Immune checkpoint inhibitor-induced hypophysitis with transient ACTH-dependent hypercortisolism.

A woman in her 70s with metastatic melanoma presenting with refractory hypokalaemia on combined immune checkpoint inhibitors, nivolumab-ipilimumab, was diagnosed with adrenocorticotropic hormone (ACTH)-dependent hypercortisolism 11 weeks following the initiation of her immunotherapy. Investigations also demonstrated central hypothyroidism and hypogonadotropic hypogonadism. She underwent imaging studies of her abdomen and brain which revealed normal adrenal glands and pituitary, respectively. She was started on levothyroxine replacement and had close pituitary function monitoring. Two weeks later, her cortisol and ACTH levels started to trend down. She finally developed secondary adrenal insufficiency and was started on hydrocortisone replacement 4 weeks thereafter.This report highlights a case of immunotherapy-related hypophysitis with well-documented transient central hypercortisolism followed, within weeks, by profound secondary adrenal insufficiency. Healthcare professionals should remain vigilant in monitoring laboratory progression in these patients. Early recognition of the phase of hypercortisolism and its likely rapid transformation into secondary adrenal insufficiency can facilitate timely hormonal replacement and prevent complications.

Effects of meal preparation training on body weight, glycemia, and blood pressure: results of a phase 2 trial in type 2 diabetes.

BACKGROUND: Modest reductions in weight and small increases in step- related activity (e.g., walking) can improve glycemic and blood pressure control in type 2 diabetes mellitus (DM2). We examined changes in these parameters following training in time- efficient preparation of balanced, low- energy meals combined with pedometer- based step count monitoring. METHODS: Seventy- two adults with DM2 were enrolled in a 24- week program (i.e., 15 three- hour group sessions). They prepared meals under a chef's supervision, and discussed eating behaviours/nutrition with a registered dietitian. They maintained a record of pedometer- assessed step counts. We evaluated changes from baseline to 24 weeks in terms of weight, step counts, hemoglobin A1c (HbA1c, glycemic control), blood pressure, and eating control ability (Weight Efficacy Lifestyle WEL Questionnaire). 53 participants (73.6%) completed assessments. RESULTS: There were improvements in eating control (11.2 point WEL score change, 95% CI 4.7 to 17.8), step counts (mean change 869 steps/day, 95% CI 198 to 1,540), weight (mean change -2.2%; 95% CI -3.6 to -0.8), and HbA1c (mean change -0.3% HbA1c, 95% CI -0.6 to -0.1), as well as suggestion of systolic blood pressure reduction (mean change -3.5 mm Hg, 95% CI -7.8 to 0.9). Findings were not attributable to medication changes. In linear regression models (adjusted for age, sex, ethnicity, insulin use, season), a -2.5% weight change was associated with a -0.3% HbA1c change (95% CI -0.4 to -0.2) and a -3.5% systolic blood pressure change (95% CI -5.5 to -1.4). CONCLUSIONS: In this 'proof of concept' study, persistence with the program led to improvements in eating and physical activity habits, glycemia reductions, and suggestion of blood pressure lowering effects. The strategy thus merits further study and development to expand the range of options for vascular risk reduction in DM2.

Trimethoprim-sulfamethoxazole-induced refractory hypoglycaemia successfully treated with octreotide.

Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly prescribed antimicrobial agent for a wide variety of infections. It is generally well tolerated in a majority of patients; however, serious adverse effects have been described with its usage. Hypoglycaemia is an exceedingly rare but potentially life-threatening side effect of this antimicrobial agent due to its sulfonylurea-like effect. We describe a case of symptomatic, refractory hypoglycaemia secondary to TMP-SMX in a patient being treated for Stenotrophomonas maltophilia bacteraemia, which required treatment with 10 hours of intravenous dextrose (including several 50% dextrose boluses), as well as intramuscular glucagon and octreotide. We reviewed previous case reports described in the literature of TMP-SMX-induced hypoglycaemia, in which renal insufficiency was noted to be a common predisposing risk factor in an overwhelming majority of cases. In refractory cases of TMP-SMX-induced hypoglycaemia, intravenous octeotride may be considered for treatment.

Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors.

BACKGROUND: The recent withdrawal of cerivastatin by the manufacturer has led to an interest in hydroxymethylglutaryl-coenzyme A (HMG-CoA) inhibitors and the incidence of myopathy. We review the epidemiology, pharmacology, and presumed mechanisms of statin-induced myopathy, with a particular focus on cerivastatin. METHODS: A MEDLINE search of English-language articles published between 1985 and 2003 was performed. Key words included HMG-CoA inhibitors, statins, myopathy, myotoxicity, rhabdomyolysis, adverse events, drug interactions, and cerivastatin. RESULTS: The initial trials, which assessed the efficacy of first-generation HMG-CoA inhibitors, did not show a clinically significant increase in the incidence of myopathy. However, on the basis of Food and Drug Administration post-marketing surveys, the rate of cerivastatin-induced rhabdomyolysis appeared to be 10-fold greater than that of the other statins, despite safe pre-clinical profiles. However, no clinical trials have been performed directly comparing the rates of myotoxicity of all commercially available statins. The mechanism of statin-induced myopathy remains unclear. The prevailing theory is that lipophilic statins lead to depletion of intermediates normally formed after cholesterol synthesis within myocytes. Risk factors for the development of myopathy include drug interactions (especially with fibrates) and the coexistence of conditions known to predispose patients to rhabdomyolysis. CONCLUSION: The cerivastatin experience emphasizes the need for large safety trials before drug approval and for vigilant post-marketing surveillance. Further research and sound clinical judgment may lead to the identification of high-risk individuals in whom statins should be avoided.

Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a very rare cause of endogenous Cushing's syndrome (CS). In this review, the clinical characteristics, the pathophysiology, and the management of AIMAH are described. AIMAH typically presents with overt CS, but subclinical oversecretion of cortisol has been increasingly described. The diagnosis is suspected by adrenal nodular enlargement on conventional imaging following the demonstration of ACTH-independent hypercortisolism. Final diagnosis is established by histological examination of the adrenal tissue. Bilateral adrenalectomy is the treatment of choice but unilateral adrenalectomy has been proposed in selected cases. In patients with subclinical CS, the decision to treat should be individualized. The pathophysiology of this condition has begun to be elucidated in recent years. Diverse aberrant membrane-bound receptors expressed in a non-mutated form in the adrenal gland have been found to be implicated in the regulation of steroidogenesis in AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. A protocol designed to screen patients for the presence of these aberrant receptors should be undertaken in all patients with AIMAH. The identification of these receptors provides the potential for novel pharmacological therapies by suppressing the endogenous ligands or blocking the receptor with specific antagonists.

Aberrant expression of hormone receptors in adrenal Cushing's syndrome.

In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has emerged. The ectopic or aberrant expression of G-protein-coupled hormone receptors in the adrenal cortex was found to play a central role in the regulation of cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in some unilateral adrenal adenomas. Various aberrant receptors, functionally coupled to steroidogenesis, have been reported: GIP, vasopressin, beta-adrenergic, LH/hCG, and serotonin receptors have been best characterized, but angiotensin, leptin, glucagon, IL-1 and TSH receptors have also been described. The molecular mechanisms responsible for the aberrant expression of these receptors are currently unknown. One or many of these aberrant receptors are present in most cases of AIMAH and in some cases of adrenal adenomas with overt or sub-clinical secretion of cortisol. Clinical protocols to screen for such aberrant receptors have been developed and should be performed in all patients with AIMAH. The identification of such aberrant regulation of steroidogenesis in AIMAH provides the novel opportunity to treat some of these patients with pharmacological agents that either suppress the endogenous ligand or block the aberrant receptor, thus avoiding bilateral adrenalectomy.

Collagenous colitis with spondyloarthropathy presenting as fibromyalgia syndrome.

Collagenous colitis is a newly recognized clinicopathologic entity that presents with diarrhea and weight loss. In some patients arthropathy may be a concomitant feature. We describe a patient whose initial presentation masqueraded as fibromyalgia with associated bowel symptoms, but who was finally diagnosed as having collagenous colitis and inflammatory spondyloarthropathy.