Congenital Adrenal Hyperplasia: Diagnostic Pitfalls in Prolonged Neonatal Jaundice

Congenital Adrenal Hyperplasia (CAH) is a genetic disorder that leads to cortisol deficiency. However, prolonged neonatal jaundice is a rare presentation of CAH. The pathophysiology of hyperbilirubinemia in CAH is still ill-defined. Plausible causes are related to the synthesis of bile, maturity of the liver and adrenal function. This case reported a neonate who presented with severe prolonged jaundice that lasted for more than a month. A short Synacthen test confirmed diagnosis of CAH. He was started on steroid replacement. He had regular follow-up under paediatric endocrinologist and primary care physician for long-term monitoring and overall health care. This case demonstrates the importance of recognizing the clinical and biochemical features of CAH for early detection and referral. Long-term follow-up and monitoring is necessary due to the risk of complications and side effects of medications. This is the first case of CAH presented with persistent hyperbilirubinemia to be reported from Malaysia. The case describes the difficult workup that has been encountered in the patient’s care and management.

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.

A Rare Cause of Severe Hypoglycaemia

A 67-year old woman presented with an unwitnessed fall and decreased oral intake. She had a learning disability, hypertension, epilepsy, asthma, chronic iron deficiency anaemia, mild lymphopenia, osteoporosis and treated uterine cancer. After clinical review, she was treated for Hospital-acquired pneumonia (following a recent hospital admission) with possible aspiration. She was noted to have hyponatraemia secondary to dehydration. She was commenced on intravenous Levofloxacin and Metronidazole along with supportive care, based on antibiotic guidance due to her known allergy to penicillin.On day 3 of admission, she was found unresponsive with a capillary blood glucose of 0.6 mmol/L, which improved with 10% glucose infusion. The low blood glucose was attributed to poor oral intake. However, her serial blood sugar results demonstrated persistent hypoglycaemia for 72h needing further intravenous glucose infusions. A medication review was undertaken and Levofloxacin was discontinued. After 24hrs of discontinuation, the hypoglycaemic episode resolved. A short synacthen test showed a normal cortisol response. There were no further episodes of hypoglycaemia. Conclusion As her persistent hypoglycaemia resolved on discontinuation of Levofloxacin, a diagnosis of fluoroquinolone induced hypoglycaemia was reported to MHRA. Fluoroquinolones are thought to induce hypoglycaemia by increasing the insulin release via blockade of adenosine triphosphate-sensitive K+channels in the β cells of the pancreas. This effect may not be clinically evident in all patients because of physiologic mechanisms that regulate blood glucose levels. Health professionals should be aware of the potential risk of severe hypoglycaemia with the use of Fluoroquinolones which are a first or second-line treatment for common infective processes. Fluoroquinolones should be stopped immediately and switch to a non-Fluoroquinolones antibiotic if possible. In elderly patients with compromised oral intake or in those with other comorbidities, regular blood glucose monitoring should be carried out to avoid life-threatening hypoglycaemic episodes.

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.

Pituitary Macroadenoma Masked by Iatrogenic Adrenal Insufficiency: A Diagnostic Blind Spot

