Corticosteroid Management of Coronavirus 2019 (COVID-19) in Patients with Bilateral Adrenalectomy

Since the World Health Organization (WHO) announced coronavirus 2019 (COVID-19) as a pandemic in March 2020, it has been wreaking havoc across countries, affecting people’s lives. Corticosteroids have proven to provide a mortality benefit in patients with COVID-19. Although dexamethasone is the most commonly used glucocorticoid and have shown to have mortality benefit in COVID-19 patients, it cannot be used in patients with adrenal insufficiency due to its lack of mineralocorticoid activity. Herein, we discuss a case of challenging corticosteroid management in a patient with COVID-19 complicated by her medical history of bilateral adrenalectomy.

Prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with cushing’s disease: a systematic review and meta-analysis

Purpose Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources Systematic literature search in four databases. Study Selection Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)]. Conclusions Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

Can Extra Adrenal Cortisol Secretion Occur in an Adrenalectomized Patient?

Background: Established medical practice is that adrenalectomized patients require lifelong steroid replacement. We report a case which challenges that assumption. Clinical Case: A 38 year old female underwent transsphenoidal resection of a proven ACTH secreting pituitary adenoma. Post operatively her pituitary function was preserved, but due to residual tumour activity and the desire to preserve fertility, she had a bilateral adrenalectomy one year later and commenced hydrocortisone replacement. Subsequent pituitary imaging did not show recurrence of the tumour and her visual fields were stable, however her ACTH remained elevated at 100 and 130ng/L (09:00 &lt;50 ng/L) despite steroid replacement.14 years after adrenalectomy she noticed weight gain and increased body hair. She also reported sometimes missing her hydrocortisone due to her busy job without ill effects. Her 9 am cortisol pre-hydrocortisone was elevated at 333 nmol/L (9am: 140–690 nmol/L) with ACTH of 203.0 ng/L (09:00 &lt;50ng/L) She was able to suppress cortisol normally after a Dexamethasone suppression test. CT of her adrenals found no adrenal tissue. By now she had weaned herself off hydrocortisone, keeping an emergency supply. SST showed a cortisol of 320 nmol/L at 30 minutes, 360 nmol/L at 60 minutes with an elevated ACTH of 140 ng/L (09:00 &lt;50 ng/L). Her weight gain and body hair growth stabilised. Discussion: We have demonstrated that this adrenalectomized patient has ACTH driven endogenous cortisol secretion which may be due to residual adrenal tissue due to seeding after surgery or the presence of steroid synthesis elsewhere. Extra adrenal sources for glucocorticoid production are known such as skin, gonads and thymus. However, the levels are insufficient to mount a significant stress response. There is evidence of adrenal regeneration in adrenalectomized animals. The regeneration is primarily of the adrenal cortex and does not involve the medulla. There has been one case report in literature of a 11 year old German boy who had adrenal regeneration detected on adrenal scintigraphy (Bilateral normal adrenal glands with normal activity) 13 years after adrenalectomy for Cushing’s disease. References: Gotlieb N, Albaz E, Shaashua L, et al. Regeneration of Functional Adrenal Tissue Following Bilateral Adrenalectomy. Endocrinology. 2018;159(1):248–259. doi:10.1210/en.2017-00505 Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab. 2011;301(1):E11-E24. doi:10.1152/ajpendo.00100.2011

Cushing Syndrome in Carney Complex: Unilateral or Bilateral Adrenalectomy?

Carney Complex (CNC) is a rare multiple endocrine syndrome dueto PRKR1A germline mutations. Primary pigmented nodular adrenal disease (PPNAD), the most frequent manifestation of the disease is responsible for non-ACTH dependent Cushing syndrome and bilateral adrenalectomy is the recommended treatment. We had followed up a CNC family with mainly Cushing syndrome disease secondary to PPNAD for more than 40 years over 2 generations. Six members carry the disease and present a germline mutation of PRKR1A, 4 women and 2 men. One patient accidently died one year after surgery and the others 5 patients were regularly followed up. The index case, a 25 years woman, was diagnosed with Cushing syndrome in 1972 with hyperandrogenism, short stature and mild manifestations of hypercortisolism. Unilateral adrenalectomy was performed on the side of a nodular adrenal and pathology described PPNAD. Her sister was subsequently diagnosed and treated the same way. The 2 sisters did well, with pregnancies for both of them but different post surgery hormonal results. The index case had partial cortisol deficiency with persistent low cortisol level at 108 nmol/L. Her sister presented a moderate increase in cortisol in the evening or after dexamethasone at 306 nmol/L at last evaluation. The only events possibly associated to hypercortisolism in this patient were central overweight and three episodes of spontaneous pulmonary embolism and veinous thrombosis. Their 2 brothers were evaluated at 17 and 39 years while they developed cushing syndrome signs (round face, HTA, amyotrophy and fatigability). As CNC have been recognized at this time by Dr Carney, bilateral adrenalectomy was performed in one patient who died accidentally a few months later. His brother chose unilateral adrenalectomy on the side of the macronodular gland, recovered hypercortisolism signs and still needs adrenal substitution. The daughter of the index case demonstrated at 21 years old a mild Cushing syndrome and chose unilateral adrenalectomy like her mother. Symptoms resumed without any recurrence during 20 years follow up. The daughter of the patient II.2 was diagnosed earlier at seven years of age because she developed hyperandrogenism, central weight gain and growth arrest due to Cushing syndrome. Bilateral adrenalectomy was successfully performed and adrenal substitution was prescribed. Surprisingly, adrenal function seemed to recover 5 to 6 years post surgery and treatment was decreased then stopped. Adrenal CT scan did not show any residual gland but noriodocholesterol scintigraphy confirmed bilateral adrenal uptake. She is now mother of 2 and present a near normal cortisol circadian rythm without any treatment. Finally, we showed in this long-term study that unilateral adrenalectomy in PPNAD could be an option for the treatment of mild Cushing syndrome in adults. Recovery after bilateral adrenalectomy occurred in one patient.

