Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:There is a growing, largely inconsistent, literature on the role of vitamin D in association with type 2 diabetes, insulin resistance/insulin secretion, glycemic indices, and complications of type 2 diabetes. Pathophysiologic, bystander, preventive, and treatment roles of vitamin D have all been proposed. In this focused review, we attempt to organize and clarify our current information in this area. RECENT FINDINGS/RESULTS:Clinical study interpretation is difficult because of variability in dosage, dosage form, study duration, and populations studied, as well as recently reported normal human polymorphisms in vitamin D synthesis and catabolism, vitamin D-binding protein, and vitamin D receptors in addition to a host of potential epigenetic confounders. Low vitamin D status appears to be associated with type 2 diabetes and most other insulin resistance disorders reported to date. The extraskeletal benefits of supplementation/repletion in these disorders in our species, with a few highlighted exceptions, remain to be established. This focused review attempts to summarize our current knowledge in this burgeoning area through a review of key meta-analyses, observational studies, randomized control trials, and Mendelian randomization studies and will hopefully serve as a guide to indicate future research directions and current best practice.

PURPOSE OF REVIEW/OBJECTIVE:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have positive effects on weight loss, blood pressure, hyperlipidemia, and glycemic control. They exhibit a broad range of effects on the cardiovascular system that are independent of changes in blood glucose. Cardiovascular outcome trials have demonstrated safety of GLP-1 RAs but results for cardiovascular efficacy were varied. The aim of the present review is the assessment of the effects of GLP-1 RAs on cardiovascular risk factors, and major cardiovascular events. RECENT FINDINGS/RESULTS:Use of GLP-1 RAs was associated with relative risk reduction in cardiovascular mortality and all-cause mortality with no significant differences for the incidence of severe hypoglycemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer when compared to placebo. Although there are differences between individual medications with respect to their effects on cardiovascular events, GLP-1 RAs offer a favorable risk-benefit profile. The present review confirms the cardiovascular safety and efficacy vs placebo of GLP-1 RAs in patients with type 2 diabetes at moderate-to-high atherosclerotic cardiovascular risk without significant side effects. Although professional guidelines recommend metformin as the sole first-line agent, GLP-1 RAs can be used as first-line therapy in individuals with type 2 diabetes who either are intolerant to metformin or have high cardiovascular risk factors.

The differential diagnosis of adrenal incidentalomas includes primary hyperaldosteronism, Cushing's syndrome, and pheochromocytoma, and, when the first 3 have been excluded,-non-classic adrenal hyperplasia (NCAH). We have previously shown that insulin-sensitizing interventions ameliorate the expression of both classic and non-classic CAH. The patient is a 56 year-old African-American man who was referred to Endocrine in 2002 for hypertension with a 3.0x2.8x2.1 cm, well circumscribed, ovoid, hypodense, soft tissue mass in the medial limb of the right adrenal first noted in 2001. Endocrine evaluation was negative for primary hyperaldosteronism, Cushing's syndrome, and pheochromocytoma, however plasma renin activity (PRA) by liquid chromatography tandem mass spectrometry (LC/MS/MS) was low at 0.52 ng/ml/hr., at least suggesting the possibility of a deoxycorticosterone-secreting adenoma (DOComa). Unstimulated serum deoxycorticosterone by LC/MS/MS on 9/20/11 was 38 ng/dl (3.5-11.5). Both hypo- and hyperkalemia were occasionally noted, but not at DOC or aldosterone sampling times. Unstimulated serum 11-deoxycortisol by LC/MS/MS on 1/31/08 was 130 ng/dl (<76). Serum 17-OH-pregnenolone was normal and serum 17-OH-progesterone by LC/MS/MS was low at 43 ng/dl (61-334). Metformin 500 mg daily after supper was started on 5/6/08, following which serum 11- deoxycortisol fell to 84 ng/dl. After this the patient was lost to follow-up for several years and ran out of metformin. On 6/13/12 his serum 25-OH-Vitamin D by immunoassay (IA) was 6 ng/ml (30-100). Between 1/8/08 and 6/8/12 the patient had lost 2.3 kg, after which he underwent right below knee amputation due to peripheral arterial disease with gangrene. On 7/15/16 serum 11-deoxycortisol fell to 53 ng/dl (<42), serum deoxycorticosterone normalized to 6ng/dl (2-19), serum 25-OH-Vitamin D was 14.4 ng/ml (30.0-100.0). On 8/5/16 serum 11-deoxycortisol fell to 47 ng/dl, DOC was 5.2 ng/dl, and 25-OH-Vitamin D was 36.3 ng/ml. The right adrenal mass has not changed in size or appearance since 2001. This case illustrates the importance of considering NCAH in the differential diagnosis of adrenal incidentaloma and again illustrates the potential benefit of improvement of insulin sensitivity by both weight loss and correction of hypovitaminosis D in NCAH

