Gabriel I. Uwaifo

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin‐sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy‐proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two‐thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin‐sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long‐term safety and benefits of pioglitazone require further study. (HEPATOLOGY 2004;39:188–196.)

Efficacy of orlistat as an adjunct to behavioral treatment in overweight African American and Caucasian adolescents with obesity-related co-morbid conditions.

This pilot study compared the efficacy of orlistat as an adjunctive treatment for obesity between African American and Caucasian adolescents. Twenty obese adolescents with obesity-related co-morbid conditions underwent measurements of body composition, glucose homeostasis by frequently sampled intravenous glucose tolerance test (FSIGT), and fasting lipids before and after 6 months treatment with orlistat 120 mg tid in conjunction with a comprehensive behavioral program. Weight (p < 0.05), BMI (p < 0.001), total cholesterol (p < 0.001), LDL cholesterol (p < 0.001), fasting insulin (p < 0.02) and fasting glucose (p < 0.003) were lower after treatment. Insulin sensitivity, measured during the FSIGT, improved significantly (p < 0.02), as did fasting indices such as the homeostasis model assessment for insulin resistance (p < 0.01). African American subjects exhibited significantly less improvement in weight (p < 0.05), BMI (p < 0.01), waist circumference (p = 0.03), and insulin sensitivity (p = 0.05). Improvements in cholesterol were not significantly different between African Americans and Caucasians. We conclude that Caucasians lost more weight and had greater improvements in insulin sensitivity than African Americans, but both exhibited improvements in plasma lipids. The true benefit of orlistat treatment over a comprehensive behavioral program remains to be determined in placebo-controlled trials.

Does Vitamin D Deficiency Cause Hypertension? Current Evidence from Clinical Studies and Potential Mechanisms

Vitamin D deficiency is widely prevalent across all ages, races, geographical regions, and socioeconomic strata. In addition to its important role in skeletal development and calcium homeostasis, several recent studies suggest its association with diabetes, hypertension, cardiovascular disease, certain types of malignancy, and immunologic dysfunction. Here, we review the current evidence regarding an association between vitamin D deficiency and hypertension in clinical and epidemiological studies. We also look into plausible biological explanations for such an association with the renin-angiotensin-aldosterone system and insulin resistance playing potential roles. Taken together, it appears that more studies in more homogeneous study populations are needed before a firm conclusion can be reached as to whether vitamin D deficiency causes or aggravates hypertension and whether vitamin D supplementation is safe and exerts cardioprotective effects. The potential problems with bias and confounding factors present in previous epidemiological studies may be overcome or minimized by well designed randomized controlled trials in the future.

Orlistat: current status in clinical therapeutics

Background: Obesity has rapidly become a life-threatening epidemic worldwide. There are a plethora of obesity-related co-morbidities and complications that increase morbidity, mortality and cost of care associated with obesity. Orlistat is approved for the treatment of obesity and has been evaluated both in obesity and in the several obesity-related co-morbidities. Objective: The purpose of this article is to provide detail of the pharmacotherapeutic role of orlistat in obesity, describe orlistat and its pharmacological properties, critique the evidence for orlistats use in obesity and obesity-related co-morbidities, and define the role of orlistat in clinical practice. Methods: A thorough, all-inclusive literature search was conducted to isolate clinical trials, case reports and meta-analyses evaluating the safety and efficacy of orlistat in various patient populations. Results: Orlistats unique mechanism of action, beneficial effects on multiple co-morbidity surrogates and relatively mild adverse effect and drug interaction profile position it favorably as the first option for pharmacotherapy in comprehensive obesity management of adults and children.

Are gastrointestinal symptoms related to diabetes mellitus and glycemic control

Table. No caption available Many patients with diabetes mellitus suffer from upper and lower GI symptoms. The reported prevalence of these symptoms varies among different ethnic groups/populations. The natural history of GI symptoms as well as their pathogenesis in patients with diabetes remains poorly understood, although it is known that gastric emptying is influenced by hyperglycemia, euglycemia, and hypoglycemia. Poor glycemic control over a long period of time can lead to neuropathy and damage the vagus nerve, resulting in diabetic gastroparesis whose signs and symptoms vary in the individual patient. Gastroparesis can further worsen glycemic control by adversely altering the pharmacokinetics of orally administered hypoglycemic agents as well as by altering the delivery of diet-derived calories to intestines from which absorption, subsequently, determines incipient blood glucose, and thus effectiveness of various injectable antidiabetics including various insulins and related insulin analogs. As GI symptoms may overlap with other disorders, including functional dyspepsia, irritable bowel syndrome, and depression, it is important to have such patients/patients with diabetes undergo standardized testing for measuring gastric emptying. Certain medications including metformin, amylin analogues (i.e. pramlintide), glucagon-like peptide 1 analogs (i.e. exenatide, liraglutide), anticholinergic agents, antidepressants, calcium-channel blockers, and others may contribute to GI symptoms observed in patients with diabetes. Given the global diabetes pandemic, it is of utmost importance to not only diagnose and treat present patients with diabetes mellitus and its comorbidities, but also to help prevent the development of further disease burden by educating children and adolescents about healthy lifestyle modifications (avoidance of overeating, portion control, healthy food choices, increased physical and reduced sedentary activity), as changing behavior in adulthood has proven to be notoriously difficult.

Is there a therapeutic role for octreotide in patients with ectopic Cushing’s syndrome?

