Clinical management of patients with Cushing syndrome treated with mifepristone: consensus recommendations.

BACKGROUND: While surgery is the first-line treatment for patients with endogenous hypercortisolism (Cushing syndrome [CS]), mifepristone has been shown to be a beneficial medical treatment option, as demonstrated in the SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. Mifepristone is a competitive glucocorticoid receptor antagonist and progesterone receptor antagonist that is associated with several treatment effects and adverse events that clinicians need to be aware of when considering its use. The objective of this review was to provide updated clinical management recommendations for patients with CS treated with mifepristone. METHODS: A panel of endocrinologists from the US with extensive experience in treating patients with CS, including with mifepristone, convened as part of a clinical advisory board to develop a consensus on the practical, real-world clinical management of patients on mifepristone. RESULTS: Comprehensive considerations and recommendations are provided for managing mifepristone-associated effects, including symptoms of cortisol withdrawal, hypokalemia, and change in thyroid function; effects related to its antiprogesterone activity; and rash. Additional management strategies to address concomitant medications and special clinical situations, such as surgery and use in specific populations, are also provided. CONCLUSION: Safe and effective use of mifepristone requires clinical judgment and close patient monitoring to ensure optimal clinical outcomes. These consensus recommendations provide useful, practical guidance to clinicians using mifepristone.

Mifepristone Treatment in Four Cases of Primary Bilateral Macronodular Adrenal Hyperplasia (BMAH).

CONTEXT: Primary bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing syndrome conventionally treated with adrenalectomy. Medical treatment is often reserved for patients not eligible for surgery. However, to date there have been few studies about the efficacy of mifepristone for the treatment of BMAH associated with hypercortisolism. OBJECTIVE: To describe a series of patients with hypercortisolism due to BMAH treated with mifepristone from multiple medical practices. DESIGN: We retrospectively assessed four patients treated with mifepristone for hypercortisolism due to BMAH who had either failed unilateral adrenalectomy, declined surgery, or were poor surgical candidates. RESULTS: Mifepristone induced clinical improvement and remission of the signs and symptoms of hypercortisolism in all described patients with BMAH. The median treatment duration at the time of efficacy response assessment was 5 months (range: 3 to 18 months). Improvement in cardiometabolic parameters was observed as early as 2 weeks after treatment was started. All patients achieved improvements in glycemic control and hypertension and had significant weight loss. The most common adverse event observed with mifepristone therapy was fatigue. Increases in TSH level occurred in two patients. CONCLUSION: Mifepristone can be an effective medical alternative to surgery in patients with hypercortisolism due to BMAH.

Impact of mulberry leaf extract on type 2 diabetes (Mul-DM): A randomized, placebo-controlled pilot study.

AIMS: Mulberry leaves have been used anecdotally in Asia to treat many disease states, including glucose abnormalities. Animal and human studies illustrate potential benefit of mulberry leaf extract (MLE) in type 2 diabetes mellitus (DM2). The purpose of this study is to evaluate the glycemic and safety effects of MLE in patients with DM2. MATERIALS & METHODS: This randomized, double-blind, placebo-controlled pilot study evaluated MLE (1000mg standardized) versus matching placebo given three times daily with meals. Patients (n=24) were included if they had DM2 on single or combination oral therapy with a stable hemoglobin A1C (A1C). A 2-week placebo run-in (baseline) was followed by initiation of randomized medication for 3 months. Primary endpoints were change in A1C and self-monitoring blood glucoses (SMBG). Safety was also evaluated. RESULTS: Of 24 patients enrolled, 17 patients completed the study. Post-prandial SMBG was significantly decreased at 3 months in the MLE group versus baseline (16.1%; p<0.05). This improvement in post-prandial SMBG persisted when compared to placebo (18.2%; p<0.05). A1C decreased from 7.30% at baseline to 6.94% in the MLE group but did not reach statistical significance (p=0.079). There was no difference in A1C between MLE and placebo. A significant 15% increase occurred in serum creatinine when the MLE group was compared to baseline or placebo (p<0.05 for both). There was no significant effect on weight, fasting SMBG, blood pressure, hypoglycemia, or other safety evaluation markers. CONCLUSIONS: These results suggest that mulberry leaf extract may be a useful complementary mealtime glucose option for patients with DM2. ClinicalTrials.gov Identifier NCT00795704.

