and biochemistry.”

“Two major issues [related to blood transfusions] remained at the end of the 19th century: the problem of clotting, which all were aware of; and the problem of blood group incompatbility, which no one had the slightest idea even existed. […] For blood transfusions to ever make a recovery the key issues of blood clotting and adverse side effects needed to be resolved. In 1875 the Swedish biochemist Olof Hammarsten showed that adding calcium accelerated the rate of blood clotting (we now know the mechanism for this is that key enzymes in blood platelets that catalyse fibrin formation require calcium for their function). It therefore made sense to use chemicals that bind calcium to try to prevent clotting. Calcium ions are positively charged; adding negatively charged ions such as oxalate and citrate neutralized the calcium, preventing its clot-promoting action. […] At the same time as anticoagulants were being discovered, the reason why some blood transfusions failed even when there were no clots was becoming clear. It had been shown that animal blood given to humans tended to clump together or agglutinate, eventually bursting and releasing free haemoglobin and causing kidney damage. In the early 1900s, working in Vienna, Karl Landsteiner showed the same effect could occur with human-to-human transfusion. The trick was the ability to separate blood cells from serum. This enabled mixing blood cells from a variety of donors with plasma from a variety of participants. Using his laboratory staff as subjects, Landsteiner showed that only some combinations caused the agglutination reaction. Some donor cells (now known as type O) never clumped. Others clumped depending on the nature of the plasma in a reproducible manner. A careful study of Landsteiner’s results revealed the ABO blood type distinctions […]. Versions of these agglutination tests still form the basis of checking transfused blood today.”

“No blood product can be made completely sterile, no matter how carefully it is processed. The best that can be done is to ensure that no new bacteria or viruses are added during the purification, storage, and transportation processes. Nothing can be done to inactivate any viruses that are already present in the donor’s blood, for the harsh treatments necessary to do this would inevitably damage the viability of the product or be prohibitively expensive to implement on the industrial scale that the blood market has become. […] In the 1980s over half the US haemophiliac population was HIV positive.”

“Three fundamentally different ways have been attempted to replace red blood cell transfusions. The first uses a completely chemical approach and makes use of perfluorocarbons, inert chemicals that, in liquid form, can dissolve gasses without reacting with them. […] Perfluorocarbons can dissolve oxygen much more effectively than water. […] The problem with their use as a blood substitute is that the amount of oxygen dissolved in these solutions is linear with increasing pressure. This means that the solution lacks the advantages of the sigmoidal binding curve of haemoglobin, which has evolved to maximize the amount of oxygen captured from the limited fraction found in air (20 per cent oxygen). However, to deliver the same amount of oxygen as haemoglobin, patients using the less efficient perfluorocarbons in their blood need to breathe gas that is almost 100 per cent pure oxygen […]; this restricts the use of these compounds. […] The second type of blood substitute makes use of haemoglobin biology. Initial attempts used purified haemoglobin itself. […] there is no haemoglobin-based blood substitute in general use today […] The problem for the lack of uptake is not that blood substitutes cannot replace red blood cell function. A variety of products have been shown to stay in the vasculature for several days, provide volume support, and deliver oxygen. However, they have suffered due to adverse side effects, most notably cardiac complications. […] In nature the plasma proteins haptoglobin and haemopexin bind and detoxify any free haemoglobin and haem released from red blood cells. The challenge for blood substitute research is to mimic these effects in a product that can still deliver oxygen. […] Despite ongoing research, these problems may prove to be insurmountable. There is therefore interest in a third approach. This is to grow artificial red blood cells using stem cell technology.”

Links:

Porphyrin. Globin.
Felix Hoppe-Seyler. Jacques Monod. Jeffries Wyman. Jean-Pierre Changeux.
Allosteric regulation. Monod-Wyman-Changeux model.
Structural Biochemistry/Hemoglobin (wikibooks). (Many of the topics covered in this link – e.g. comments on affinity, T/R-states, oxygen binding curves, the Bohr effect, etc. – are also covered in the book, so although I do link to some of the other topics also covered in this link below it should be noted that I did in fact leave out quite a few potentially relevant links on account of those topics being covered in the above link).
1,3-Bisphosphoglycerate.
Erythrocruorin.
Haemerythrin.
Hemocyanin.
Cytoglobin.
Neuroglobin.
Sickle cell anemia. Thalassaemia. Hemoglobinopathy. Porphyria.
Pulse oximetry.
Daniel Bernoulli. Hydrodynamica. Stephen Hales. Karl von Vierordt.
Arterial line.
Sphygmomanometer. Korotkoff sounds. Systole. Diastole. Blood pressure. Mean arterial pressure. Hypertension. Antihypertensive drugs. Atherosclerosis Pathology. Beta blocker. Diuretic.
Autoregulation.
Guanylate cyclase. Glyceryl trinitrate.
Blood transfusion. Richard Lower. Jean-Baptiste Denys. James Blundell.
Parabiosis.
Penrose Inquiry.
ABLE (Age of Transfused Blood in Critically Ill Adults) trial.
RECESS trial.

June 7, 2018 Posted by | Biology, Books, Cardiology, Chemistry, History, Medicine, Molecular biology, Pharmacology, Studies | Leave a comment

Molecular biology (II)

Below I have added some more quotes and links related to the book’s coverage:

“[P]roteins are the most abundant molecules in the body except for water. […] Proteins make up half the dry weight of a cell whereas DNA and RNA make up only 3 per cent and 20 per cent respectively. […] The approximately 20,000 protein-coding genes in the human genome can, by alternative splicing, multiple translation starts, and post-translational modifications, produce over 1,000,000 different proteins, collectively called ‘the proteome‘. It is the size of the proteome and not the genome that defines the complexity of an organism. […] For simple organisms, such as viruses, all the proteins coded by their genome can be deduced from its sequence and these comprise the viral proteome. However for higher organisms the complete proteome is far larger than the genome […] For these organisms not all the proteins coded by the genome are found in any one tissue at any one time and therefore a partial proteome is usually studied. What are of interest are those proteins that are expressed in specific cell types under defined conditions.”

“Enzymes are proteins that catalyze or alter the rate of chemical reactions […] Enzymes can speed up reactions […] but they can also slow some reactions down. Proteins play a number of other critical roles. They are involved in maintaining cell shape and providing structural support to connective tissues like cartilage and bone. Specialized proteins such as actin and myosin are required [for] muscular movement. Other proteins act as ‘messengers’ relaying signals to regulate and coordinate various cell processes, e.g. the hormone insulin. Yet another class of protein is the antibodies, produced in response to foreign agents such as bacteria, fungi, and viruses.”

“Proteins are composed of amino acids. Amino acids are organic compounds with […] an amino group […] and a carboxyl group […] In addition, amino acids carry various side chains that give them their individual functions. The twenty-two amino acids found in proteins are called proteinogenic […] but other amino acids exist that are non-protein functioning. […] A peptide bond is formed between two amino acids by the removal of a water molecule. […] each individual unit in a peptide or protein is known as an amino acid residue. […] Chains of less than 50-70 amino acid residues are known as peptides or polypeptides and >50-70 as proteins, although many proteins are composed of more than one polypeptide chain. […] Proteins are macromolecules consisting of one or more strings of amino acids folded into highly specific 3D-structures. Each amino acid has a different size and carries a different side group. It is the nature of the different side groups that facilitates the correct folding of a polypeptide chain into a functional tertiary protein structure.”

“Atoms scatter the waves of X-rays mainly through their electrons, thus forming secondary or reflected waves. The pattern of X-rays diffracted by the atoms in the protein can be captured on a photographic plate or an image sensor such as a charge coupled device placed behind the crystal. The pattern and relative intensity of the spots on the diffraction image are then used to calculate the arrangement of atoms in the original protein. Complex data processing is required to convert the series of 2D diffraction or scatter patterns into a 3D image of the protein. […] The continued success and significance of this technique for molecular biology is witnessed by the fact that almost 100,000 structures of biological molecules have been determined this way, of which most are proteins.”

“The number of proteins in higher organisms far exceeds the number of known coding genes. The fact that many proteins carry out multiple functions but in a regulated manner is one way a complex proteome arises without increasing the number of genes. Proteins that performed a single role in the ancestral organism have acquired extra and often disparate functions through evolution. […] The active site of an enzyme employed in catalysis is only a small part of the protein, leaving spare capacity for acquiring a second function. […] The glycolytic pathway is involved in the breakdown of sugars such as glucose to release energy. Many of the highly conserved and ancient enzymes from this pathway have developed secondary or ‘moonlighting’ functions. Proteins often change their location in the cell in order to perform a ‘second job’. […] The limited size of the genome may not be the only evolutionary pressure for proteins to moonlight. Combining two functions in one protein can have the advantage of coordinating multiple activities in a cell, enabling it to respond quickly to changes in the environment without the need for lengthy transcription and translational processes.”

Post-translational modifications (PTMs) […] is [a] process that can modify the role of a protein by addition of chemical groups to amino acids in the peptide chain after translation. Addition of phosphate groups (phosphorylation), for example, is a common mechanism for activating or deactivating an enzyme. Other common PTMs include addition of acetyl groups (acetylation), glucose (glucosylation), or methyl groups (methylation). […] Some additions are reversible, facilitating the switching between active and inactive states, and others are irreversible such as marking a protein for destruction by ubiquitin. [The difference between reversible and irreversible modifications can be quite important in pharmacology, and if you’re curious to know more about these topics Coleman’s drug metabolism text provide great coverage of related topics – US.] Diseases caused by malfunction of these modifications highlight the importance of PTMs. […] in diabetes [h]igh blood glucose lead to unwanted glocosylation of proteins. At the high glucose concentrations associated with diabetes, an unwanted irreversible chemical reaction binds the gllucose to amino acid residues such as lysines exposed on the protein surface. The glucosylated proteins then behave badly, cross-linking themselves to the extracellular matrix. This is particularly dangerous in the kidney where it decreases function and can lead to renal failure.”

“Twenty thousand protein-coding genes make up the human genome but for any given cell only about half of these are expressed. […] Many genes get switched off during differentiation and a major mechanism for this is epigenetics. […] an epigenetic trait […] is ‘a stably heritable phenotype resulting from changes in the chromosome without alterations in the DNA sequence’. Epigenetics involves the chemical alteration of DNA by methyl or other small molecular groups to affect the accessibility of a gene by the transcription machinery […] Epigenetics can […] act on gene expression without affecting the stability of the genetic code by modifying the DNA, the histones in chromatin, or a whole chromosome. […] Epigenetic signatures are not only passed on to somatic daughter cells but they can also be transferred through the germline to the offspring. […] At first the evidence appeared circumstantial but more recent studies have provided direct proof of epigenetic changes involving gene methylation being inherited. Rodent models have provided mechanistic evidence. […] the importance of epigenetics in development is highlighted by the fact that low dietary folate, a nutrient essential for methylation, has been linked to higher risk of birth defects in the offspring.” […on the other hand, well…]

The cell cycle is divided into phases […] Transition from G1 into S phase commits the cell to division and is therefore a very tightly controlled restriction point. Withdrawal of growth factors, insufficient nucleotides, or energy to complete DNA replication, or even a damaged template DNA, would compromise the process. Problems are therefore detected and the cell cycle halted by cell cycle inhibitors before the cell has committed to DNA duplication. […] The cell cycle inhibitors inactive the kinases that promote transition through the phases, thus halting the cell cycle. […] The cell cycle can also be paused in S phase to allow time for DNA repairs to be carried out before cell division. The consequences of uncontrolled cell division are so catastrophic that evolution has provided complex checks and balances to maintain fidelity. The price of failure is apoptosis […] 50 to 70 billion cells die every day in a human adult by the controlled molecular process of apoptosis.”

“There are many diseases that arise because a particular protein is either absent or a faulty protein is produced. Administering a correct version of that protein can treat these patients. The first commercially available recombinant protein to be produced for medical use was human insulin to treat diabetes mellitus. […] (FDA) approved the recombinant insulin for clinical use in 1982. Since then over 300 protein-based recombinant pharmaceuticals have been licensed by the FDA and the European Medicines Agency (EMA) […], and many more are undergoing clinical trials. Therapeutic proteins can be produced in bacterial cells but more often mammalian cells such as the Chinese hamster ovary cell line and human fibroblasts are used as these hosts are better able to produce fully functional human protein. However, using mammalian cells is extremely expensive and an alternative is to use live animals or plants. This is called molecular pharming and is an innovative way of producing large amounts of protein relatively cheaply. […] In plant pharming, tobacco, rice, maize, potato, carrots, and tomatoes have all been used to produce therapeutic proteins. […] [One] class of proteins that can be engineered using gene-cloning technology is therapeutic antibodies. […] Therapeutic antibodies are designed to be monoclonal, that is, they are engineered so that they are specific for a particular antigen to which they bind, to block the antigen’s harmful effects. […] Monoclonal antibodies are at the forefront of biological therapeutics as they are highly specific and tend not to induce major side effects.”

“In gene therapy the aim is to restore the function of a faulty gene by introducing a correct version of that gene. […] a cloned gene is transferred into the cells of a patient. Once inside the cell, the protein encoded by the gene is produced and the defect is corrected. […] there are major hurdles to be overcome for gene therapy to be effective. One is the gene construct has to be delivered to the diseased cells or tissues. This can often be difficult […] Mammalian cells […] have complex mechanisms that have evolved to prevent unwanted material such as foreign DNA getting in. Second, introduction of any genetic construct is likely to trigger the patient’s immune response, which can be fatal […] once delivered, expression of the gene product has to be sustained to be effective. One approach to delivering genes to the cells is to use genetically engineered viruses constructed so that most of the viral genome is deleted […] Once inside the cell, some viral vectors such as the retroviruses integrate into the host genome […]. This is an advantage as it provides long-lasting expression of the gene product. However, it also poses a safety risk, as there is little control over where the viral vector will insert into the patient’s genome. If the insertion occurs within a coding gene, this may inactivate gene function. If it integrates close to transcriptional start sites, where promoters and enhancer sequences are located, inappropriate gene expression can occur. This was observed in early gene therapy trials [where some patients who got this type of treatment developed cancer as a result of it. A few more details hereUS] […] Adeno-associated viruses (AAVs) […] are often used in gene therapy applications as they are non-infectious, induce only a minimal immune response, and can be engineered to integrate into the host genome […] However, AAVs can only carry a small gene insert and so are limited to use with genes that are of a small size. […] An alternative delivery system to viruses is to package the DNA into liposomes that are then taken up by the cells. This is safer than using viruses as liposomes do not integrate into the host genome and are not very immunogenic. However, liposome uptake by the cells can be less efficient, resulting in lower expression of the gene.”

Links:

One gene–one enzyme hypothesis.
Molecular chaperone.
Protein turnover.
Isoelectric point.
Gel electrophoresis. Polyacrylamide.
Two-dimensional gel electrophoresis.
Mass spectrometry.
Proteomics.
Peptide mass fingerprinting.
Worldwide Protein Data Bank.
Nuclear magnetic resonance spectroscopy of proteins.
Immunoglobulins. Epitope.
Western blot.
Immunohistochemistry.
Crystallin. β-catenin.
Protein isoform.
Prion.
Gene expression. Transcriptional regulation. Chromatin. Transcription factor. Gene silencing. Histone. NF-κB. Chromatin immunoprecipitation.
The agouti mouse model.
X-inactive specific transcript (Xist).
Cell cycle. Cyclin. Cyclin-dependent kinase.
Retinoblastoma protein pRb.
Cytochrome c. CaspaseBcl-2 family. Bcl-2-associated X protein.
Hybridoma technology. Muromonab-CD3.
Recombinant vaccines and the development of new vaccine strategies.
Knockout mouse.
Adenovirus Vectors for Gene Therapy, Vaccination and Cancer Gene Therapy.
Genetically modified food. Bacillus thuringiensis. Golden rice.

 

May 29, 2018 Posted by | Biology, Books, Chemistry, Diabetes, Engineering, Genetics, Immunology, Medicine, Molecular biology, Pharmacology | Leave a comment

Alcohol and Aging (II)

I gave the book 3 stars on goodreads.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

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

A few diabetes papers of interest

i. Economic Costs of Diabetes in the U.S. in 2017.

