Low-dose short synacthen test with salivary cortisol in patients with suspected central adrenal insufficiency

Context The low-dose short synacthen test (LDSST) is recommended for patients with suspected central adrenal insufficiency (AI) if their basal serum cortisol (F) levels are not indicative of an intact hypothalamic–pituitary–adrenal (HPA) axis. Objective To evaluate diagnostic threshold for salivary F before and 30 min after administering 1 μg of synacthen, performed before 09:30 h. Design A cross-sectional study from 2014 to 2020. Setting A tertiary referral university hospital. Patients In this study, 174 patients with suspected AI, 37 with central AI and 137 adrenal sufficient (AS), were included. Main outcome measure The diagnostic accuracy (sensitivity (SE), specificity (SP)) of serum and salivary F levels measured, respectively, by chemiluminescence immunoassay and liquid chromatography-tandem mass spectrometry. Results Low basal serum or salivary F levels could predict AI. For the LDSST, the best ROC-calculated threshold for serum F to differentiate AI from AS was 427 nmol/L (SE 79%, SP 89%), serum F > 500 nmol/L reached SP 100%. A salivary F peak > 12.1 nmol/L after administering synacthen reached SE 95% and SP 84% for diagnosing central AI, indicating a conclusive reduction in the likelihood of AI. This ROC-calculated threshold for salivary F was similar to the 2.5th percentile of patients with a normal HPA axis, so it was considered sufficient to exclude AI. Considering AS those patients with salivary F > 12.1 nmol/L after LDSST, we could avoid unnecessary glucocorticoid treatment: 99/150 subjects (66%) had an inadequate serum F peak after synacthen, but salivary F was >12.1 nmol/L in 79 cases, who could, therefore, be considered AS. Conclusions Salivary F levels > 12.1 nmol/L after synacthen administration can indicate an intact HPA axis in patients with an incomplete serum F response, avoiding the need to start glucocorticoid replacement treatment.

The Majority of Inpatient Short Synacthen Tests Are Performed Incorrectly, Due to Imprecise Timing, Incorrect Sampling and Failure to Interrupt Steroid Administration

Introduction: The short synacthen test (SST) is commonly used to assess adrenal function. Accurate timing and appropriate holding of exogenous steroids are essential to ensure correct interpretation of results. Aims & Methods: We reviewed all SSTs performed on inpatients in our hospital over a 1-year period, in order to determine accuracy of testing. Results: 42 patients (Male 15, Female 27), with mean age 68 years (range 43–90), underwent SST. The majority (39/42; 93%) of tests were requested by internal medicine physicians. The indications for testing were; suspected adrenal insufficiency (18), HPA axis suppression (9), fatigue (7), hyponatremia (5), suspected pituitary disease (2) and vomiting (1). 7 (44%) of the 16 patients taking steroids did not have medication appropriately held. 31 (74%) patients did not have serum ACTH measured prior to the test. 28 (66%) tests were not started at the correct time. Only 10 (24%) of the 30 minute samples were completed within the 25-35min sample window. The mean time between the 0min and 30min samples was 42mins (median 62mins; range 0-209mins). 12 (29%) tests involved an unnecessary 60min sample. 8 (19%) tests had no interpretation of results documented in the medical notes. 4 (10%) patients underwent repeat testing, necessitated by an incorrect first test. Discussion: The vast majority of inpatient SSTs (33/42;79%) were performed suboptimally, with the most common errors pertaining to incorrect timing of the test, inaccurate sampling and inappropriate pre-test steroid administration. Considering these errors, some results may have been interpreted incorrectly. Repeat tests were recognised as required in 10% of patients, with associated inconvenience, cost and discomfort. Improved training and guidelines for performing SSTs should be available to hospital staff to ensure more accurate application of the test.

