How good is a morning cortisol in predicting an adequate response to intramuscular synacthen stimulation?

CONTEXT: Previous studies have demonstrated that a morning serum cortisol of <100 nmol/l makes further dynamic testing such as the Synacthen stimulation test (SST) unnecessary to confirm adrenal insufficiency. The morning cortisol level that reliably predicts adrenal sufficiency (AS) is less well established, and values ranging from 300 to 500 nmol/l have been proposed. OBJECTIVE: The aim of this study was to determine the ambulatory morning cortisol level that predicts adrenal sufficiency, as defined by an adequate response to SST, using a receiver operating characteristics (ROC) curve. DESIGN: Observational retrospective cross-sectional study. METHOD & SUBJECTS: We conducted a retrospective audit of SST performed at PathWest Laboratory QEII from January 2006 to August 2008. A total of 761 results were obtained. Patients who were acutely ill or in intensive care, on glucocorticoid therapy, and those with inadequate data or multiple records were excluded from the analysis leaving 505 available for analysis. Baseline serum was obtained prior to intramuscular injection of 250 mcg Synacthen, and a second sample was obtained 30 min post-Synacthen. AS was defined as a 30-min post-Synacthen cortisol of >550 nmol/l; values ≤550 nmol/l were considered inadequate. RESULTS: Based on SST criteria, of the 505 patients included in the study, 350 patients (69%) were adrenal sufficient and 155 (31%) had adrenal insufficiency. Using the minimum ROC distance criterion, a basal cortisol value of >236 nmol/l was identified to predict AS with sensitivity 84% and specificity 71%. However, to increase the specificity to 95%, we recommend a basal cortisol cut-off of >375 nmol/l. For patients with known pituitary disease (n = 152), basal cortisol of >214 nmol/l (sensitivity 85% and specificity 71%) may obviate the need for SST in the appropriate clinical context, although 330 nmol/l gives a specificity of 95%. CONCLUSION: Basal morning cortisol is a viable first step in the evaluation of patients with suspected adrenal insufficiency.

Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion: This study shows the importance of examining patient's family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister's unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.