“This study updates previous estimates of the economic burden of diagnosed diabetes and quantifies the increased health resource use and lost productivity associated with diabetes in 2017. […] The total estimated cost of diagnosed diabetes in 2017 is $327 billion, including $237 billion in direct medical costs and $90 billion in reduced productivity. For the cost categories analyzed, care for people with diagnosed diabetes accounts for 1 in 4 health care dollars in the U.S., and more than half of that expenditure is directly attributable to diabetes. People with diagnosed diabetes incur average medical expenditures of ∼$16,750 per year, of which ∼$9,600 is attributed to diabetes. People with diagnosed diabetes, on average, have medical expenditures ∼2.3 times higher than what expenditures would be in the absence of diabetes. Indirect costs include increased absenteeism ($3.3 billion) and reduced productivity while at work ($26.9 billion) for the employed population, reduced productivity for those not in the labor force ($2.3 billion), inability to work because of disease-related disability ($37.5 billion), and lost productivity due to 277,000 premature deaths attributed to diabetes ($19.9 billion). […] After adjusting for inflation, economic costs of diabetes increased by 26% from 2012 to 2017 due to the increased prevalence of diabetes and the increased cost per person with diabetes. The growth in diabetes prevalence and medical costs is primarily among the population aged 65 years and older, contributing to a growing economic cost to the Medicare program.”

The paper includes a lot of details about how they went about estimating these things, but I decided against including these details here – read the full paper if you’re interested. I did however want to add some additional details, so here goes:

Absenteeism is defined as the number of work days missed due to poor health among employed individuals, and prior research finds that people with diabetes have higher rates of absenteeism than the population without diabetes. Estimates from the literature range from no statistically significant diabetes effect on absenteeism to studies reporting 1–6 extra missed work days (and odds ratios of more absences ranging from 1.5 to 3.3) (1214). Analyzing 2014–2016 NHIS data and using a negative binomial regression to control for overdispersion in self-reported missed work days, we estimate that people with diabetes have statistically higher missed work days—ranging from 1.0 to 4.2 additional days missed per year by demographic group, or 1.7 days on average — after controlling for age-group, sex, race/ethnicity, diagnosed hypertension status (yes/no), and body weight status (normal, overweight, obese, unknown). […] Presenteeism is defined as reduced productivity while at work among employed individuals and is generally measured through worker responses to surveys. Multiple recent studies report that individuals with diabetes display higher rates of presenteeism than their peers without diabetes (12,1517). […] We model productivity loss associated with diabetes-attributed presenteeism using the estimate (6.6%) from the 2012 study—which is toward the lower end of the 1.8–38% range reported in the literature. […] Reduced performance at work […] accounted for 30% of the indirect cost of diabetes.”

It is of note that even with a somewhat conservative estimate of presenteeism, this cost component is an order of magnitude larger than the absenteeism variable. It is worth keeping in mind that this ratio is likely to be different elsewhere; due to the way the American health care system is structured/financed – health insurance is to a significant degree linked to employment – you’d expect the estimated ratio to be different from what you might observe in countries like the UK or Denmark. Some more related numbers from the paper:

Inability to work associated with diabetes is estimated using a conservative approach that focuses on unemployment related to long-term disability. Logistic regression with 2014–2016 NHIS data suggests that people aged 18–65 years with diabetes are significantly less likely to be in the workforce than people without diabetes. […] we use a conservative approach (which likely underestimates the cost associated with inability to work) to estimate the economic burden associated with reduced labor force participation. […] Study results suggest that people with diabetes have a 3.1 percentage point higher rate of being out of the workforce and receiving disability payments compared with their peers without diabetes. The diabetes effect increases with age and varies by demographic — ranging from 2.1 percentage points for non-Hispanic white males aged 60–64 years to 10.6 percentage points for non-Hispanic black females aged 55–59 years.”

“In 2017, an estimated 24.7 million people in the U.S. are diagnosed with diabetes, representing ∼7.6% of the total population (and 9.7% of the adult population). The estimated national cost of diabetes in 2017 is $327 billion, of which $237 billion (73%) represents direct health care expenditures attributed to diabetes and $90 billion (27%) represents lost productivity from work-related absenteeism, reduced productivity at work and at home, unemployment from chronic disability, and premature mortality. Particularly noteworthy is that excess costs associated with medications constitute 43% of the total direct medical burden. This includes nearly $15 billion for insulin, $15.9 billion for other antidiabetes agents, and $71.2 billion in excess use of other prescription medications attributed to higher disease prevalence associated with diabetes. […] A large portion of medical costs associated with diabetes costs is for comorbidities.”

Insulin is ~$15 billion/year, out of a total estimated cost of $327 billion. This is less than 5% of the total cost. Take note of the 70 billion. I know I’ve said this before, but it bears repeating: Most of diabetes-related costs are not related to insulin.

“…of the projected 162 million hospital inpatient days in the U.S. in 2017, an estimated 40.3 million days (24.8%) are incurred by people with diabetes [who make up ~7.6% of the population – see above], of which 22.6 million days are attributed to diabetes. About one-fourth of all nursing/residential facility days are incurred by people with diabetes. About half of all physician office visits, emergency department visits, hospital outpatient visits, and medication prescriptions (excluding insulin and other antidiabetes agents) incurred by people with diabetes are attributed to their diabetes. […] The largest contributors to the cost of diabetes are higher use of prescription medications beyond antihyperglycemic medications ($71.2 billion), higher use of hospital inpatient services ($69.7 billion), medications and supplies to directly treat diabetes ($34.6 billion), and more office visits to physicians and other health providers ($30.0 billion). Approximately 61% of all health care expenditures attributed to diabetes are for health resources used by the population aged ≥65 years […] we estimate the average annual excess expenditures for the population aged <65 years and ≥65 years, respectively, at $6,675 and $13,239. Health care expenditures attributed to diabetes generally increase with age […] The population with diabetes is older and sicker than the population without diabetes, and consequently annual medical expenditures are much higher (on average) than for people without diabetes“.

“Of the estimated 24.7 million people with diagnosed diabetes, analysis of NHIS data suggests that ∼8.1 million are in the workforce. If people with diabetes participated in the labor force at rates similar to their peers without diabetes, there would be ∼2 million additional people aged 18–64 years in the workforce.”

Comparing the 2017 estimates with those produced for 2012, the overall cost of diabetes appears to have increased by ∼25% after adjusting for inflation, reflecting an 11% increase in national prevalence of diagnosed diabetes and a 13% increase in the average annual diabetes-attributed cost per person with diabetes.”

ii. Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers.

“Diabetic foot ulcers remain a major health care problem. They are common, result in considerable suffering, frequently recur, and are associated with high mortality, as well as considerable health care costs. While national and international guidance exists, the evidence base for much of routine clinical care is thin. It follows that many aspects of the structure and delivery of care are susceptible to the beliefs and opinion of individuals. It is probable that this contributes to the geographic variation in outcome that has been documented in a number of countries. This article considers these issues in depth and emphasizes the urgent need to improve the design and conduct of clinical trials in this field, as well as to undertake systematic comparison of the results of routine care in different health economies. There is strong suggestive evidence to indicate that appropriate changes in the relevant care pathways can result in a prompt improvement in clinical outcomes.”

“Despite considerable advances made over the last 25 years, diabetic foot ulcers (DFUs) continue to present a very considerable health care burden — one that is widely unappreciated. DFUs are common, the median time to healing without surgery is of the order of 12 weeks, and they are associated with a high risk of limb loss through amputation (14). The 5-year survival following presentation with a new DFU is of the order of only 50–60% and hence worse than that of many common cancers (4,5). While there is evidence that mortality is improving with more widespread use of cardiovascular risk reduction (6), the most recent data — derived from a Veterans Health Adminstration population—reported that 1-, 2-, and 5-year survival was only 81, 69, and 29%, respectively, and the association between mortality and DFU was stronger than that of any macrovascular disease (7). […] There is […] wide variation in clinical outcome within the same country (1315), suggesting that some people are being managed considerably less well than others.”

“Data on community-wide ulcer incidence are very limited. Overall incidences of 5.8 and 6.0% have been reported in selected populations of people with diabetes in the U.S. (2,12,20) while incidences of 2.1 and 2.2% have been reported from less selected populations in Europe—either in all people with diabetes (21) or in those with type 2 disease alone (22). It is not known whether the incidence is changing […] Although a number of risk factors associated with the development of ulceration are well recognized (23), there is no consensus on which dominate, and there are currently no reports of any studies that might justify the adoption of any specific strategy for population selection in primary prevention.”