Background: Exogenous steroid use is the most common cause of central adrenal insufficiency. Depending on the duration and strength used, it may take months to years for the hypothalamic-pituitary-adrenal (HPA) axis to recover after the steroid is stopped. We report a case of iatrogenic hypoadrenalism with persistent suppression of the HPA axis for 13 years, discovered later to be due to a second pathology. Case: A 48 year old lady presented in 2005 with weight gain of 20 kg over 1 year and florid Cushingoid features. 9AM cortisol was undetectable (<12 nmol/L). History taking revealed use of oral dexamethasone at various dosages over the past 9 years for her knee pains. A diagnosis of iatrogenic adrenal insufficiency was made. She was started on hydrocortisone replacement, and was advised to stop the over-the-counter steroids. By 2011 her short Synacthen test (SST) showed much improved functioning of the HPA axis (cortisol 182 (0 min) -> 329 (30 min) -> 408 nmol/L (60 min) [N peak>500 nmol/L]), and she was back to her usual body weight. However, subsequent monitoring revealed declining trend of 9AM cortisol from 135 nmol/L (2013) -> 99 nmol/L (2014) -> 57 nmol/L (2015) -> 64 nmol/L (2016) -> 18 nmol/L (2017) [N 166–507 nmol/L]. Hydrocortisone compliance and abstinence from exogenous steroids was confirmed with the patient. The ongoing hypofunction of the HPA axis was continually attributed by multiple physicians to her history of prolonged use of dexamethasone. In 2018, at the age of 60, the lady presented with new onset headaches, blurred vision, and bitemporal hemianopia for 3 months. MRI showed a 1.8x1.8x3.5 cm (WxAPxH) pituitary mass with suprasellar extension compressing the optic chiasm. Blood tests revealed panhypopituitarism: SST cortisol 17 -> 59 -> 49 nmol/L, ACTH 2.7 pmol/L [N <10.1 pmol/L]; fT4 9.5 pmol/L [N 12–22 pmol/L], TSH 0.97 mIU/L [N 0.27–4.2 mIU/L]; LH <0.1 IU/L, FSH 0.52 IU/L (menopause at age of 48); IGF-1 27 µg/L [N 41–279 µg/L]; prolactin 17 mIU/L [N 102–496 mIU/L]. After partial excision of the mass her vision improved, but remained dependent on hydrocortisone and thyroxine supplements. The lesion was pathologically proven to be a pituitary macroadenoma. Discussion: This case presents the uncommon course of a patient who had almost recovered from iatrogenic hypoadrenalism, only to lapse back into worsened central adrenal insufficiency, as part of panhypopituitarism related to an undiagnosed pituitary mass. In retrospect, the unusually protracted state of hypocortisolemia and the atypical waxing and waning HPA axis should have alerted one to consider alternative etiologies at work. As LH-FSH and GH deficiencies commonly develop before ACTH and TSH deficiencies in most pituitary macroadenomas, a lower threshold for testing the other anterior pituitary hormones followed by imaging of the pituitary could have picked up the tumor earlier in this patient.

Anterior Pituitary Failure in Patients with Granulomatous Inflammation

Introduction: Langerhan cell histiocytosis (LCH) is a rare cause of eosinophilic granulomatous inflammation that can affect multiple organ systems, mainly diagnosed in children. Hypothalamic-pituitary axis involvement is well established and is the characteristic intracranial manifestation of LCH. Patients can present with several presentations including anterior pituitary axis failure; however, the most common presentation is Diabetes Insipidus (DI). Here, we present a rare case of isolated pituitary LHC in male adult. Clinical Case: 47 years old gentleman presented with 4 week history of insidious headaches associated with persistent nausea. He also noticed drooping of his left eyelid and presented to hospital with complete ptosis. His CT head did not show any abnormalities. However finding on his MRI brain were consistent with a central skull base inflammatory process centred on the pituitary, extending cranially to the chiasm and third ventricular floor as well as laterally to the cavernous sinuses. His anterior pituitary profile was as follow: LH - 0.7 U/L (1.2-8.6 U/L), FSH - 4.2 U/L (1.3-19.3 U/L), Testosterone - <0.3 nmol/L (6.1 - 27.1 nmol/L), IGF-1 - 9.8 (8.8-31), Prolactin - 197 mIU/L (56-278 mIU/L), TSH - 1.18 mU/L (0.38 - 5.33 mU/L), FT4 - 4.4 pmol/L (8.4 - 19.1 pmol/L). He underwent a Short Synacthen test with a baseline cortisol of 19 nmol/L, rising to 100 nmol/L at 30 minutes and 130 nmol/l at 60 minutes. Following initiation of high dose steroid replacement (Prednisolone 15 mg daily), Levothyroxine and Testosterone, his Prednisolone was slowly weaned to 4 mg once a day in line with an improvement in his ptosis & left temporal hemianopia. His pituitary biopsy showed infiltrates of abundant histiocytes and inflammatory cells (lymphocytes). Histiocytes were organised in a granulomatous fashion with multinucleated giant cells and eosinophils (CD 68 staining positive). Langerin stain (positive) / S100 stain (some) / CD1a (few) - cells positive, confirming a diagnosis of LCH. Additional CT (chest/abdomen/pelvis) and PET imaging confirmed no additional organ involvement. Conclusion: LCH is a rare cause of anterior pituitary failure. Limited information regarding treatment for isolated pituitary LCH is available. This case suggests that a conservative approach to successful treatment with steroids can be considered.

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.