Impact of vitamin D status on statin-induced myopathy.

INTRODUCTION: There is a multitude of evidence supporting the benefit of statin use in cardiovascular disease; however, statin-induced myopathy is a major reason for statin discontinuation and non-adherence. Vitamin D deficiency has been independently associated with muscle weakness and severe myopathy, and may be a confounder for statin-induced myopathies. Since there is no consensus on a treatment course of action for statin-induced myopathy, investigation into potential confounders to elucidate the dynamics of statin-induced myopathy is warranted. METHODS: A retrospective chart review was conducted on 105 patients in a cardiometabolic clinic with a vitamin D drawn from December 2006 to April 2008. Patients exposed to statins were divided into two groups: (1) patients with low vitamin D (<32 ng/mL) [n = 52] and (2) patients with a sufficient vitamin D level (⩾32 ng/mL) [n = 32]. Data were compared via t-tests or Fisher's Exact, as appropriate. RESULTS: There were 41 statin-specific myopathies amongst the 24 statin-intolerant patients. Low vitamin D was significantly associated with statin-induced myopathy (p = 0.048). Following prescription vitamin D supplementation, statin tolerance rates were significantly higher in patients with a baseline vitamin D ⩽20 ng/mL than those with a baseline vitamin D >20 ng/mL (90% vs 33%; p = 0.036). CONCLUSION: Vitamin D status may be considered a modifiable risk factor for muscle-related adverse effects of statins, and supplementation of vitamin D (particularly when ⩽20 ng/mL) may improve statin tolerance.

What causes a prolactinoma to be aggressive or to become a pituitary carcinoma?

INTRODUCTION: Malignant prolactinoma is an exceedingly rare endocrine tumor and cannot be diagnosed on histological grounds alone. Similarly to other neuroendocrine tumors such as pheochromocytoma, the mitoses index, Ki-67, p53, and others are utilized in helping understand whether a tumor is benign or malignant or to better predict tumor behavior. We here present the unusual case of an unfortunate young man with an aggressive prolactinoma, the complications of which led to his premature death. CASE REPORT: A 25-year-old white man developed severe headaches, low energy, and decreased libido. A brain magnetic resonance imaging (MRI) showed a 4 x 3 x 2 cm pituitary tumor invading the left cavernous sinus. Laboratory findings revealed elevated prolactin (470 ng/mL) and adrenocorticotropic hormone (ACTH, 82 pg/ml) and decreased total testosterone (176 ng/dl). Visual fields showed superior quadrantanopia in the left eye. Transsphenoidal pituitary resection was undertaken. Pathology revealed a prolactinoma with atypical cells, diffuse p53 nuclear labeling, and a Ki-67 index of 23% (high). Postoperatively, prolactin remained elevated (725-891 ng/ml) and cabergoline was increased to 1 mg three times weekly, with serum prolactin further increasing to 3507 ng/ml five months postoperatively. Repeat MRI revealed extension of the tumor with optic chiasm compression and left orbit invasion. Because of acute left vision loss with ophthalmoplegia, an urgent left frontotemporal craniotomy and tumor resection were conducted. The Ki-67 index of the tumor was 24.8%, the mitotic figure immunostain phosphohistone-H3 positive. Sixty percent (60%) of tumor cells were positive for p53. Cabergoline was increased to 1 mg daily but prolactin remained elevated (770 ng/ml). The patient then underwent proton beam radiation to the area of concern involving the sella. Prolactin thereafter improved to 44 ng/ml. He then developed acute vision loss of the right eye with an MRI showing tumor in the right cavernous sinus. A 15 mm dural-based right temporal mass believed to be a metastasis was also noted. Following this scan, he was considered too high risk for debulking surgery and instead underwent gamma knife irradiation to the sella area. This shrank the right cavernous sinus tumor mass, while the right temporal mass increased in size. The patient developed blindness and left-sided weakness and required enteral feeding and tracheostomy after prolonged intubation. A trial of chemotherapy with temozolomide (350 mg daily for 5 days) near the end of his life was unsuccessful. He died on home hospice 31 months after his first surgery. CONCLUSION: Headaches, vision changes, and symptoms of androgen deficiency syndrome can be manifestations of an aggressive prolactinoma that might require surgery and additional medical therapy including cabergoline and temozolomide with an unpredictable time of survival.