“The incidence of major amputation is used as a surrogate measure of the failure of DFUs to heal. Its main value lies in the relative ease of data capture, but its value is limited because it is essentially a treatment and not a true measure of disease outcome. In no other major disease (including malignancies, cardiovascular disease, or cerebrovascular disease) is the number of treatments used as a measure of outcome. But despite this and other limitations of major amputation as an outcome measure (36), there is evidence that the overall incidence of major amputation is falling in some countries with nationwide databases (37,38). Perhaps the most convincing data come from the U.K., where the unadjusted incidence has fallen dramatically from about 3.0–3.5 per 1,000 people with diabetes per year in the mid-1990s to 1.0 or less per 1,000 per year in both England and Scotland (14,39).”

New ulceration after healing is high, with ∼40% of people having a new ulcer (whether at the same site or another) within 12 months (10). This is a critical aspect of diabetic foot disease—emphasizing that when an ulcer heals, foot disease must be regarded not as cured, but in remission (10). In this respect, diabetic foot disease is directly analogous to malignancy. It follows that the person whose foot disease is in remission should receive the same structured follow-up as a person who is in remission following treatment for cancer. Of all areas concerned with the management of DFUs, this long-term need for specialist surveillance is arguably the one that should command the greatest attention.

“There is currently little evidence to justify the adoption of very many of the products and procedures currently promoted for use in clinical practice. Guidelines are required to encourage clinicians to adopt only those treatments that have been shown to be effective in robust studies and principally in RCTs. The design and conduct of such RCTs needs improved governance because many are of low standard and do not always provide the evidence that is claimed.”

Incidence numbers like the ones included above will not always give you the full picture when there are a lot of overlapping data points in the sample (due to recurrence), but sometimes that’s all you have. However in the type 1 context we also do have some additional numbers that make it easier to appreciate the scale of the problem in that context. Here are a few additional data from a related publication I blogged some time ago (do keep in mind that estimates are likely to be lower in community samples of type 2 diabetics, even if perhaps nobody actually know precisely how much lower):

“The rate of nontraumatic amputation in T1DM is high, occurring at 0.4–7.2% per year (28). By 65 years of age, the cumulative probability of lower-extremity amputation in a Swedish administrative database was 11% for women with T1DM and 20.7% for men (10). In this Swedish population, the rate of lower-extremity amputation among those with T1DM was nearly 86-fold that of the general population.” (link)

Do keep in mind that people don’t stop getting ulcers once they reach retirement age (the 11%/20.7% is not lifetime risk, it’s a biased lower bound).

iii. Excess Mortality in Patients With Type 1 Diabetes Without Albuminuria — Separating the Contribution of Early and Late Risks.

“The current study investigated whether the risk of mortality in patients with type 1 diabetes without any signs of albuminuria is different than in the general population and matched control subjects without diabetes.”

“Despite significant improvements in management, type 1 diabetes remains associated with an increase in mortality relative to the age- and sex-matched general population (1,2). Acute complications of diabetes may initially account for this increased risk (3,4). However, with increasing duration of disease, the leading contributor to excess mortality is its vascular complications including diabetic kidney disease (DKD) and cardiovascular disease (CVD). Consequently, patients who subsequently remain free of complications may have little or no increased risk of mortality (1,2,5).”

“Mortality was evaluated in a population-based cohort of 10,737 children (aged 0–14 years) with newly diagnosed type 1 diabetes in Finland who were listed on the National Public Health Institute diabetes register, Central Drug Register, and Hospital Discharge Register in 1980–2005 […] We excluded patients with type 2 diabetes and diabetes occurring secondary to other conditions, such as steroid use, Down syndrome, and congenital malformations of the pancreas. […] FinnDiane participants who died were more likely to be male, older, have a longer duration of diabetes, and later age of diabetes onset […]. Notably, none of the conventional variables associated with complications (e.g., HbA1c, hypertension, smoking, lipid levels, or AER) were associated with all-cause mortality in this cohort of patients without albuminuria. […] The most frequent cause of death in the FinnDiane cohort was IHD [ischaemic heart disease, US] […], largely driven by events in patients with long-standing diabetes and/or previously established CVD […]. The mortality rate ratio for IHD was 4.34 (95% CI 2.49–7.57, P < 0.0001). There remained a number of deaths due to acute complications of diabetes, including ketoacidosis and hypoglycemia. This was most significant in patients with a shorter duration of diabetes but still apparent in those with long-standing diabetes[…]. Notably, deaths due to “risk-taking behavior” were lower in adults with type 1 diabetes compared with matched individuals without diabetes: mortality rate ratio was 0.42 (95% CI 0.22–0.79, P = 0.006) […] This was largely driven by the 80% reduction (95% CI 0.06–0.66) in deaths due to alcohol and drugs in males with type 1 diabetes (Table 3). No reduction was observed in female patients (rate ratio 0.90 [95% CI 0.18–4.44]), although the absolute event rate was already more than seven times lower in Finnish women than in men.”

The chief determinant of excess mortality in patients with type 1 diabetes is its complications. In the first 10 years of type 1 diabetes, the acute complications of diabetes dominate and result in excess mortality — more than twice that observed in the age- and sex-matched general population. This early excess explains why registry studies following patients with type 1 diabetes from diagnosis have consistently reported reduced life expectancy, even in patients free of chronic complications of diabetes (68). By contrast, studies of chronic complications, like FinnDiane and the Pittsburgh Epidemiology of Diabetes Complications Study (1,2), have followed participants with, usually, >10 years of type 1 diabetes at baseline. In these patients, the presence or absence of chronic complications of diabetes is critical for survival. In particular, the presence and severity of albuminuria (as a marker of vascular burden) is strongly associated with mortality outcomes in type 1 diabetes (1). […] the FinnDiane normoalbuminuric patients showed increased all-cause mortality compared with the control subjects without diabetes in contrast to when the comparison was made with the Finnish general population, as in our previous publication (1). Two crucial causes behind the excess mortality were acute diabetes complications and IHD. […] Comparisons with the general population, rather than matched control subjects, may overestimate expected mortality, diluting the SMR estimate”.

Despite major improvements in the delivery of diabetes care and other technological advances, acute complications remain a major cause of death both in children and in adults with type 1 diabetes. Indeed, the proportion of deaths due to acute events has not changed significantly over the last 30 years. […] Even in patients with long-standing diabetes (>20 years), the risk of death due to hypoglycemia or ketoacidosis remains a constant companion. […] If it were possible to eliminate all deaths from acute events, the observed mortality rate would have been no different from the general population in the early cohort. […] In long-term diabetes, avoiding chronic complications may be associated with mortality rates comparable with those of the general population; although death from IHD remains increased, this is offset by reduced risk-taking behavior, especially in men.”

“It is well-known that CVD is strongly associated with DKD (15). However, in the current study, mortality from IHD remained higher in adults with type 1 diabetes without albuminuria compared with matched control subjects in both men and women. This is concordant with other recent studies also reporting increased mortality from CVD in patients with type 1 diabetes in the absence of DKD (7,8) and reinforces the need for aggressive cardiovascular risk reduction even in patients without signs of microvascular disease. However, it is important to note that the risk of death from CVD, though significant, is still at least 10-fold lower than observed in patients with albuminuria (1). Alcohol- and drug-related deaths were substantially lower in patients with type 1 diabetes compared with the age-, sex-, and region-matched control subjects. […] This may reflect a selection bias […] Nonparticipation in health studies is associated with poorer health, stress, and lower socioeconomic status (17,18), which are in turn associated with increased risk of premature mortality. It can be speculated that with inclusion of patients with risk-taking behavior, the mortality rate in patients with diabetes would be even higher and, consequently, the SMR would also be significantly higher compared with the general population. Selection of patients who despite long-standing diabetes remained free of albuminuria may also have included individuals more accepting of general health messages and less prone to depression and nihilism arising from treatment failure.”

I think the selection bias problem is likely to be quite significant, as these results don’t really match what I’ve seen in the past. For example a recent Norwegian study on young type 1 diabetics found high mortality in their sample in significant degree due to alcohol-related causes and suicide: “A relatively high proportion of deaths were related to alcohol. […] Death was related to alcohol in 15% of cases. SMR for alcohol-related death was 6.8 (95% CI 4.5–10.3), for cardiovascular death was 7.3 (5.4–10.0), and for violent death was 3.6 (2.3–5.3).” That doesn’t sound very similar to the study above, and that study’s also from Scandinavia. In this study, in which they used data from diabetic organ donors, they found that a large proportion of the diabetics included in the study used illegal drugs: “we observed a high rate of illicit substance abuse: 32% of donors reported or tested positive for illegal substances (excluding marijuana), and multidrug use was common.”