A number of case reports and small series have been published suggesting an association between hyperthyroidism and pulmonary artery hypertension (PAH), although such an association is not widely appreciated among endocrinologists, cardiologists, or pulmonologists. Some authors have speculated that PAH in this setting is autoimmune in origin and, thus, likely to occur in Graves' disease, but unlikely to occur in non-autoimmune hyperthyroidism. We evaluated 24 patients with hyperthyroid Graves' disease (GD) - confirmed by the combination of hyperthyroidism with increased titers of thyroid-stimulating immunoglobulin (TSIG) or thyroid peroxidase (TPO) antibody or thyroglobulin antibody - and 3 patients with antibody-negative toxic multinodular goiter (TMG with trans-thoracic 2-D echocardiography while they were hyperthyroid. In a smaller number of patients (3), we were able to repeat their echocardiograms when their hyperthyroidism had either much improved or they had actually become euthyroid. The cardiologist reading the echocardiograms was blinded as to their thyroid status. 54.2 % of the patients with GD and 100% of the patients with TMG had PAH. In the patients with repeat echocardiograms, mean pulmonary artery pressure dropped from 35.8 to 24.3 mmHg. One, previously reported patient closed a patent foramen ovale in association with amelioration of her hyperthyroidism and PAH. We conclude that PAH is common in both GD and TMG. The observation that it was present in a larger percentage of TMG patients than GD patients suggests that the phenomenon is more likely related to hyperthyroidism itself or to upper airway obstruction related to the goiter than to autoimmunity. Future studies involving patients with thyrotoxic adenoma, TSH-dependent hyperthyroidism, and athyreotic patients with iatrogenic hyperthyroidism would be of interest in clarifying the etiology of this common association

An elderly woman presented with acne and male pattern alopecia, which upon diagnostic evaluation was found to be due to nonclassic 11-hydroxylase deficiency. We previously reported that Ashwagandha root ameliorates nonclassic 3-beta-ol dehydrogenase and aldosterone synthase deficiencies. This is the first report of its use being associated with amelioration of nonclassic 11-hydroxylase deficiency, where its apparent effects appear to be dose-related.

Cortisol production by hepatocellular carcinoma (HCC) has not been previously reported and dehydroepiandrosterone (DHEA) secretion by HCC is rare. We report a case of a 53-year-old woman admitted with dyspnoea and headache. Serum cortisol by immunoassay (IA) was 42.3 mug/dL, urine free cortisol (UFC) by liquid chromatography mass spectrometry (LC/MS/MS) was 106.1 mug/24 h, serum DHEA by LC/MS/MS was 4886 ng/mL, serum DHEA-S by LC/MS/MS was 4477 ng/mL and plasma adrenocorticotrophic hormone (ACTH) by IA was 10 pg/mL. CT showed likely HCC metastatic to the left adrenal gland, brain and lungs. Liver and adrenal gland biopsies confirmed HCC. ACTH tumour staining was negative. High serum and UFC levels and high serum DHEA and DHEA-S with low-normal plasma ACTH and negative tumour ACTH staining suggested ACTH-independent ectopic Cushing's syndrome (CS); cortisol and DHEA being likely secreted by the HCC. To the best of our knowledge, this is the first reported case of HCC associated with CS.

A 71-year-old woman with type 2 diabetes mellitus, chronic kidney disease stage IV, primary hypothyroidism and osteoarthritis, whose prescribed treatment included miglitol 50 mg thrice daily with the first bite of meals, reported that she suffered visual hallucinations while taking miglitol, which resolved within a few days of stopping the drug. When she resumed miglitol, hallucinations recurred within a few days and again resolved within a few days of stopping the drug. To our knowledge, this is the first reported case of hallucinations associated with the use of an alpha-glucosidase inhibitor and highlights a previously unappreciated risk associated with the use of this generally quite benign drug class.

Background: Interventions that are effective in treating PCOS are often effective in treating CAH. Both Vitamin D replacement and HMGCoA inhibitors (statins) have been reported to be effective in treating PCOS, while we have reported that ergocalciferol is effective in treating patients with both classical and non-classic 11-hydroxylase deficiency. Use of these agents in treating non-classic 21-hydroxylase deficiency has not been previously reported, with the exception of one previous report in 4 women with non-classic 21-hydroylase deficiency treated with simvastatin only. Clinical case: A 56 year old woman presented with complaints of hirsutism, male pattern alopecia, and acne; reproductive history was normal. Physical examination was remarkable for the above as well as for acanthosis nigricans in the axillae, neck, and groin. Investigation revealed a serum 17-OH-progesterone (17OHP) concentration by liquid chromatography/ tandem mass spectrometry (LC/MS/MS) of 46 ng/dl (<45) and a baseline serum 25-OH-Vitamin D (25OHD) concentration by immunoextraction of 15 ng/dl (30-100). LDL cholesterol by calculation was 171.0 mg/dl (<100). Treatment was commenced with ergocalciferol 50,000 IU every 2 weeks and simvastatin 10 mg daily at bedtime. Thirteen months later 17-OHP was 27 ng/dl; 25OHD was 37 ng/dl. LDL fell to 157.4 mg/dl. There were no new acne lesions, alopecia had resolved, and hirsutism had diminished. Conclusion: This is the 5th patient reported whose non-classic 21-hydroxylase deficiency improved with simvastatin and the first patient with this disorder who responded to Vitamin D replacement. Further studies may confirm that this combination is an effective treatment for patients with non-classic 21-hydroxylase deficiency with hypercholesterolemia and Vitamin D deficiency. Our findings are consistent with our earlier reports showing that reduction of insulin levels is associated with improvement in CAH parameters