David S. H. Bell

Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy.

Chronic metformin use results in vitamin B12 deficiency in 30% of patients. Exhaustion of vitamin B12 stores usually occurs after twelve to fifteen years of absolute vitamin B12 deficiency. Metformin has been available in the United States for approximately fifteen years. Vitamin B12 deficiency, which may present without anemia and as a peripheral neuropathy, is often misdiagnosed as diabetic neuropathy, although the clinical findings are usually different. Failure to diagnose the cause of the neuropathy will result in progression of central and/or peripheral neuronal damage which can be arrested but not reversed with vitamin B12 replacement. To my knowledge, this is the first report of metformin-induced vitamin B12 deficiency causing neuropathy.

Resolution of statin-induced myalgias by correcting vitamin D deficiency.

Correction of hyperlipidemia with statins is often limited by the side-effect of statin-induced myalgias. Vitamin D deficiency is also associated with myalgias that resolve with correction of the vitamin D deficiency. Myalgias associated with statin therapy may also resolve with correction of vitamin D deficiency. This case report presents a case where cardioprotective lipid levels were achieved with a powerful statin only after correction of vitamin D deficiency.

Protean manifestations of vitamin D deficiency, part 2: deficiency and its association with autoimmune disease, cancer, infection, asthma, dermopathies, insulin resistance, and type 2 diabetes.

Vitamin D deficiency is epidemic and its manifestations are protean. Vitamin D deficiency is associated with autoimmune diseases (particularly multiple sclerosis and type 1 diabetes) and has been associated with infection, allergy, asthma, and dermopathies (particularly psoriasis). Asthma may be worsened by vitamin D deficiency and correction of the deficiency has been shown to improve the manifestations of asthma. Vitamin D deficiency has been associated with multiple cancers, including those of the breast, colon, ovary, and prostate. Due mainly to increased insulin resistance but also to an impairment in insulin release, vitamin D deficiency is associated with the development of type 2 diabetes. In addition, the complications of diabetes may be worsened by vitamin D deficiency.

Protean manifestations of vitamin D deficiency, part 3: association with cardiovascular disease and disorders of the central and peripheral nervous systems.

Vitamin D deficiency is associated with the risk factors of inflammation, insulin resistance and endothelial dysfunction, and left ventricular hypertrophy. As a result there is an increase in cardiovascular events (CVEs) associated with vitamin D deficiency. Vitamin D deficiency itself or secondary hyperparathyroidism or both may be responsible for the increase in CVEs. Correction of vitamin D deficiency may decrease the incidence of CVEs. Vitamin D deficiency is also associated with Alzheimer disease, schizophrenia, depression, and chronic pain and muscle weakness. Vitamin D deficiency is early treated with oral vitamin D supplements which may improve the manifestations of the diseases associated with vitamin D deficiency.

Peyronie disease in association with carvedilol: a case report.

Beta blockade is associated with the onset and progression of Peyronie disease (PD). To date, there has not been a report of PD occurring with the alpha/beta blocker carvedilol. It remains unproven but likely that carvedilol was the cause of the PD in the patient described in this case. It is hypothesized that because of carvedilol’s vasodilating alpha adrenergic receptor stimulation and its anti-inflammatory effect, PD occurs less frequently with carvedilol than with other beta blockers. However, in this case the protective properties of carvedilol, like vasodilation and the anti-inflammatory effect, may not be sufficient to overcome its vasoconstricting beta adrenergic receptor blockade.

Successful utilization of aliskiren, a direct renin inhibitor in Bartter syndrome.

Bartter syndrome is traditionally treated with large doses of oral potassium with or without suppression of the renin-angiotensin system. Since plasma renin activity is invariably elevated in Bartter syndrome, the availability of the direct renin inhibitor aliskiren should lead to the ability to maintain potassium levels without utilizing large doses of oral potassium. This case report is, to my knowledge, the first to show the efficacy of a renin receptor blocker in Bartter syndrome.

Hyperinsulinemic hypoglycemia precipitated by weight loss.

Objective: To describe a case of hyperinsulinemic hypoglycemia precipitated by weight loss. Methods: We present a detailed case report and results of a related literature search on hyperinsulinemic hypoglycemia precipitated by weight loss. Results: The presence of an insulinoma was unveiled by voluntary weight loss and reduction of insulin resistance. Hypoglycemia occurred during the postprandial period and not at night. The diagnostic workup was accomplished without hospital admission. Conclusion: Classically, insulinomas present with weight gain and fasting hypoglycemia but may present with postprandial hypoglycemia and weight loss. Voluntary weight loss, by lowering insulin resistance, accelerates the time to clinical presentation of an asymptomatic insulinoma.

The association of obesity, metabolic syndrome, diabetes, and cardiovascular disease with nonalcoholic fatty liver disease.

In this issue, Helzberg et al 1 report that in a group of National Football League (NFL) players, elevation of the liver enzyme alanine aminotransferase (ALT) was associated with obesity and markers of the metabolic (insulin resistance) syndrome and speculate that these elevations signify the presence of nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disease in the United States and its prevalence is increasing as the epidemic of obesity worsens. Patients with NAFLD have all of the characteristics of the metabolic syndrome, which means that these patients are at increased risk of cardiovascular disease and diabetes. However, NAFLD also results in varying degrees of liver injury. Around 25% of NAFLD patients progress to nonalcoholic steatohepatitis (NASH) due to the production of excess adipocytokines from hepatic fat. The greater the deposition of hepatic fat, the greater the production of adipocytokines, particularly tumor necrosis factor alfa (TNF) and, therefore, the higher the prevalence of NASH. These adipocytokines lead to inflammation, hepatic injury, and apoptosis so that in 25% of subjects with NASH, cirrhosis develops leading to portal hypertension, hepatic failure and an increased prevalence of hepatocellular carcinoma. Treatment of NAFLD and NASH can avoid future hepatic problems. While weight loss should be the principle therapy for NASH, the most promising treatment is the use of insulin sensitizers, particularly the thiazolidinediones. However, of much greater importance is that NAFLD is a marker for the metabolic syndrome, diabetes and cardiovascular disease. There are two easily measured clinical criteria that accurately establish the presence of the metabolic syndrome. The first is the waist circumference, which should be greater than forty inches in a man and thirty five inches in a woman. The waist circumference is more meaningful if it is related to height. The waist to height ratio should ideally be 0.5, i.e., the waist circumference should be half of the height. The second is the ratio of fasting triglycerides to high density lipoprotein (HDL), which if greater than 3.5 signifies the presence of the metabolic syndrome. Both of these parameters correlated with elevated ALTs in NFL players (particularly linemen). The presence of excessive peritoneal and hepatic fat results in the production of excess adipocytokines, e.g., interleukin-6, which increases hepatic C-reactive protein production. Elevated C-reactive protein is almost invariably elevated in type 2 diabetic patients. The increased levels of inflammatory cytokines (particularly TNF) leads to oxidative stress and endothelial dysfunction which in turn results in vasoconstriction, coagulation, microalbuminuria and atherogenesis. Furthermore, the systemic inflammation extends to the atheromatous plaque where inflammation makes the plaque less stable and more likely to rupture, causing a cardiovascular event. Higher insulin levels, which are invariably present in the metabolic syndrome, result in sodium retention, stimulation of the sympathetic nervous system and renin-angiotensin systems, and hypertension. At least half of all hypertensive patients are insulin resistant and 75% of diabetic patients are hypertensive. Due to excess free fatty acid release from peritoneal adipocytes and hepatic fat, more triglyceride is produced in the liver causing a decrease in the number and size of the HDL particles and smaller, more atherogenic low density lipoprotein (LDL) particles. Furthermore, increased levels of the adipocytokine PAI1 cause decreased fibrinolysis and, in combination with increased platelet activity, more thromboembolic events. The addition of diabetes, which occurs in a third of patients with the metabolic syndrome, dramatically increases cardiovascular risk. The metabolic syndrome is not only associated with increases in cardiovascular risk factors, but is associated with surrogate measures of atherosclerosis such as carotid intimal medial thickening. An increased volume of coronary artery atheroma as assessed by intravascular ultrasonography has been well documented. Furthermore, decreased acceleration of atherosclerosis and a lowering of cardiac events has been documented with the use of the thiazolidinedione, pioglitazone. Therefore, the documentation of increased ALT and peritoneal and hepatic fat and insulin resistance in NFL linemen predicts a future where chronic metabolic and cardiovascular diseases result in a decreased life expectancy for these players. The concept that increased body weight that is not accompanied by increased muscle mass and strength is beneficial needs to be abandoned. The Players Association needs to negotiate for better medical assessment, counseling, earlier interventions and therapies for their players, not only while they are playing, but also after retirement from football. Only in this way will longevity and a better quality of life be achieved for these athletes.

Goals for HbA1c need to be individualized based on clinical judgment, instead of third party recommendations.