Do keep in mind that one of the main reasons why ‘alcohol-related’ deaths are higher in diabetes is likely to be that ‘drinking while diabetic’ is a lot more risky than is ‘drinking while not diabetic’. On a related note, diabetics may not appreciate the level of risk they’re actually exposed to while drinking, due to community norms etc., so there might be a disconnect between risk preferences and observed behaviour (i.e., a diabetic might be risk averse but still engage in risky behaviours because he doesn’t know how risky those behaviours in which he’s engaging actually are).

Although the illicit drugs study indicates that diabetics at least in some samples are not averse to engaging in risky behaviours, a note of caution is probably warranted in the alcohol context: High mortality from alcohol-mediated acute complications needn’t be an indication that diabetics drink more than non-diabetics; that’s a separate question, you might see numbers like these even if they in general drink less. And a young type 1 diabetic who suffers a cardiac arrhythmia secondary to long-standing nocturnal hypoglycemia and subsequently is found ‘dead in bed’ after a bout of drinking is conceptually very different from a 50-year old alcoholic dying from a variceal bleed or acute pancreatitis. Parenthetically, if it is true that illicit drugs use is common in type 1 diabetics one reason might be that they are aware of the risks associated with alcohol (which is particularly nasty in terms of the metabolic/glycemic consequences in diabetes, compared to some other drugs) and thus they deliberately make a decision to substitute this drug with other drugs less likely to cause acute complications like severe hypoglycemic episodes or DKA (depending on the setting and the specifics, alcohol might be a contributor to both of these complications). If so, classical ‘risk behaviours’ may not always be ‘risk behaviours’ in diabetes. You need to be careful, this stuff’s complicated.

iv. Are All Patients With Type 1 Diabetes Destined for Dialysis if They Live Long Enough? Probably Not.

“Over the past three decades there have been numerous innovations, supported by large outcome trials that have resulted in improved blood glucose and blood pressure control, ultimately reducing cardiovascular (CV) risk and progression to nephropathy in type 1 diabetes (T1D) (1,2). The epidemiological data also support the concept that 25–30% of people with T1D will progress to end-stage renal disease (ESRD). Thus, not everyone develops progressive nephropathy that ultimately requires dialysis or transplantation. This is a result of numerous factors […] Data from two recent studies reported in this issue of Diabetes Care examine the long-term incidence of chronic kidney disease (CKD) in T1D. Costacou and Orchard (7) examined a cohort of 932 people evaluated for 50-year cumulative kidney complication risk in the Pittsburgh Epidemiology of Diabetes Complications study. They used both albuminuria levels and ESRD/transplant data for assessment. By 30 years’ duration of diabetes, ESRD affected 14.5% and by 40 years it affected 26.5% of the group with onset of T1D between 1965 and 1980. For those who developed diabetes between 1950 and 1964, the proportions developing ESRD were substantially higher at 34.6% at 30 years, 48.5% at 40 years, and 61.3% at 50 years. The authors called attention to the fact that ESRD decreased by 45% after 40 years’ duration between these two cohorts, emphasizing the beneficial roles of improved glycemic control and blood pressure control. It should also be noted that at 40 years even in the later cohort (those diagnosed between 1965 and 1980), 57.3% developed >300 mg/day albuminuria (7).”

Numbers like these may seem like ancient history (data from the 60s and 70s), but it’s important to keep in mind that many type 1 diabetics are diagnosed in early childhood, and that they don’t ‘get better’ later on – if they’re still alive, they’re still diabetic. …And very likely macroalbuminuric, at least if they’re from Pittsburgh. I was diagnosed in ’87.

“Gagnum et al. (8), using data from a Norwegian registry, also examined the incidence of CKD development over a 42-year follow-up period in people with childhood-onset (<15 years of age) T1D (8). The data from the Norwegian registry noted that the cumulative incidence of ESRD was 0.7% after 20 years and 5.3% after 40 years of T1D. Moreover, the authors noted the risk of developing ESRD was lower in women than in men and did not identify any difference in risk of ESRD between those diagnosed with diabetes in 1973–1982 and those diagnosed in 1989–2012. They concluded that there is a very low incidence of ESRD among patients with childhood-onset T1D diabetes in Norway, with a lower risk in women than men and among those diagnosed at a younger age. […] Analyses of population-based studies, similar to the Pittsburgh and Norway studies, showed that after 30 years of T1D the cumulative incidences of ESRD were only 10% for those diagnosed with T1D in 1961–1984 and 3% for those diagnosed in 1985–1999 in Japan (11), 3.3% for those diagnosed with T1D in 1977–2007 in Sweden (12), and 7.8% for those diagnosed with T1D in 1965–1999 in Finland (13) (Table 1).”

Do note that ESRD (end stage renal disease) is not the same thing as DKD (diabetic kidney disease), and that e.g. many of the Norwegians who did not develop ESRD nevertheless likely have kidney complications from their diabetes. That 5.3% is not the number of diabetics in that cohort who developed diabetes-related kidney complications, it’s the proportion of them who did and as a result of this needed a new kidney or dialysis in order not to die very soon. Do also keep in mind that both microalbuminuria and macroalbuminuria will substantially increase the risk of cardiovascular disease and -cardiac death. I recall a study where they looked at the various endpoints and found that more diabetics with microalbuminuria eventually died of cardiovascular disease than did ever develop kidney failure – cardiac risk goes up a lot long before end-stage renal disease. ESRD estimates don’t account for the full risk profile, and even if you look at mortality risk the number accounts for perhaps less than half of the total risk attributable to DKD. One thing the ESRD diagnosis does have going for it is that it’s a much more reliable variable indicative of significant pathology than is e.g. microalbuminuria (see e.g. this paper). The paper is short and not at all detailed, but they do briefly discuss/mention these issues:

“…there is a substantive difference between the numbers of people with stage 3 CKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) versus those with stages 4 and 5 CKD (eGFR <30 mL/min/1.73 m2): 6.7% of the National Health and Nutrition Examination Survey (NHANES) population compared with 0.1–0.3%, respectively (14). This is primarily because of competing risks, such as death from CV disease that occurs in stage 3 CKD; hence, only the survivors are progressing into stages 4 and 5 CKD. Overall, these studies are very encouraging. Since the 1980s, risk of ESRD has been greatly reduced, while risk of CKD progression persists but at a slower rate. This reduced ESRD rate and slowed CKD progression is largely due to improvements in glycemic and blood pressure control and probably also to the institution of RAAS blockers in more advanced CKD. These data portend even better future outcomes if treatment guidance is followed. […] many medications are effective in blood pressure control, but RAAS blockade should always be a part of any regimen when very high albuminuria is present.”

v. New Understanding of β-Cell Heterogeneity and In Situ Islet Function.

“Insulin-secreting β-cells are heterogeneous in their regulation of hormone release. While long known, recent technological advances and new markers have allowed the identification of novel subpopulations, improving our understanding of the molecular basis for heterogeneity. This includes specific subpopulations with distinct functional characteristics, developmental programs, abilities to proliferate in response to metabolic or developmental cues, and resistance to immune-mediated damage. Importantly, these subpopulations change in disease or aging, including in human disease. […] We will discuss recent findings revealing functional β-cell subpopulations in the intact islet, the underlying basis for these identified subpopulations, and how these subpopulations may influence in situ islet function.”

I won’t cover this one in much detail, but this part was interesting:

“Gap junction (GJ) channels electrically couple β-cells within mouse and human islets (25), serving two main functions. First, GJ channels coordinate oscillatory dynamics in electrical activity and Ca2+ under elevated glucose or GLP-1, allowing pulsatile insulin secretion (26,27). Second, GJ channels lower spontaneous elevations in Ca2+ under low glucose levels (28). GJ coupling is also heterogeneous within the islet (29), leading to some β-cells being highly coupled and others showing negligible coupling. Several studies have examined how electrically heterogeneous cells interact via GJ channels […] This series of experiments indicate a “bistability” in islet function, where a threshold number of poorly responsive β-cells is sufficient to totally suppress islet function. Notably, when islets lacking GJ channels are treated with low levels of the KATP activator diazoxide or the GCK inhibitor mannoheptulose, a subpopulation of cells are silenced, presumably corresponding to the less functional population (30). Only diazoxide/mannoheptulose concentrations capable of silencing >40% of these cells will fully suppress Ca2+ elevations in normal islets. […] this indicates that a threshold number of poorly responsive cells can inhibit the whole islet. Thus, if there exists a threshold number of functionally competent β-cells (∼60–85%), then the islet will show coordinated elevations in Ca2+ and insulin secretion.