Xanthomas associated with homozygous familial hypercholesterolemia.

An 18-year-old African-American female was diagnosed with homozygous familial hypercholesterolemia (HFH) during early childhood. Physical examination revealed tuberous xanthomas on the processus olecrani, as well as smaller tendinous and tuberous xanthomas on the hands. Both tendinous and tuberous xanthomas may occur in patients with HFH. The prevalence of HFH is 1 case/1 million persons, and it is reported less frequently in African-Americans. These photographs were taken shortly after the patient's highest low-density lipoprotein cholesterol (LDL) level was recorded at our medical center (766 mg/dl). At that time, she was only receiving atorvastatin. The patient is now taking four drugs at maximum doses for her HFH: atorvastatin, colesevelam, ezetimibe, and niacin. She is also receiving twice-monthly LDL apheresis. Her only cardiovascular risk factor was a low high-density lipoprotein cholesterol level (dependent on apheresis). The patient's xanthomas tend to improve when she is compliant with her cholesterol-lowering regimen. Six years after these photographs were taken, the patient's LDL level was 184 mg/dl, and she remained cardiovascular event free.

Impact of sitagliptin on markers of beta-cell function: a meta-analysis.

BACKGROUND: Progressive beta-cell dysfunction and beta-cell failure are fundamental pathogenic consequences of type 2 diabetes. Dipeptidyl peptidase-IV inhibitors may exhibit improvement on preclinical measures of both beta-cell function, homeostasis model assessment of beta-cell (HOMA-beta) index, and beta-cell dysfunction, proinsulin/insulin ratio (PI/IR), correlating to beta-cell survival. RESEARCH DESIGN AND METHODS: A systematic literature search through July 2008 was conducted to extract a consensus of randomized, controlled trials of sitagliptin therapy on measures of beta-cell function. A random-effects model meta-analysis evaluated effects on HOMA-beta and PI/IR versus placebo. Several subgroup analyses, including active control, were conducted. Studies were included if they met the following criteria: (1) randomized trials on sitagliptin; (2) placebo or active control; and (3) data reported on HOMA-beta or PI/IR. RESULTS: A total of 11 trials (n = 3039) reported effects on HOMA-beta and 8 trials (n = 2325) on PI/IR versus placebo. Four trials (n = 1425) were included in the active control subgroup analysis. Sitagliptin significantly improved HOMA-beta index by 12.03% [95% confidence interval (CI), 9.45-14.60] versus placebo. Sitagliptin also significantly decreased PI/IR -0.06 (95% CI, -0.08 to -0.04). Sitagliptin was inferior to active control for HOMA-beta index [5.64% (95% CI, 0.38-10.90)], but not different in terms of PI/IR [0.01 (95% CI, -0.04 to 0.06)]. CONCLUSIONS: Despite significant improvement in HOMA-beta index and PI/IR from placebo, there does not seem to be a benefit of dipeptidyl peptidase-IV inhibitors over other agents with respect to beta-cell function/activity. Long-term prevention of beta-cell dysfunction cannot be ruled out.

Practical management of dyslipidemia with elevated lipoprotein(a).

OBJECTIVE: To report a case and describe a practical approach to treating dyslipidemia in a very-high-risk patient with elevated lipoprotein(a) [Lp(a)]. SETTING: Pharmacist-managed lipid clinic, from November 2006 to July 2007. PATIENT DESCRIPTION: A 50-year-old white woman with a recent history of multiple myocardial infarctions presented for management of dyslipidemia. CASE SUMMARY: At baseline, the patient had elevated low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC), and Lp(a) (306 nmol/L) levels and low high-density lipoprotein cholesterol (HDL-C) levels. Early initiation of combination therapy with a statin and niacin extended release (ER) titration was started. After 3 months, despite progressive weight gain caused by dietary indiscretion, LDL-C decreased by 24% and TG and TC levels reached goal. Lp(a) levels did not change. Niacin ER titration continued, pravastatin was maximized, and ezetimibe 10 mg daily was started. Despite dramatic 9-month weight gain (68 lb total), LDL-C and HDL-C reached goal and Lp(a) levels decreased by 33% (204 nmol/L) after niacin ER maximization. RESULTS: Lp(a) is an emerging risk factor in cardiovascular disease (CVD). Elevated Lp(a) (>30 mg/dL) has been implicated as both an independent and an additive risk factor for CVD and stroke, particularly in women. In this case, the patient did not reach the optimal goal (<30 mg/dL) but did experience more than 30% reduction in Lp(a) levels. Although multiple factors, including subclinical hypothyroidism, hormonal changes, and renal disease, increase Lp(a) levels, few beneficial treatment options exist (i.e., estrogen and niacin). Although the exact mechanism of action is unknown, niacin ER has been documented to reduce Lp(a) by 36% to 38%. Some effect of ezetimibe on Lp(a) in this patient cannot be ruled out. CONCLUSION: This case illustrates a practical use of currently available therapy options to address Lp(a) as a secondary cardiovascular risk factor. Niacin is a preferred option for Lp(a) lowering in very-high-risk patients with coronary heart disease and dyslipidemia. The importance of moderate reductions in Lp(a) is not known.

Impact of statins on risk of stroke: a meta-analysis.

BACKGROUND: Evidence from randomized, controlled trials suggests that reduction of low-density lipoprotein cholesterol with hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) therapy in patients at high risk for cardiovascular disease reduces the incidence of ischemic stroke; however, data from large epidemiologic observational studies suggest an inverse relationship between risk of hemorrhagic stroke and cholesterol levels. OBJECTIVE: To perform a meta-analysis of randomized controlled trials to assess the effect of statin therapy on all cerebrovascular events (CVEs), ischemic stroke, and hemorrhagic stroke. METHODS: A systematic literature search of MEDLINE, EMBASE, Cumulative Index to Nursing & Allied Health Literature, and Web of Science citations from June 1975 through September 2006 was performed to identify randomized controlled trials of statin therapy. Trials were included if they met the following criteria: (1) controlled clinical trials of statin therapy versus placebo, (2) well-described protocol, and (3) data reported on incidence of all CVEs, ischemic stroke, or hemorrhagic stroke. All data were independently extracted by 3 investigators. RESULTS: Weighted averages are reported as relative risk with 95% confidence intervals. A total of 26 trials (N = 100,560) reported incidence on all CVEs. Six trials (n = 37,292) reported incidence of ischemic stroke and 9 trials (n = 57,895) were included in the hemorrhagic stroke analysis. Statin therapy significantly reduced the risk of all CVEs (RR 0.83; 95% CI 0.76 to 0.91) and the risk of ischemic stroke (RR 0.79; 95% CI 0.63 to 0.99). Statin therapy did not significantly reduce risk of hemorrhagic stroke (RR 1.11; 95% CI 0.77 to 1.60). CONCLUSIONS: Statin therapy significantly reduces risk of developing all CVEs and ischemic stroke; however, it is associated with a nonsignificant increase in risk of hemorrhagic stroke.

Osborn wave in accidental hypothermia.

After prolonged exposure to cold, an elderly man was found with altered mentation by his family physical examination revealed hypothermia. The electrocardiogram demonstrated characteristic changes. Results of an extensive diagnostic workup revealed only adrenal insufficiency, and the electrocardiographic abnormalities resolved after warming. Hypothermia can result from a variety of endogenous and exogenous causes; the most common of these, however, is accidental exposure. While history and physical exam are the best means for diagnosing hypothermia, several laboratory abnormalities are typical. One finding on electrocardiogram, while not pathognomic, is highly suggestive of hypothermia: the Osborn wave. Other findings on electrocardiogram can assist in diagnosis as well, but the only factors shown to predict outcome are atrial fibrillation and shivering artifact.

