Steven B. Magill

The Adrenal Vein Sampling International Study (AVIS) for Identifying the Major Subtypes of Primary Aldosteronism

CONTEXT In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.

Coccidioidomycosis-induced Thyroiditis and Calcitriol-mediated Hypercalcemia in a Heart Transplantation Patient

A 56-year-old man with a history of cardiac transplantation developed disseminated coccidioidomycosis involving the upper extremities. Suppression of thyrotropin was followed by marked biochemical hypothyroidism. Biopsy of an enlarged left thyroid lobe demonstrated infiltration with coccidioidomycosis. He also developed hypercalcemia thought to be mediated by 1,25-dihydroxyvitamin D and was treated with a bis-phosphonate. This rare case of disordered calcium metabolism and thyroiditis should alert physicians of the potential endocrinopathies that can develop in patients who have undergone solid organ transplantation.

Pathophysiology, Diagnosis, and Treatment of Mineralocorticoid Disorders

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure control, fluid, and electrolyte balance in humans. Chronic activation of mineralocorticoid production leads to dysregulation of the cardiovascular system and to hypertension. The key mineralocorticoid is aldosterone. Hyperaldosteronism causes sodium and fluid retention in the kidney. Combined with the actions of angiotensin II, chronic elevation in aldosterone leads to detrimental effects in the vasculature, heart, and brain. The adverse effects of excess aldosterone are heavily dependent on increased dietary salt intake as has been demonstrated in animal models and in humans. Hypertension develops due to complex genetic influences combined with environmental factors. In the last two decades, primary aldosteronism has been found to occur in 5% to 13% of subjects with hypertension. In addition, patients with hyperaldosteronism have more end organ manifestations such as left ventricular hypertrophy and have significant cardiovascular complications including higher rates of heart failure and atrial fibrillation compared to similarly matched patients with essential hypertension. The pathophysiology, diagnosis, and treatment of primary aldosteronism will be extensively reviewed. There are many pitfalls in the diagnosis and confirmation of the disorder that will be discussed. Other rare forms of hyper- and hypo-aldosteronism and unusual disorders of hypertension will also be reviewed in this article.

Endocrine Manifestations of Celiac Disease

Celiac disease is a disorder resulting from exposure of predisposed individuals to certain grain proteins and is associated with many autoimmune endocrine disorders. This condition may occur with classic symptoms of malabsorption or with minimal or no gastrointestinal symptoms. Patients may present with hypocalcemia, osteoporosis, or osteomalacia. Because of decreased intestinal absorption of levothyroxine, celiac disease may present with excessive levothyroxine requirements in hypothyroid patients. Furthermore, celiac disease is seen in increased frequency in patients with type 1 diabetes mellitus and should strongly be considered in the differential diagnosis of diarrhea or weight loss in patients with type 1 diabetes mellitus. This article describes the authors’ experience with celiac disease and emphasizes the ways it may present to clinical endocrinologists.

High affinity binding of the calcium channel blocker, (+)-[methyl-3H]PN200-110(3HPN) in rat brain

PN200-110 is a recently introduced 1,4-dihydropyridine which has been demonstrated to be a potent calcium channel blocker. 3HPN has been shown to bind in a specific saturable manner to P2 fractions obtained from brain homogenates from male Sprague-Dawley rats. 3HPN binding was found to be temperature-dependent. Specific 3HPN binding was maximal at 25 degrees C; binding decreased at 2 degrees C and 37 degrees C. The KD calculated from Scatchard analysis was 0.0943 +/- 0.0038 nM while the Bmax was found to be 109.1 +/- 2.3 fmol/mg protein. A concentration dependent inhibition of 3HPN binding by various cations was determined and found to be as follows: ZN2+ greater than La3+ greater than Rh3+, Al3+ greater than Co2+, Ni2+, Mn2+ greater than Ca2+, Mg2+ greater than Ba2+ greater than Sr2+. These results provide evidence for the existence of central high affinity dihydropyridine receptor sites in rat brain.

Is the hypothalamic–pituitary–adrenal axis disrupted in type 2 diabetes mellitus?