Below this threshold number, the islet will lack Ca2+ elevation and insulin secretion (Fig. 2). The precise threshold depends on the characteristics of the excitable and inexcitable populations: small numbers of inexcitable cells will increase the number of functionally competent cells required for islet activity, whereas small numbers of highly excitable cells will do the opposite. However, if GJ coupling is lowered, then inexcitable cells will exert a reduced suppression, also decreasing the threshold required. […] Paracrine communication between β-cells and other endocrine cells is also important for regulating insulin secretion. […] Little is known how these paracrine and juxtacrine mechanisms impact heterogeneous cells.”

vi. Closing in on the Mechanisms of Pulsatile Insulin Secretion.

“Insulin secretion from pancreatic islet β-cells occurs in a pulsatile fashion, with a typical period of ∼5 min. The basis of this pulsatility in mouse islets has been investigated for more than four decades, and the various theories have been described as either qualitative or mathematical models. In many cases the models differ in their mechanisms for rhythmogenesis, as well as other less important details. In this Perspective, we describe two main classes of models: those in which oscillations in the intracellular Ca2+ concentration drive oscillations in metabolism, and those in which intrinsic metabolic oscillations drive oscillations in Ca2+ concentration and electrical activity. We then discuss nine canonical experimental findings that provide key insights into the mechanism of islet oscillations and list the models that can account for each finding. Finally, we describe a new model that integrates features from multiple earlier models and is thus called the Integrated Oscillator Model. In this model, intracellular Ca2+ acts on the glycolytic pathway in the generation of oscillations, and it is thus a hybrid of the two main classes of models. It alone among models proposed to date can explain all nine key experimental findings, and it serves as a good starting point for future studies of pulsatile insulin secretion from human islets.”

This one covers material closely related to the study above, so if you find one of these papers interesting you might want to check out the other one as well. The paper is quite technical but if you were wondering why people are interested in this kind of stuff, one reason is that there’s good evidence at this point that insulin pulsativity is disturbed in type 2 diabetics and so it’d be nice to know why that is so that new drugs can be developed to correct this.

April 25, 2018 Posted by | Biology, Cardiology, Diabetes, Epidemiology, Health Economics, Medicine, Nephrology, Pharmacology, Studies | Leave a comment

A few (more) diabetes papers of interest

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

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

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

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

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

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

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

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

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

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

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

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

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

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

“Our most important findings are:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Endocrinology (part 5 – calcium and bone metabolism)

Some observations from chapter 6:

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

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

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

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

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

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

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

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

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

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

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

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

Prevention of Late-Life Depression (II)

Some more observations from the book:

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

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

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

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

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

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

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

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

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

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

Peripheral Neuropathy (I)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Endocrinology (part 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

Systems Biology (I)

This book is really dense and is somewhat tough for me to blog. One significant problem is that: “The authors assume that the reader is already familiar with the material covered in a classic biochemistry course.” I know enough biochem to follow most of the stuff in this book, and I was definitely quite happy to have recently read John Finney’s book on the biochemical properties of water and Christopher Hall’s introduction to materials science, as both of those books’ coverage turned out to be highly relevant (these are far from the only relevant books I’ve read semi-recently – Atkins introduction to thermodynamics is another book that springs to mind) – but even so, what do you leave out when writing a post like this? I decided to leave out a lot. Posts covering books like this one are hard to write because it’s so easy for them to blow up in your face because you have to include so many details for the material included in the post to even start to make sense to people who didn’t read the original text. And if you leave out all the details, what’s really left? It’s difficult..

Anyway, some observations from the first chapters of the book below.

“[T]he biological world consists of self-managing and self-organizing systems which owe their existence to a steady supply of energy and information. Thermodynamics introduces a distinction between open and closed systems. Reversible processes occurring in closed systems (i.e. independent of their environment) automatically gravitate toward a state of equilibrium which is reached once the velocity of a given reaction in both directions becomes equal. When this balance is achieved, we can say that the reaction has effectively ceased. In a living cell, a similar condition occurs upon death. Life relies on certain spontaneous processes acting to unbalance the equilibrium. Such processes can only take place when substrates and products of reactions are traded with the environment, i.e. they are only possible in open systems. In turn, achieving a stable level of activity in an open system calls for regulatory mechanisms. When the reaction consumes or produces resources that are exchanged with the outside world at an uneven rate, the stability criterion can only be satisfied via a negative feedback loop […] cells and living organisms are thermodynamically open systems […] all structures which play a role in balanced biological activity may be treated as components of a feedback loop. This observation enables us to link and integrate seemingly unrelated biological processes. […] the biological structures most directly involved in the functions and mechanisms of life can be divided into receptors, effectors, information conduits and elements subject to regulation (reaction products and action results). Exchanging these elements with the environment requires an inflow of energy. Thus, living cells are — by their nature — open systems, requiring an energy source […] A thermodynamically open system lacking equilibrium due to a steady inflow of energy in the presence of automatic regulation is […] a good theoretical model of a living organism. […] Pursuing growth and adapting to changing environmental conditions calls for specialization which comes at the expense of reduced universality. A specialized cell is no longer self-sufficient. As a consequence, a need for higher forms of intercellular organization emerges. The structure which provides cells with suitable protection and ensures continued homeostasis is called an organism.”

“In biology, structure and function are tightly interwoven. This phenomenon is closely associated with the principles of evolution. Evolutionary development has produced structures which enable organisms to develop and maintain its architecture, perform actions and store the resources needed to survive. For this reason we introduce a distinction between support structures (which are akin to construction materials), function-related structures (fulfilling the role of tools and machines), and storage structures (needed to store important substances, achieving a compromise between tight packing and ease of access). […] Biology makes extensive use of small-molecule structures and polymers. The physical properties of polymer chains make them a key building block in biological structures. There are several reasons as to why polymers are indispensable in nature […] Sequestration of resources is subject to two seemingly contradictory criteria: 1. Maximize storage density; 2. Perform sequestration in such a way as to allow easy access to resources. […] In most biological systems, storage applies to energy and information. Other types of resources are only occasionally stored […]. Energy is stored primarily in the form of saccharides and lipids. Saccharides are derivatives of glucose, rendered insoluble (and thus easy to store) via polymerization.Their polymerized forms, stabilized with α-glycosidic bonds, include glycogen (in animals) and starch (in plantlife). […] It should be noted that the somewhat loose packing of polysaccharides […] makes them unsuitable for storing large amounts of energy. In a typical human organism only ca. 600 kcal of energy is stored in the form of glycogen, while (under normal conditions) more than 100,000 kcal exists as lipids. Lipids deposit usually assume the form of triglycerides (triacylglycerols). Their properties can be traced to the similarities between fatty acids and hydrocarbons. Storage efficiency (i.e. the amount of energy stored per unit of mass) is twice that of polysaccharides, while access remains adequate owing to the relatively large surface area and high volume of lipids in the organism.”

“Most living organisms store information in the form of tightly-packed DNA strands. […] It should be noted that only a small percentage of DNA (about few %) conveys biologically relevant information. The purpose of the remaining ballast is to enable suitable packing and exposure of these important fragments. If all of DNA were to consist of useful code, it would be nearly impossible to devise a packing strategy guaranteeing access to all of the stored information.”

“The seemingly endless diversity of biological functions frustrates all but the most persistent attempts at classification. For the purpose of this handbook we assume that each function can be associated either with a single cell or with a living organism. In both cases, biological functions are strictly subordinate to automatic regulation, based — in a stable state — on negative feedback loops, and in processes associated with change (for instance in embryonic development) — on automatic execution of predetermined biological programs. Individual components of a cell cannot perform regulatory functions on their own […]. Thus, each element involved in the biological activity of a cell or organism must necessarily participate in a regulatory loop based on processing information.”

“Proteins are among the most basic active biological structures. Most of the well-known proteins studied thus far perform effector functions: this group includes enzymes, transport proteins, certain immune system components (complement factors) and myofibrils. Their purpose is to maintain biological systems in a steady state. Our knowledge of receptor structures is somewhat poorer […] Simple structures, including individual enzymes and components of multienzyme systems, can be treated as “tools” available to the cell, while advanced systems, consisting of many mechanically-linked tools, resemble machines. […] Machinelike mechanisms are readily encountered in living cells. A classic example is fatty acid synthesis, performed by dedicated machines called synthases. […] Multiunit structures acting as machines can be encountered wherever complex biochemical processes need to be performed in an efficient manner. […] If the purpose of a machine is to generate motion then a thermally powered machine can accurately be called a motor. This type of action is observed e.g. in myocytes, where transmission involves reordering of protein structures using the energy generated by hydrolysis of high-energy bonds.”

“In biology, function is generally understood as specific physiochemical action, almost universally mediated by proteins. Most such actions are reversible which means that a single protein molecule may perform its function many times. […] Since spontaneous noncovalent surface interactions are very infrequent, the shape and structure of active sites — with high concentrations of hydrophobic residues — makes them the preferred area of interaction between functional proteins and their ligands. They alone provide the appropriate conditions for the formation of hydrogen bonds; moreover, their structure may determine the specific nature of interaction. The functional bond between a protein and a ligand is usually noncovalent and therefore reversible.”

“In general terms, we can state that enzymes accelerate reactions by lowering activation energies for processes which would otherwise occur very slowly or not at all. […] The activity of enzymes goes beyond synthesizing a specific protein-ligand complex (as in the case of antibodies or receptors) and involves an independent catalytic attack on a selected bond within the ligand, precipitating its conversion into the final product. The relative independence of both processes (binding of the ligand in the active site and catalysis) is evidenced by the phenomenon of noncompetitive inhibition […] Kinetic studies of enzymes have provided valuable insight into the properties of enzymatic inhibitors — an important field of study in medicine and drug research. Some inhibitors, particularly competitive ones (i.e. inhibitors which outcompete substrates for access to the enzyme), are now commonly used as drugs. […] Physical and chemical processes may only occur spontaneously if they generate energy, or non-spontaneously if they consume it. However, all processes occurring in a cell must have a spontaneous character because only these processes may be catalyzed by enzymes. Enzymes merely accelerate reactions; they do not provide energy. […] The change in enthalpy associated with a chemical process may be calculated as a net difference in the sum of molecular binding energies prior to and following the reaction. Entropy is a measure of the likelihood that a physical system will enter a given state. Since chaotic distribution of elements is considered the most probable, physical systems exhibit a general tendency to gravitate towards chaos. Any form of ordering is thermodynamically disadvantageous.”

“The chemical reactions which power biological processes are characterized by varying degrees of efficiency. In general, they tend to be on the lower end of the efficiency spectrum, compared to energy sources which drive matter transformation processes in our universe. In search for a common criterion to describe the efficiency of various energy sources, we can refer to the net loss of mass associated with a release of energy, according to Einstein’s formula:
E = mc2
The
M/M coefficient (relative loss of mass, given e.g. in %) allows us to compare the efficiency of energy sources. The most efficient processes are those involved in the gravitational collapse of stars. Their efficiency may reach 40 %, which means that 40 % of the stationary mass of the system is converted into energy. In comparison, nuclear reactions have an approximate efficiency of 0.8 %. The efficiency of chemical energy sources available to biological systems is incomparably lower and amounts to approximately 10(-7) % […]. Among chemical reactions, the most potent sources of energy are found in oxidation processes, commonly exploited by biological systems. Oxidation tends  to result in the largest net release of energy per unit of mass, although the efficiency of specific types of oxidation varies. […] given unrestricted access to atmospheric oxygen and to hydrogen atoms derived from hydrocarbons — the combustion of hydrogen (i.e. the synthesis of water; H2 + 1/2O2 = H2O) has become a principal source of energy in nature, next to photosynthesis, which exploits the energy of solar radiation. […] The basic process associated with the release of hydrogen and its subsequent oxidation (called the Krebs cycle) is carried by processes which transfer electrons onto oxygen atoms […]. Oxidation occurs in stages, enabling optimal use of the released energy. An important byproduct of water synthesis is the universal energy carrier known as ATP (synthesized separately). As water synthesis is a highly spontaneous process, it can be exploited to cover the energy debt incurred by endergonic synthesis of ATP, as long as both processes are thermodynamically coupled, enabling spontaneous catalysis of anhydride bonds in ATP. Water synthesis is a universal source of energy in heterotrophic systems. In contrast, autotrophic organisms rely on the energy of light which is exploited in the process of photosynthesis. Both processes yield ATP […] Preparing nutrients (hydrogen carriers) for participation in water synthesis follows different paths for sugars, lipids and proteins. This is perhaps obvious given their relative structural differences; however, in all cases the final form, which acts as a substrate for dehydrogenases, is acetyl-CoA“.

“Photosynthesis is a process which — from the point of view of electron transfer — can be treated as a counterpart of the respiratory chain. In heterotrophic organisms, mitochondria transport electrons from hydrogenated compounds (sugars, lipids, proteins) onto oxygen molecules, synthesizing water in the process, whereas in the course of photosynthesis electrons released by breaking down water molecules are used as a means of reducing oxydised carbon compounds […]. In heterotrophic organisms the respiratory chain has a spontaneous quality (owing to its oxidative properties); however any reverse process requires energy to occur. In the case of photosynthesis this energy is provided by sunlight […] Hydrogen combustion and photosynthesis are the basic sources of energy in the living world. […] For an energy source to become useful, non-spontaneous reactions must be coupled to its operation, resulting in a thermodynamically unified system. Such coupling can be achieved by creating a coherent framework in which the spontaneous and non-spontaneous processes are linked, either physically or chemically, using a bridging component which affects them both. If the properties of both reactions are different, the bridging component must also enable suitable adaptation and mediation. […] Direct exploitation of the energy released via the hydrolysis of ATP is possible usually by introducing an active binding carrier mediating the energy transfer. […] Carriers are considered active as long as their concentration ensures a sufficient release of energy to synthesize a new chemical bond by way of a non-spontaneous process. Active carriers are relatively short-lived […] Any active carrier which performs its function outside of the active site must be sufficiently stable to avoid breaking up prior to participating in the synthesis reaction. Such mobile carriers are usually produced when the required synthesis consists of several stages or cannot be conducted in the active site of the enzyme for sterical reasons. Contrary to ATP, active energy carriers are usually reaction-specific. […] Mobile energy carriers are usually formed as a result of hydrolysis of two high-energy ATP bonds. In many cases this is the minimum amount of energy required to power a reaction which synthesizes a single chemical bond. […] Expelling a mobile or unstable reaction component in order to increase the spontaneity of active energy carrier synthesis is a process which occurs in many biological mechanisms […] The action of active energy carriers may be compared to a ball rolling down a hill. The descending snowball gains sufficient energy to traverse another, smaller mound, adjacent to its starting point. In our case, the smaller hill represents the final synthesis reaction […] Understanding the role of active carriers is essential for the study of metabolic processes.”

“A second category of processes, directly dependent on energy sources, involves structural reconfiguration of proteins, which can be further differentiated into low and high-energy reconfiguration. Low-energy reconfiguration occurs in proteins which form weak, easily reversible bonds with ligands. In such cases, structural changes are powered by the energy released in the creation of the complex. […] Important low-energy reconfiguration processes may occur in proteins which consist of subunits. Structural changes resulting from relative motion of subunits typically do not involve significant expenditures of energy. Of particular note are the so-called allosteric proteins […] whose rearrangement is driven by a weak and reversible bond between the protein and an oxygen molecule. Allosteric proteins are genetically conditioned to possess two stable structural configurations, easily swapped as a result of binding or releasing ligands. Thus, they tend to have two comparable energy minima (separated by a low threshold), each of which may be treated as a global minimum corresponding to the native form of the protein. Given such properties, even a weakly interacting ligand may trigger significant structural reconfiguration. This phenomenon is of critical importance to a variety of regulatory proteins. In many cases, however, the second potential minimum in which the protein may achieve relative stability is separated from the global minimum by a high threshold requiring a significant expenditure of energy to overcome. […] Contrary to low-energy reconfigurations, the relative difference in ligand concentrations is insufficient to cover the cost of a difficult structural change. Such processes are therefore coupled to highly exergonic reactions such as ATP hydrolysis. […]  The link between a biological process and an energy source does not have to be immediate. Indirect coupling occurs when the process is driven by relative changes in the concentration of reaction components. […] In general, high-energy reconfigurations exploit direct coupling mechanisms while indirect coupling is more typical of low-energy processes”.