Predictive Accuracy of Delta Cortisol on Recovery of Adrenal Function in Patients With Drug Induced Cushing’s Syndrome With Secondary Adrenal Insufficiency

There is a growing concern upon the finding of many drug induced Cushing’s syndrome because of inadvertent use of glucocorticoids (GC) either prescribed or as alternative medicine in Myanmar. These patients are presenting with diversity of clinical problems ranging from hypertension, diabetes to acute adrenal crisis due to hypothalamic-pituitary-adrenal (HPA) axis suppression and secondary adrenal insufficiency (AI). The present study aimed to assess the delta cortisol (the degree of cortisol increments) during the first short Synacthen test (SST) as a factor predictive of adrenal function recovery in patients with drug induced Cushing’ syndrome with secondary AI and to determine the proportion of patients who recovered from AI within six-month follow-up. This was a hospital based prospective analytical study that enrolled a total of 52 patients with drug induced Cushing’s syndrome with secondary AI from January 2018 to June 2019. Secondary AI is defined by morning basal serum cortisol ≤ 400 nmol/L with Synacthen stimulated peak cortisol level ≤ 550 nmol/L and serum ACTH < 60 pg/ml. The follow-up SSTs were performed at three-month and six-month after first SST, and the patients with morning basal serum cortisol > 400 nmol/L (or) Synacthen stimulated peak serum cortisol > 550 nmol/L during follow-up SSTs are defined as recovered adrenal function group. In this study, a total of 52 patients were treated with modified regimen of physiological dose of prednisolone with tapering schedule or stress dose GC based on the basal serum cortisol levels up to six months. Among them, nearly half (n=25 / 48.1%) of the patients with drug induced Cushing’s syndrome with secondary AI achieved normal adrenal function within six-month follow-up. It was found that mean values for delta cortisol were not statistically significant between recovered and non-recovered groups, 118.6 nmol/L (SD 72.3) and 97.2 nmol/L (SD 64.2) respectively. The delta cortisol during the first SST could not predict strongly (AUC - 0.6, 95% CI - 0.44 to 0.76, P = 0.2) the recovery of adrenal function in patients with drug induced Cushing’s syndrome with secondary AI and it was inconsistent with previous studies. The older age of the patients, oral route of administration of drugs causing Cushing’s syndrome and comorbid hypertension were found to be more significant in the non-recovered group. In conclusion, the present study did not support the evidence that the delta cortisol during the first SST could predict adrenal function recovery in patients with drug induced Cushing’ syndrome with secondary AI. Reference: (1) Baek et al., 2016; Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary AI. Endocrinol Metab.31, pp. 153–160. (2) Pofi et al., 2018; The Short Synacthen Test Can Be Used to Predict Recovery of HPA Axis Function. J Clin Endocrinol Metab.103(8), pp. 3050–3059.

Long-Term Corticotroph Function Following Cure of Cushing’s Syndrome

Introduction: Hyper- and hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in Cushing’s syndrome (CS) and Addison’s disease (AD) is associated with disturbances of classical feedback mechanisms. Time to recovery of adrenal function after CS remission depends on the etiology of CS and is longest after adrenal CS. To date there are no data on the recovery of corticotroph function following CS remission, and the synacthen test is recommended for testing adrenal function in patients with hypopituitarism. Aim Here we aim to test corticotroph function after long-term cure of Cushing’s syndrome following bilateral adrenalectomy (BADx), compared to patients with primary glucocorticoid deficiency due the presence of 21-hydroxylase antibodies or adrenoleucodystrophy, a pathophysiological model of glucocorticoid and mineralocorticoid deficiency. Methods: We retrospectively evaluated data from patients with CS and AD attending our endocrine department between 2000 and 2020, using the following inclusion criteria: BADx performed for pituitary/ectopic/adrenal or occult CS or primary adrenal insufficiency confirmed either by the presence of 21-hydroxylase antibodies or genetically in adrenoleucodystrophy. Results: Full data were available for 93 patients: 43 patients with BADx due to CS (18 patients with pituitary CS, 14 patients with adrenal CS and 11 patients with ectopic/occult CS, F:M 29:14, mean age at BADx 45.4 years age range 13-74 years) and 50 patients with AD (47 cases with positive 21-hydroxylase antibodies, 3 cases with adrenoleucodystrophy, F:M ratio 27:23, mean age at diagnosis 35 years, age range 6-57 years). The observation period was 537.5 patient-years after BADx (mean 12.5 years, range 1-38 years) and 647 patient-years following AD diagnosis (mean 14.2 years, range 1-46 years). At the last visit, there were no differences between the hormone substitution regimes between the groups. ACTH concentrations during the whole observation period and also at the last visit were lowest in patients with adrenal CS (56.5 pg/ml) when compared to patients with AD (487 pg/ml, p<0.001), or with patients with pituitary CS (377.5 pg/mL, p=0.011). ACTH values in patients with AD in long-term follow-up were significantly higher when compared to all patients with CS (141 pg/mL, p<0.001). Conclusion: These data highlight a long-term defective corticotroph function in patients with CS following BADx. Low ACTH concentrations long term after BADx for adrenal CS corroborate that corticotroph function fails to recover after CS cure. In the light of these findings, the utility of the synacthen test for excluding secondary/tertiary adrenal insufficiency following CS remission is disputable and remains to be evaluated in future studies dedicated to CS cohorts.