A case of severe hemorrhagic diarrhea.

A 50-year-old white female presented to the emergency department with diarrhea, abdominal pain, and hematochezia. The illness started four days prior to presentation and escalated to 10-15 bowel movements daily. She was tachycardic and hypotensive upon presentation with a diffusely tender abdomen. Her anemia and persistent hematochezia prompted endoscopy by a gastroenterologist. Flexible sigmoidoscopy was performed to the splenic flexure and revealed evidence of severe active colitis. The mucosa was friable and severely ulcerated. Numerous biopsies were obtained that revealed acute colitis with fibrinopurulent exudates. A stool culture showed Escherichia coli O157:H7, which was confirmed by the Mississippi State Board of Health. Infection with E. coli O157:H7 affects nearly 1.1 per 100,000 Americans annually. It accounts for about 3% of all bacterial and protozoal causes of foodborne illnesses and possesses a mortality rate of about 1-2%.

The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study.

OBJECTIVE: To assess the magnitude of the association between the National Cholesterol Education Program's Third Adult Treatment Panel Report (ATP III) definition of the metabolic syndrome and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Cox regression was used to estimate the relative risk of incident coronary heart disease (CHD) and stroke among 12,089 black and white middle-aged individuals in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: The metabolic syndrome was present in approximately 23% of individuals without diabetes or prevalent CVD at baseline. Over an average of 11 years of follow-up, 879 incident CHD and 216 ischemic stroke events occurred. Among the components of the metabolic syndrome, elevated blood pressure and low levels of HDL cholesterol exhibited the strongest associations with CHD. Men and women with the metabolic syndrome were approximately 1.5 and 2 times more likely to develop CHD than control subjects after adjustment for age, smoking, LDL cholesterol, and race/ARIC center (sex interaction P < 0.03). Similar associations were found between the metabolic syndrome and incident ischemic stroke. Comparison of receiver operating characteristic curves indicated that the metabolic syndrome did not materially improve CHD risk prediction beyond the level achieved by the Framingham Risk Score (FRS). CONCLUSIONS: Individuals without diabetes or CVD, but with the metabolic syndrome, were at increased risk for long-term cardiovascular outcomes, although statistical models suggested that most of that risk was accounted for by the FRS. Nevertheless, identification of individuals with the metabolic syndrome may provide opportunities to intervene earlier in the development of shared disease pathways that predispose individuals to both CVD and diabetes.

Prevalence of coronary heart disease and carotid arterial thickening in patients with the metabolic syndrome (The ARIC Study).

We determined the prevalence of the metabolic syndrome (MS) with the criteria recommended by the National Cholesterol and Education Program, Adult Treatment Panel III report and estimated the magnitude of cross-sectional associations between the MS, coronary heart disease (CHD), and atherosclerosis in 14,502 black and white middle-age patients in the Atherosclerosis Risk in Communities Study. CHD was ascertained by standardized procedures and subclinical atherosclerosis was determined by measuring carotid intimal medial wall thickness using B-mode ultrasonography. The prevalence of MS was 30%, with substantial variation across race and gender subgroups. Among women but not among men, MS was significantly associated with increasing low-density lipoprotein cholesterol. CHD prevalence was 7.4% among those with the MS compared with 3.6% in comparison subjects (p <0.0001). After adjustment for established risk factors, subjects who had MS were 2 times more likely to have prevalent CHD than were those who did not have the syndrome. Among individuals free of CHD and stroke, after adjustment for age, gender, and race/center, the average intimal-medial wall thickness of carotid arteries was greater among those with versus those without MS (747 vs 704 mum, p <0.0001). Thus, MS was significantly associated with the presence of CHD and carotid intimal medial wall thickness. Identification of patients who have MS may provide opportunities to initiate CHD prevention strategies.