Muscle action requires a major expenditure of energy. There is a nonlinear dependence between the degree of physical exertion and the corresponding energy requirements. […] Training may improve the power and endurance of muscle tissue. Muscle fibers subjected to regular exertion may improve their glycogen storage capacity, ATP production rate, oxidative metabolism and the use of fatty acids as fuel.

February 4, 2018 Posted by | Biology, Books, Chemistry, Genetics, Molecular biology, Pharmacology, Physics | 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

A few diabetes papers of interest

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Depression (II)

I have added some more quotes from the last half of the book as well as some more links to relevant topics below.

“The early drugs used in psychiatry were sedatives, as calming a patient was probably the only treatment that was feasible and available. Also, it made it easier to manage large numbers of individuals with small numbers of staff at the asylum. Morphine, hyoscine, chloral, and later bromide were all used in this way. […] Insulin coma therapy came into vogue in the 1930s following the work of Manfred Sakel […] Sakel initially proposed this treatment as a cure for schizophrenia, but its use gradually spread to mood disorders to the extent that asylums in Britain opened so-called insulin units. […] Recovery from the coma required administration of glucose, but complications were common and death rates ranged from 1–10 per cent. Insulin coma therapy was initially viewed as having tremendous benefits, but later re-examinations have highlighted that the results could also be explained by a placebo effect associated with the dramatic nature of the process or, tragically, because deprivation of glucose supplies to the brain may have reduced the person’s reactivity because it had induced permanent damage.”

“[S]ome respected scientists and many scientific journals remain ambivalent about the empirical evidence for the benefits of psychological therapies. Part of the reticence appears to result from the lack of very large-scale clinical trials of therapies (compared to international, multi-centre studies of medication). However, a problem for therapy research is that there is no large-scale funding from big business for therapy trials […] It is hard to implement optimum levels of quality control in research studies of therapies. A tablet can have the same ingredients and be prescribed in almost exactly the same way in different treatment centres and different countries. If a patient does not respond to this treatment, the first thing we can do is check if they receive the right medication in the correct dose for a sufficient period of time. This is much more difficult to achieve with psychotherapy and fuels concerns about how therapy is delivered and potential biases related to researcher allegiance (i.e. clinical centres that invent a therapy show better outcomes than those that did not) and generalizability (our ability to replicate the therapy model exactly in a different place with different therapists). […] Overall, the ease of prescribing a tablet, the more traditional evidence-base for the benefits of medication, and the lack of availability of trained therapists in some regions means that therapy still plays second fiddle to medications in the majority of treatment guidelines for depression. […] The mainstay of treatments offered to individuals with depression has changed little in the last thirty to forty years. Antidepressants are the first-line intervention recommended in most clinical guidelines”.

“[W]hilst some cases of mild–moderate depression can benefit from antidepressants (e.g. chronic mild depression of several years’ duration can often respond to medication), it is repeatedly shown that the only group who consistently benefit from antidepressants are those with severe depression. The problem is that in the real world, most antidepressants are actually prescribed for less severe cases, that is, the group least likely to benefit; which is part of the reason why the argument about whether antidepressants work is not going to go away any time soon.”

“The economic argument for therapy can only be sustained if it is shown that the long-term outcome of depression (fewer relapses and better quality of life) is improved by receiving therapy instead of medication or by receiving both therapy and medication. Despite claims about how therapies such as CBT, behavioural activation, IPT, or family therapy may work, the reality is that many of the elements included in these therapies are the same as elements described in all the other effective therapies (sometimes referred to as empirically supported therapies). The shared elements include forming a positive working alliance with the depressed person, sharing the model and the plan for therapy with the patient from day one, and helping the patient engage in active problem-solving, etc. Given the degree of overlap, it is hard to make a real case for using one empirically supported therapy instead of another. Also, there are few predictors (besides symptom severity and personal preference) that consistently show who will respond to one of these therapies rather than to medication. […] One of the reasons for some scepticism about the value of therapies for treating depression is that it has proved difficult to demonstrate exactly what mediates the benefits of these interventions. […] despite the enthusiasm for mindfulness, there were fewer than twenty high-quality research trials on its use in adults with depression by the end of 2015 and most of these studies had fewer than 100 participants. […] exercise improves the symptoms of depression compared to no treatment at all, but the currently available studies on this topic are less than ideal (with many problems in the design of the study or sample of participants included in the clinical trial). […] Exercise is likely to be a better option for those individuals whose mood improves from participating in the experience, rather than someone who is so depressed that they feel further undermined by the process or feel guilty about ‘not trying hard enough’ when they attend the programme.”

“Research […] indicates that treatment is important and a study from the USA in 2005 showed that those who took the prescribed antidepressant medications had a 20 per cent lower rate of absenteeism than those who did not receive treatment for their depression. Absence from work is only one half of the depression–employment equation. In recent times, a new concept ‘presenteeism’ has been introduced to try to describe the problem of individuals who are attending their place of work but have reduced efficiency (usually because their functioning is impaired by illness). As might be imagined, presenteeism is a common issue in depression and a study in the USA in 2007 estimated that a depressed person will lose 5–8 hours of productive work every week because the symptoms they experience directly or indirectly impair their ability to complete work-related tasks. For example, depression was associated with reduced productivity (due to lack of concentration, slowed physical and mental functioning, loss of confidence), and impaired social functioning”.

“Health economists do not usually restrict their estimates of the cost of a disorder simply to the funds needed for treatment (i.e. the direct health and social care costs). A comprehensive economic assessment also takes into account the indirect costs. In depression these will include costs associated with employment issues (e.g. absenteeism and presenteeism; sickness benefits), costs incurred by the patient’s family or significant others (e.g. associated with time away from work to care for someone), and costs arising from premature death such as depression-related suicides (so-called mortality costs). […] Studies from around the world consistently demonstrate that the direct health care costs of depression are dwarfed by the indirect costs. […] Interestingly, absenteeism is usually estimated to be about one-quarter of the costs of presenteeism.”

Jakob Klaesi. António Egas Moniz. Walter Jackson Freeman II.
Electroconvulsive therapy.
Psychosurgery.
Vagal nerve stimulation.
Chlorpromazine. Imipramine. Tricyclic antidepressant. MAOIs. SSRIs. John CadeMogens Schou. Lithium carbonate.
Psychoanalysis. CBT.
Thomas Szasz.
Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration (Kirsch et al.).
Chronobiology. Chronobiotics. Melatonin.
Eric Kandel. BDNF.
The global burden of disease (Murray & Lopez) (the author discusses some of the data included in that publication).

January 8, 2018 Posted by | Books, Health Economics, Medicine, Pharmacology, Psychiatry, Psychology | 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

Analgesia and Procedural Sedation

I didn’t actually like this lecture all that much, in part because I obviously disagree to some extent with the ideas expressed, but I try to remember to blog lectures I watch these days even if I don’t think they’re all that great. It’s a short lecture, but why not at least add a comment about urine drug screening and monitoring or patient selection/segmentation when you’re talking about patients whom you’re considering discharging with an opioid prescription? Recommending acupuncture in a pain management context? Etc.

Anyway, below a few links to stuff related to the coverage:

Pain Management in the Emergency Department.
Oligoanalgesia.
WHO analgesic ladder.
Nonsteroidal anti-inflammatory drug.
Ketorolac.
Fentanyl (“This medication should not be used to treat pain other than chronic cancer pain, especially short-term pain such as migraines or other headaches, pain from an injury, or pain after a medical or dental procedure.” …to put it mildly, that’s not the impression you get from watching this lecture…)
Parenteral opioids in emergency medicine – A systematic review of efficacy and safety.
Procedural Sedation (medscape).

December 22, 2017 Posted by | Lectures, Medicine, Pharmacology | Leave a comment

A few diabetes papers of interest

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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