Fowler et al 1 in this issue of the SMJ recommend a comprehensive approach to achieving a desirable HbA1c by controlling both postprandial and fasting glucose levels and are careful to emphasize that, in achieving a desirable HbA1c, hypoglycemia should be avoided. Very often, in patients utilizing insulin and sulfonlyureas, even with careful monitoring, the desired HbA1c cannot be achieved because of hypoglycemia. In the current medical environment where the HbA1c is used to judge the quality of healthcare delivery and may even result in financial gain or loss, “treating to goal” may not always be in the best interest of the patient. Furthermore, the use of the HbA1c as a “quality control” often makes endocrinologists and diabetologists who are seeing the more difficult to manage diabetic patient appear to be providing inferior care. Therefore, the “one size fits all” concept of the HbA1c is entirely inappropriate and goals for the HbA1c need to be individualized and based on clinical judgment. Goals for HbA1c vary according to the recommending group. Based on the Diabetes Control and Complications Trial (DCCT), a trial which was preformed in type 1 diabetic subjects, the American Diabetes Association (ADA) recommends a goal for HbA1c of 7% or below. Based on the United Kingdom Prospective Study (UKPDS) a study performed on new-onset type 2 diabetic subjects, the American Association of Clinical Endocrinologists (AACE) and the International Diabetes Federation (IDF) recommend a goal for the HbA1c of 6.5% or below. On the other hand, the Veterans Administration and the American Geriatrics Society both recommend that the goal for HbA1c should take into account comorbidities and life expectancy and, in patients with a poor prognosis, a goal for the HbA1c of 8% or even higher is acceptable. However, even in patients with a poor prognosis, having an HbA1c of above 8% is not advisable since this level represents an average glucose level of above 200 mg/ dL. Average glucose levels above 180 mg/dL are associated with leukocyte malfunction, ie, impaired chemotaxis, endocytosis, and opsonization leading to an increased risk of infection and sepsis. It is also above an HbA1c level of 8% that the prevalence of microvascular complications (retinopathy, nephropathy, and neuropathy) increases exponentially. At the other end of the spectrum, the lower the HbA1c, even within the normal range, the lower the incidence of cardiac events. In the Norfolk Epic study, a population study in the English county of Norfolk, the higher the HbA1c was above a baseline of 5%, the greater was the risk of a cardiac event. Indeed, for every 1% the HbA1c was above 5%, cardiac events increased by 26%, and, for every 1% the HbA1c was above 8%, cardiac events increased by 40%. Therefore, an ideal HbA1c is within the low normal range, a level that cannot be reached with medications that cause hypoglycemia (insulin and insulin secretagogues). However, these levels can be obtained with combinations of medicines (metformin, thiazolidinediones, alfa glucosidase inhibitors, DPP-4 inhibitors, and incretin mimetics) that do not cause severe or frequent hypoglycemia. Even with insulin therapy, lower HbA1c levels can often be achieved if endogenous insulin is still being produced, because severe hypoglycemia can be avoided by suppression of endogenous insulin production. The presence of endogenous insulin can be confirmed through measurement of a C-peptide level and if the C-peptide is very low or absent, the risk of severe hypoglycemia with insulin therapy is greatly increased. It has always been recognized that severe hypoglycemia should be avoided, especially in the elderly, to prevent cerebral damage. However, it has only recently been recognized that severe hypoglycemia is also associated with an increased incidence of cardiac arrhythmias and cardiovascular events. This is because the hyperadrenergic state induced by hypoglycemia increases the Q-T interval on the echocardiogram, which then increases the incidence of cardiac arrhythmias. Catecholamines also increase inflammation within the atheromatous plaque, which leads to an increased incidence of cardiovascular events, particularly myocardial infarction. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, over 10,000 type 2 diabetic subjects, of whom 35% had a history of a previous cardiac event, were randomized to intensive glycemic control (HbA1c 6% or below) or standard therapy (HbA1c 7.0% to 7.9%). The intensive glycemic control arm was terminated because of a higher mortality even though in this group nonfatal myocardial infarction occurred less frequently. In addition, those without a history of a prior cardiovascular event and those who had an initial HbA1c level of less than 8% had significantly fewer cardiovascular events. Two other prospective trials of intensive glucose control—the Action in Diabetes and Vascular Disease (ADVANCE) trial and the Veterans Affairs Diabetes Trial (VADT)—also showed no benefits of intensive glycemic control on cardiovascular events. However, in the VADT, those who had diabetes for over twelve years or who at baseline had increased coronary artery or aortic calcificaFrom the Division of Endocrinology, Southside Endocrinology and University of Alabama Medical School, Birmingham, AL.