What is the Value of the 60 Minute Cortisol Measurement in the Short Synacthen Test (SST)? Evidence for the Defence

The Short Synacthen Test is the way that we most often determine whether people’s adrenal glands are working. We here have shown that an extra blood sample taken at 60 minutes post Synacthen vs a 30 minute sample alone, may make the test more effective at excluding those people who do not need to go on hydrocortisone supplementation or need further evaluation.

Addison’s disease with primary hypothyroidism in a case of visceral leishmaniasis and HIV coinfection

A 41-year-old man presented with vomiting and loose stools. He had a history of long-term intermittent fever, generalised skin hyperpigmentation, dragging sensation in the left hypochondrium and unintentional weight loss. He was receiving combination antiretroviral therapy since 2010 for HIV infection. He also received antitubercular therapy for tuberculous spondylitis. During the hospital stay, he was found to have postural hypotension, hypoglycaemia, hyponatraemia, hyperkalaemia, pancytopenia, hypothyroidism, hyperglobulinaemia and hypoalbuminaemia with reversal of serum albumin/globulin ratio. The morning plasma cortisol was lower than normal and could not be appropriately stimulated after the Synacthen test. The bone marrow histopathology was suggestive of visceral leishmaniasis. He was diagnosed as a case of visceral leishmaniasis and HIV coinfection with primary adrenal insufficiency (Addison’s disease) and primary hypothyroidism, as a rare and unusual presentation.

Bilateral adrenal haemorrhage complicated by sepsis, coagulopathy, influenza A and adrenal crisis

Bilateral adrenal haemorrhage is a rare and often fatal condition that most commonly occurs under conditions of severe physiological stress. We describe a 33-year-old male patient with ulcerative colitis who presented with acute worsening epigastric pain, vomiting and raised inflammatory markers. Initial differentials included gastritis and peptic ulceration. Gastroscopy revealed no abnormalities. By day 3, he had developed sepsis with a sequential organ failure assessment score of 2 as well as coagulopathy. A subsequent CT scan diagnosed bilateral adrenal haemorrhage. A short Synacthen Test confirmed adrenal insufficiency and he was treated with replacement steroids and antibiotics for a possible urinary tract infection or pyelonephritis and he recovered well. Several days later he developed fever, dyspnoea and a productive cough. Subsequently, he became hypotensive (Blood Pressure (BP) 95/65 mm Hg) and unresponsive with a Glasgow Coma Scale of 7 and was hyponatraemic and hyperkalaemic. He was intubated and transferred to a tertiary hospital for intensive care unit management where investigations confirmed the patient to be influenza A positive.

Adrenal haemorrhage as a complication of COVID-19 infection

We report an unusual complication of COVID-19 infection in a 53-year-old Caucasian man. He presented with shortness of breath, fever and pleuritic chest pain. A CT pulmonary angiogram (CTPA) demonstrated acute bilateral pulmonary embolism and bilateral multifocal parenchymal ground glass change consistent with COVID-19 (SARS-CoV-2) infection. Right adrenal haemorrhage was suspected on the CTPA which was confirmed on triple-phase abdominal CT imaging. A short Synacthen test revealed normal adrenal function. He was treated initially with an intravenous heparin infusion, which was changed to apixaban with a planned outpatient review in 3 months’ time. He made an uncomplicated recovery and was discharged. Follow-up imaging nearly 5 months later showed near complete resolution of the right adrenal haemorrhage with no CT evidence of an underlying adrenal lesion.