Cushing’s syndrome (CS) due to ectopic ACTH secretion (EAS) has a high morbidity and mortality, because of the underlying tumor and the sequelae of severe hypercortisolemia. Therefore, rapid treatment of ectopic CS is mandatory. Scintigraphy shows that up to 80% of ectopic ACTH-producing tumors have somatostatin receptors. While this suggests that somatostatin analogs may reduce ACTH production and treat patients with EAS, the therapeutic role of these agents is still evolving. Here we demonstrate the spectrum of responses to octreotide therapy in 3 patients with EAS. Diagnostic imaging with the 111In-pentetreotide scan did not predict the therapeutic response to octreotide. Two patients with positive somatostatin receptor scintigraphy failed to respond to octreotide, while one with a negative scan reached eucortisolemia on a maintenance dose of 75 μg octreotide twice daily or octreotide LAR 30 mg per month. We conclude that octreotide is not a first line agent to control hypercortisolemia but may be a useful agent when other inhibitors of steroidogenesis fail or parenteral administration is required. Before therapy an octreotide challenge test may predict therapeutic response. Cortisol levels should be monitored regularly on somatostatin analog therapy, because of its unpredictable long-term pharmacodynamic profile.

Fuel on the fire

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A case of spurious hypercalcitoninemia: A cautionary tale on the use of plasma calcitonin assays in the screening of patients with thyroid nodules for neoplasia

The measurement of plasma CT has an important role as a screening test for medullary thyroid carcinoma (MTC) in patients with thyroid nodules. However, elevated plasma CT levels should be interpreted within the context of the overall clinical picture in each individual case and carefully validated before therapeutic decisions are made. We present the case of a 17-yrold girl who was referred to us with a thyroid nodule and elevated plasma CT levels, as measured by a one-site RIA not involving prior plasma extraction. Plasma CT was re-measured using two different methods, a RIA with prior plasma extraction and a two-site immunochemiluminometric assay (ICMA), and was either very low or undetectable. Subsequently, samples were re-assayed using the initially applied CT RIA; plasma CT levels were again found to be elevated. These elevations were of a spurious nature, probably caused by the presence of an unidentified substance in the patient’s plasma interfering with the measurement of CT in the initially used RIA. Our patient was eventually diagnosed with Hashimoto’s thyroiditis, and had no evidence of MTC. As several conditions can cause either true or spurious hypercalcitoninemia, we suggest that elevated plasma CT levels should be confirmed at least once before other extensive diagnostic investigations are initiated or thyroidectomy is recommended. Finally, the assay selected should detect only the mature CT molecule.

Sex-Associated Differences in Free Fatty Acid Flux of Obese Adolescents

CONTEXT In obesity, increases in free fatty acid (FFA) flux can predict development of insulin resistance. Adult women release more FFA relative to resting energy expenditure (REE) and have greater FFA clearance rates than men. In adolescents, it is unknown whether sex differences in FFA flux occur. OBJECTIVE Our objective was to determine the associations of sex, REE, and body composition with FFA kinetics in obese adolescents. PARTICIPANTS Participants were from a convenience sample of 112 non-Hispanic white and black adolescents (31% male; age range, 12-18 years; body mass index SD score range, 1.6-3.1) studied before initiating obesity treatment. MAIN OUTCOME MEASURES Glucose, insulin, and FFA were measured during insulin-modified frequently sampled iv glucose tolerance tests. Minimal models for glucose and FFA calculated insulin sensitivity index (SI) and FFA kinetics, including maximum (l0 + l2) and insulin-suppressed (l2) lipolysis rates, clearance rate constant (cf), and insulin concentration for 50% lipolysis suppression (ED50). Relationships of FFA measures to sex, REE, fat mass (FM), lean body mass (LBM) and visceral adipose tissue (VAT) were examined. RESULTS In models accounting for age, race, pubertal status, height, FM, and LBM, we found sex, pubertal status, age, and REE independently contributed to the prediction of l2 and l0 + l2 (P < .05). Sex and REE independently predicted ED50 (P < .05). Sex, FM/VAT, and LBM were independent predictors of cf. Girls had greater l2, l0 + l2 and ED50 (P < .05, adjusted for REE) and greater cf (P < .05, adjusted for FM or VAT) than boys. CONCLUSION Independent of the effects of REE and FM, FFA kinetics differ significantly in obese adolescent girls and boys, suggesting greater FFA flux among girls.

Clustering of sebaceous gland carcinoma, papillary thyroid carcinoma and breast cancer in a woman as a new cancer susceptibility disorder: a case report

IntroductionMultiple distinct tumors arising in a single individual or within members of a family raise the suspicion of a genetic susceptibility disorder.Case presentationWe present the case of a 52-year-old Caucasian woman diagnosed with sebaceous gland carcinoma of the eyelid, followed several years later with subsequent diagnoses of breast cancer and papillary carcinoma of the thyroid. Although the patient was also exposed to radiation from a pipe used in the oil field industry, the constellation of neoplasms in this patient suggests the manifestation of a known hereditary susceptibility cancer syndrome. However, testing for the most likely candidates such as Muir-Torre and Cowden syndrome proved negative.ConclusionWe propose that our patients clustering of neoplasms either represents a novel cancer susceptibility disorder, of which sebaceous gland carcinoma is a characteristic feature, or is a variant of the Muir-Torre syndrome.