Resistant Hypertension Due to Familial Hyperaldosteronism Type III: First Report From Indian Sub-Continent

Background: Familial hyperaldosteronism type III (FH-III) is caused by germline mutations in KCNJ5 gene. FH-III presents with phenotypic variability from spironolactone-responsive hypertension to massive adrenal hyperplasia requiring bilateral adrenalectomy. Till date, seven different pathogenic mutations in KCNJ5 gene have been identified. Here we describe a sporadic FH-III case, due to a Gly151Arg mutation, first from Indian subcontinent, presenting with extremely high plasma aldosterone concentration (PAC) values, further expanding our knowledge of this rare condition. Clinical Case: A 24-year-old female, symptomatic since age of 5 years with periodic limb weakness and gradual increase in frequency of episodes over the years. Her blood pressure (BP) was recorded for first time at 9 years of age, and it was 170/110 mm Hg. On evaluation at this time, PAC was highly elevated at 1007 ng/dL and plasma renin activity (PRA) was suppressed at 0.04 ng/ml/h with aldosterone renin ratio (ARR) of 25,175 ng/dL per ng/mL/h (&gt;20 suggestive of primary aldosteronism). CT scan demonstrated mild enlargement of bilateral adrenal glands. A presumptive diagnosis of Glucocorticoid-remediable aldosteronism was made. She was started on dexamethasone, spironolactone and nifedipine but was not improved. Dexamethasone was stopped after 1 year of initiation. Before presenting to our referral center in 2018, she was having uncontrolled hypertension with recurrent episodes of hypokalemic paralysis. She was on maximal doses on four antihypertensive agents, further increased to six agents (including spironolactone 100 mg BD), and potassium chloride supplementation (120 mEq/day). Despite this, she had a serum potassium of 2.6 mEq/L. Her biochemical investigations demonstrated that PAC was 2070 ng/dL, direct renin concentration (DRC) was 2.35 µIU/mL (PRA 0.2 ng/ml/h) and ARR was 880.9 ng/dL per µIU/mL. CT scan revealed massive bilateral adrenal hyperplasia. Genetic analysis by whole exome sequencing detected KCNJ5 (p.Gly151Arg) mutation, confirming the diagnosis of FH-III. She was subjected to bilateral adrenalectomy and she became normokalemic. Dramatic reduction in antihypertensives with BP control achieved only on amlodipine post-operatively. Genetic testing of family members was not done but they were normotensive and normokalemic. Histopathological examination revealed bilateral adrenal hyperplasia. PAC levels up to 297 ng/dL have been described previously in FH-III but our patient had exceedingly high-level of 2070 ng/dL. Conclusion: This case demonstrates florid clinical and biochemical manifestations of FH-III and gradual worsening of symptoms, consistent with progression of disease with age. It illustrates that proper investigations and treatment can lead to remission of symptoms. Further studies are warranted to elucidate the full clinical and biochemical spectrum of FH-III.

Laparoscopic Bilateral Adrenalectomy Should Be an Early Consideration in Ectopic Adrenocorticopic Hormone Secretion

Introduction: Ectopic ACTH secretion (EAS) causes myriad metabolic derangements which may be effectively managed with laparoscopic bilateral adrenalectomy (LBA) in fit-for-surgery candidates. Clinical Case: A 67-year old woman with a remote 12-pack year smoking history presented with unintentional weight loss, cough, fever and chest pain. Imaging revealed a right-sided lung mass with liver lesions. Liver biopsy confirmed a well-differentiated neuroendocrine tumour (NET). Attempt at palliative lung resection was aborted due to disease extent. She was treated with multiple courses of chemotherapy but her disease progressed. Two years later, she presented with hypokalemia of 2.8 mmol/L (3.5 - 5.0 mmol/L) and uncontrolled hypertension. She was treated with spironolactone and oral potassium. She was notably hyperglycaemic with clinical features of cortisol excess. A random cortisol of 2742 nmol/L (&lt;500 nmol/L), corresponding ACTH of 201 ng/L (5 - 50 ng/L) and lack of diurnal variation in cortisol day curve were in keeping with EAS. Metyrapone and spironolactone normalised blood pressure and biochemical derangement. With her initially high cortisol levels and its associated immunocompromised state, she developed pneumocystis jirovecii pneumonia (PCP), and was briefly admitted to the intensive care unit. In hospital, monitoring her response to EAS management necessitated multiple blood investigations, which proved burdensome for the patient. To effect definitive management of EAS and reduce invasive monitoring, she wished to have LBA and underwent an uneventful procedure. She was discharged on fludrocortisone and hydrocortisone along with lanreotide for primary disease management. Metyrapone and spironolactone were stopped. At initial outpatient follow up, she had normal blood pressure and electrolytes. By her report, her quality of life had improved tremendously, given the reduced need for multiple clinic visits and blood investigations. Unfortunately, her primary disease progressed with gradual deterioration of physical function. She died six months after LBA but, as per her desire, spent her final months with loved ones. Clinical Lesson: In patients with EAS who have unresectable primary disease but otherwise good performance status, LBA is a viable alternative to medical management and should be discussed with patients early after diagnosis. References1. Alberda et al., Endoscopic bilateral adrenalectomy in patients with ectopic Cushing’s syndrome. Surgical Endoscopy 2012; 26:1140-1145 2. Reincke et al., A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur Journal of Endocrinology 2015, 173M23-M32