There is an intimate relationship between the hypothalamic–pituitary–adrenal (HPA) axis and the control of blood glucose and intermediary metabolism; hence, cortisol is considered the archetypal “glucocorticoid” [1]. Patients with Cushing’s syndrome often develop hyperglycemia because of the dual effects of increased hepatic gluconeogenesis and peripheral insulin resistance [1]. Furthermore, glucocorticoids have dramatic hyperphagic effects leading to weight gain and the characteristic fat distribution of Cushing’s syndrome [2]. Type 2 diabetes mellitus (T2DM) has many similarities to Cushing’s syndrome with insulin resistance, increased hepatic gluconeogenesis, and development of central obesity [1–4]. As a result of these obvious similarities, the prevalence of Cushing’s syndrome has been evaluated in patients with poorly controlled T2DM and, in some studies, found to be increased although not uniformly so [5, 6]. More importantly for this Editorial, patients with T2DM may have altered HPA axis activity in the absence of frank hypercortisolism [7]. Obesity per se may correlate with HPA axis hyperactivity, although this is not a uniform finding [8]. Several studies have found an increase in various indices of HPA axis activity that correlate with the degree of insulin resistance and T2DM complications [9– 12]. On the other hand, one study showed that a decrease in hippocampal volume was associated with the severity of T2DM and with a reduced cortisol awakening response (CAR), which is thought to be an index of HPA axis reactivity [13]. It is interesting to note that there may be sex differences in this phenomenon with men with T2DM having a greater CAR and women having increased night time cortisol levels [14]. Furthermore, these sexually dimorphic alterations are associated with higher hemoglobin A1c levels. Two studies reported in this journal evaluated this phenomenon [15, 16]. Spanakis et al. performed a longitudinal, 6-year study of the association of T2DM with several characteristics of the HPA axis, including awakening and bed-time salivary cortisol, the CAR, and a salivary cortisol AUC over one day. Although some trivial effects were found, Spanakis et al. did not find any major changes in HPA dynamics during a 6-year span in patients with T2DM. They concluded that diabetes status did not cause HPA axis dysregulation, although they also suggested that a larger study was necessary to confirm this lack of association. In addition, Spanakis et al. used a single elevated fasting glucose of ≥126 mg/dl as one of the criteria for diagnosis of diabetes. Thus, some of the patients in their study may not have had frank diabetes. Bellastella et al. studied hospitalized patients with poorly controlled T2DM and found an association of increased late-night serum cortisol with morning fasting glycemia and with continuous overlapping net glycemic action [16]. Latenight salivary cortisol (LNSC) did not seem to show the * Hershel Raff hraff@mcw.edu

EVOLUTION OF A PHEOCHROMOCYTOMA

OBJECTIVE To present a case that demonstrates the evolution of a pheochromocytoma over a several-year period and to emphasize the importance of a thorough work-up for pheochromocytoma in patients with neurofibromatosis type 1 (NF1) and hypertension. METHODS We review the long-term clinical, biochemical, and imaging findings in a man with a complex medical history of hypertension, NF1, and cardiomyopathy. RESULTS A 44-year-old man, with a well-documented history of headaches, hypertension, and NF1, was referred for evaluation of a right adrenal enlargement. He had developed cardiomyopathy and undergone an evaluation for cardiac transplantation. Initial computed tomography revealed subtle asymmetry in the upper right adrenal gland. Biochemical studies for pheochromocytoma yielded equivocal findings, with a 1.5-fold elevation in the urinary norepinephrine and near-normal urinary metanephrine level. Because 131I-metaiodobenzylguanidine imaging showed no tracer uptake in the area of the right adrenal gland, the patient was thought not to have a pheochromocytoma. The patient eventually underwent cardiac transplantation and did well. On reassessment 3 1/2 years later, he was found to have a larger right adrenal mass. The second endocrine evaluation demonstrated substantial elevation in the urinary metanephrine level, and the patient underwent laparoscopic right adrenalectomy to remove the tumor (3.5 by 3.0 by 2.5 cm), which proved to be a pheochromocytoma. CONCLUSION This case shows that a pheochromocytoma can be difficult to diagnose and can evolve to become a large, biochemically active tumor. It is imperative that patients with an adrenal tumor undergo periodic reevaluation to ensure that the tumor remains stable in size. If the tumor enlarges, further biochemical testing is warranted.

Mechanisms for the Increased Fatigability of the Lower Limb in People with Type 2 Diabetes

Fatiguing exercise is the basis of exercise training and a cornerstone of management of type 2 diabetes mellitus (T2D); however, little is known about the fatigability of limb muscles and the involved mechanisms in people with T2D. The purpose of this study was to compare fatigability of knee extensor muscles between people with T2D and controls without diabetes and determine the neural and muscular mechanisms for a dynamic fatiguing task. Seventeen people with T2D [ten men and seven women: 59.6 (9.0) yr] and twenty-one age-, body mass index-, and physical activity-matched controls [eleven men and ten women: 59.5 (9.6) yr] performed one hundred twenty high-velocity concentric contractions (one contraction/3 s) with a load equivalent to 20% maximal voluntary isometric contraction (MVIC) torque with the knee extensors. Transcranial magnetic stimulation (TMS) and electrical stimulation of the quadriceps were used to assess voluntary activation and contractile properties. People with T2D had larger reductions than controls in power during the fatiguing task [42.8 (24.2) vs. 26.4 (15.0)%; P < 0.001] and MVIC torque after the fatiguing task [37.6 (18.2) vs. 26.4 (12.1)%; P = 0.04]. People with T2D had greater reductions than controls in the electrically evoked twitch amplitude after the fatiguing task [44.0 (20.4) vs. 35.4 (12.1)%, respectively; P = 0.01]. However, the decrease in voluntary activation was similar between groups when assessed with electrical stimulation [12.1 (2.6) vs. 12.4 (4.4)% decrease; P = 0.84] and TMS ( P = 0.995). A greater decline in MVIC torque was associated with larger reductions of twitch amplitude ( r2 = 0.364, P = 0.002). Although neural mechanisms contributed to fatigability, contractile mechanisms were responsible for the greater knee extensor fatigability in men and women with T2D compared with healthy controls. NEW & NOTEWORTHY Transcranial magnetic stimulation and percutaneous muscle stimulation were used to determine the contributions of neural and contractile mechanisms of fatigability of the knee extensor muscles after a dynamic fatiguing task in men and women with type 2 diabetes (T2D) and healthy age-, body mass index-, and physical activity-matched controls. Although neural and contractile mechanisms contributed to greater fatigability of people with T2D, fatigability was primarily associated with impaired contractile mechanisms and glycemic control.