Mineralocorticoid hypertension and hypokalaemia induced by posaconazole

We describe severe hypokalaemia and hypertension due to a mineralocorticoid effect in a patient with myelodysplastic syndrome taking posaconazole as antifungal prophylaxis. Two distinct mechanisms due to posaconazole are identified: inhibition of 11β hydroxylase leading to the accumulation of the mineralocorticoid hormone 11-deoxycorticosterone (DOC) and secondly, inhibition of 11β hydroxysteroid dehydrogenase type 2 (11βHSD2), as demonstrated by an elevated serum cortisol-to-cortisone ratio. The effects were ameliorated by spironolactone. We also suggest that posaconazole may cause cortisol insufficiency. Patients taking posaconazole should therefore be monitored for hypokalaemia, hypertension and symptoms of hypocortisolaemia, at the onset of treatment and on a monthly basis. Treatment with mineralocorticoid antagonists (spironolactone or eplerenone), supplementation of glucocorticoids (e.g. hydrocortisone) or dose reduction or cessation of posaconazole should all be considered as management strategies

Challenges and benefits of endogenous steroid analysis by LC-MS/MS

Quantification of endogenous hormonal steroids and their precursors is essential for diagnosing a wide range of endocrine disorders. Historically, these analyses have been carried out using immunoassay, but such methods are problematic, especially for low-concentration analytes, due to assay interference by other endogenous steroids. MS offers improved specificity over immunoassay and can be highly sensitive. GC–MS, with use of stable isotopically labeled internal standards, is considered the ‘gold standard’ method for serum steroid analysis. GC–MS is the method of choice for profiling steroid metabolites in urine, but these techniques are not appropriate for routine use in clinical laboratories owing to a need for extensive sample preparation, as well as analytical expertise. LC–MS/MS compares well to GC–MS in terms of accuracy, precision and sensitivity, but allows simplified sample preparation. While most publications have featured only one or a limited number of steroids, we consider that steroid paneling (which we propose as the preferred term for multitargeted steroid analysis) has great potential to enable clinicians to make a definitive diagnosis. It is adaptable for use in a number of matrices, including serum, saliva and dried blood spots. However, LC–MS/MS-based steroid analysis is not straightforward, and understanding the chemical and analytical processes involved is essential for implementation of a robust clinical service. This article discusses specific challenges in the measurement of endogenous steroids using LC–MS/MS, and provides examples of the benefits it offers. </jats:p

Posaconazole-Induced Hypertension Masquerading as Congenital Adrenal Hyperplasia in a Child with Cystic Fibrosis

Background. Deficiency of 11β-hydroxylase is the second most common cause of congenital adrenal hyperplasia (CAH), presenting with hypertension, hypokalaemia, precocious puberty, and adrenal insufficiency. We report the case of a 6-year-old boy with cystic fibrosis (CF) found to have hypertension and cortisol insufficiency, which were initially suspected to be due to CAH, but were subsequently identified as being secondary to posaconazole therapy. Case Presentation. A 6-year-old boy with CF was noted to have developed hypertension after administration of two doses of Orkambi™ (ivacaftor/lumacaftor), which was subsequently discontinued, but the hypertension persisted. Further investigations, including echocardiogram, abdominal Doppler, thyroid function, and urinary catecholamine levels, were normal. A urine steroid profile analysis raised the possibility of CAH due to 11β-hydroxylase deficiency, and a standard short synacthen test (SST) revealed suboptimal cortisol response. Clinically, there were no features of androgen excess. Detailed evaluation of the medical history revealed exposure to posaconazole for more than 2 months, and the hypertension had been noted to develop two weeks after the initiation of posaconazole. Hence, posaconazole was discontinued, following which the blood pressure, cortisol response to the SST, and urine steroid profile were normalized. Conclusion. Posaconazole can induce a clinical and biochemical picture similar to CAH due to 11β-hydroxylase deficiency, which is reversible. It is prudent to monitor patients on posaconazole for cortisol insufficiency, hypertension, and electrolyte abnormalities

The impact of mitotane therapy on serum free proteins in patients with adrenocortical carcinoma

Adrenocortical Carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or in the absence of surgery to attenuate progression.Aims: To evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort.Methods: Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels noted to be sub-/supra-/therapeutic. Data were tested for normality, reported as Means ± SD, and compared to other two cohorts using paired-sample t-test with 5% p-value for significance and 95% confidence interval (CI).Results: Patients on mitotane therapy had higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI:33.6, 125.4nmol/L), therapeutic: 85.3 (95% CI:37.1-133.6nmol/L), supra-therapeutic: 75.7 (95% CI: -19.3,170.6nmol/L): adrenal neoplasm 25.5 (95% CI:17.5,33.5nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-/therapeutic plasma mitotane and adrenal neoplasm groups.Conclusion: Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. While there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect