Relative Adrenal Insufficiency: Crisis Averted?

Relative adrenal insufficiency (AI) is a disease process commonly associated with preterm birth and critical illness. Further, the incidence of AI is inversely proportional to gestational age. The incidence of AI is likely underreported; however, it is reported to occur in 150–280/1,000,000 live births worldwide. Functional development of the adrenal gland does not occur until after 30 weeks of gestation; however, advances made in neonatal care increase the survivability of infants born well before this period. Among infants with AI, the adrenal gland is transiently incapable of secreting physiologic levels of cortisol in response to stressors. Common and nonspecific signs include hypotension, poor perfusion, and dysregulation of fluid, electrolytes, and euglycemia. Recognition, diagnosis, and steroid therapy is critical, as inappropriately managed AI can lead to an adrenal crisis, shock, and death. Understanding the presentation and common risk factors for developing relative AI is crucial for quick diagnosis and timely management to prevent morbidity and mortality in this vulnerable population.

38 Clinical features and echocardiographic parameters of relative adrenal insufficiency (RAI) among preterm infants: A five-year review

Primary Subject area Neonatal-Perinatal Medicine Background Infants born at low gestational age (GA) often present with a septic shock-like picture in the neonatal intensive care unit (NICU). Some of these premature infants are noticed to exhibit inadequate cortisol levels at such a time of stress, an entity termed ‘relative adrenal insufficiency’ (RAI), which is postulated to compromise the compensatory mechanisms and further circulatory collapse. Objectives To review the clinical features and echocardiographic parameters of RAI in preterm infants, and their correlation with adrenocorticotropic hormone (ACTH) stimulation tests in a quaternary NICU over 5 years. Design/Methods This is a single centre retrospective study. Infants born at < 32 weeks GA between January 2015 to June 2019, admitted to the British Columbia Women’s Hospital NICU (Vancouver, British Columbia), were reviewed. Infants who presented with a shock-like picture with a cortisol level at this time of stress of < 250 nmol/L were included. Infants who have received corticosteroid prior to cortisol collection were excluded. Results There were 798 infants < 32 weeks admitted to the BCWH NICU over a 5 year period, of which 284 had a spot cortisol drawn. We identified 45 eligible infants in our study (5.6% of NICU admissions). Their median (IQR) for GA, birth weight, cortisol level, and age of onset of RAI were 25 weeks (24, 26), 690 g (590, 815), 83 (58, 127), and 13 days of life (8, 24), respectively. Among these infants, 73% developed significant hypotension or respiratory failure (Table 1). 13 infants (28.9%) had echocardiogram performed at the time of cardiopulmonary deterioration, and all had normal left ventricular (LV) fractioning shortening (median [IQR]: 42% [38-49%]) and LV output (median [IQR]: 242 mL/kg/min [155-330 mL/kg/min]). Only 19 infants (42.2%) received hydrocortisone, with a median [range] treatment duration of 2 days [1–8]. Lower cortisol level was associated with lower GA at the presentation of RAI (p=0.049), but not predictive of adverse clinical and laboratory outcomes (Table 2). ACTH stimulation tests were performed in 20 (44.5%) infants and 3 (15%) were found to be abnormal, and results were not correlated with clinical features. Conclusion In our cohort, we identified 5% of NICU admission with RAI, based on the cut-off of cortisol < 250 nmol/L at the time of shock-like presentation. Lower cortisol level was associated with lower GA at the presentation of RAI. Further prospective study with a well-defined protocol is needed to understand the use of cortisol and its clinical implications.

Efficacy of Glucocorticoid Administration in Patients with Cardiac Arrest: A Systematic Review of Clinical Studies

Background: The pathophysiology of cardiac arrest (CA) involves over-activation of systemic inflammatory responses, relative adrenal insufficiency, and glycocalyx damage. Corticosteroids have beneficial effects in preventing the perturbation of the endothelial glycocalyx. Objectives: The aim of this systematic review was to determine the efficacy of glucocorticoids in patients with cardiac arrest. Methods: We searched PubMed, Scopus, ISI Web of Science, Google Scholar and Cochrane central register for relevant clinical trials and cohort studies until September 2019. Results: We retrieved 7 peer-reviewed published studies for the systematic review. Two studies were clinical trials evaluating 147 patients, while five illustrated cohort design, evaluating 196,192 patients. In total, 196,339 patients were assessed. There was limited evidence and conflicting results to establish a correlation between glucocorticoids and the survival of patients suffering from cardiac arrest. However, the link between these medications and survival-to-admission, survival-to discharge, and 1-year survival rates was strong and consistent in observational studies. Conclusion: The clinical evidence regarding the efficacy and safety of glucocorticoids in CA is limited to observational studies with inconsistent methodology and few clinical trials with small sample size. Nevertheless, it seems that glucocorticoid supplementation during and after cardiopulmonary resuscitation (CPR) may have significant effects in terms of survival-to-admission, survival to discharge, 1-year survival rates and an improved return of spontaneous circulation (ROSC) rate, especially in patients with hemodynamic instability and cardiovascular diseases (i.e., refractory hemodynamic shock). Future studies with high-quality, large-scale, long-term intervention and precise baseline characteristics are needed to evaluate the exact effective dose, duration, and efficacy of glucocorticoids in CA.

An Opportunity Missed: Managing an Aggressive Adrenal Cortical Carcinoma

Introduction: Adrenal cortical carcinoma (ACC) is a rare endocrine tumor with an incidence of up to 2 persons per million population. Complete surgical resection is the first-line therapy for localized tumors, while debulking surgery, radiation therapy, and/or chemotherapy may also be options for palliation in advanced ACC. Biochemical and radiographic evaluation of a newly discovered adrenal mass maximizes the opportunity for the patient to undergo a complete, margin-negative resection of the primary tumor, which is the most powerful determinate of long-term survival. Here we present the case of an extremely aggressive high grade adrenal cortical carcinoma that increased from 4 cm to 17 cm within 4 months, metastasizing to the lung, liver and left kidney prior to resection. Case summary: A 42-year-old woman presented to the Emergency Department (ED) with abdominal pain and was found to have hypokalemia and an incidental left adrenal mass measuring 4.9 x 4.6 cm. She was discharged home with instructions to follow up with her primary care physician for further workup. Unfortunately, she was lost to follow-up for 3 months. Her initial biochemical evaluation at follow-up did not show evidence of adrenal insufficiency or elevated metanephrines. A repeat outpatient CT chest abdomen pelvis revealed increased tumor size to 12.3 x 10.8 x 12.5 cm, with unclear renal vs adrenal origin, and multiple liver and lung metastases. She subsequently underwent left radical nephrectomy, adrenalectomy, splenectomy as well as a partial diaphragmatic resection 4 months after her initial ED presentation. The surgical specimen measured 17 x 11.5 x 8 cm. Endocrinology was consulted post-operatively to evaluate for relative adrenal insufficiency given hypotension & altered mental status. Further evaluation revealed new-onset hirsutism, male-pattern hair loss, proximal muscle weakness, and significant weight loss over the prior 3 months. Post-operative laboratory evaluation was significant for sustained hypokalemia of 2.4 mmol/L, 24 hour urine cortisol of 1326 mcg/24 hr (normal 3.5–45), as well as elevated DHEA-S of 994 mcg/dL (normal 27–240), and testosterone of 294 ng/dL (normal 10–75). Surgical pathology demonstrated a high-grade adrenal cortical carcinoma. Oncology was consulted and the patient was started on spironolactone for the hypokalemia, but declined any further therapy for her ACC and subsequently died 2 weeks later. Conclusion: This case illustrates how ACC can behave aggressively and further emphasizes the need for timely and complete biochemical evaluation of adrenal incidentalomas. This is particularly true with the presence of suspicious radiologic features such as size more than 4 cm and heterogeneous appearance. All patients with an adrenal incidentaloma should undergo biochemical and imaging evaluation, guided by thorough history-taking and physical exam, to ensure optimal outcomes.

Adrenal Insufficiency Presenting as Hypoglycemia & Hyponatremia in a Patient With Liver Cirrhosis; Hepatoadrenal Syndrome

Hepatoadrenal syndrome is described as a progressive impairment in the adrenocortical reserve in advanced liver disease resulting in relative adrenal insufficiency (AI). This can present as critical hypoglycemia and hyponatremia as in the case described. 54 year old male with past medical history of hypothyroidism, pericardial effusion, liver cirrhosis and prior alcohol use disorder presented to the hospital with altered mental status. He felt lethargic and complained of recurrent diarrhea for a month. His blood sugar was 30 mg/dl (n=70–140 mg/dl) for which he received dextrose and his mentation improved. He was hypothermic with stable vitals otherwise. There was no skin hyperpigmentation. Labs demonstrated sodium of 123 mmol/L (n=136–145 mmol/L) and pancytopenia. TSH, ammonia, renal and hepatic functions were within normal limits except mildly elevated AST and total bilirubin. Total protein, albumin, HDL, Insulin and cortisol levels were low. Hepatitis panel was negative. CT Chest, abdomen and pelvis revealed massive abdominopelvic ascites, hepatic cirrhosis and splenomegaly. Adrenal glands appeared normal. Urine studies were consistent with salt-wasting nephropathy. Patient was started on intravenous fluids as well as dexamethasone. Diagnostic and therapeutic paracentesis was performed. Cosyntropin stimulation test revealed a baseline AM cortisol of 2.0 ug/dl (n=4.3–22.4 ug/dl), 30 min value of 4.0 ug/dl and 60 min value of 5.8 ug/dl (n=18-22ug/dl). Delta cortisol level was also low. Treatment with hydrocortisone was initiated until ACTH levels became available. To rule out sarcoidosis, ACE levels were obtained, which were normal. Dihydroxy 1,25 Vitamin D levels were low. ACTH returned as 21.7 pg/ml (n=7.2–63.3 pg/ml). 21 hydroxylase antibody was negative. MRI brain with IV contrast demonstrated no pituitary mass or abnormality. Blood cultures, body fluid cultures, AMA and ASMA were negative. Anti- tTG and Anti Gliadin antibodies were positive confirming celiac disease. Patient was started on gluten free diet which resolved his diarrhea. He responded well to steroids however, he remained intermittently confused which was thought to be related to hypoglycemic brain injury. Patient was converted to hydrocortisone PO 20 mg in AM and 10 mg in PM and advised to follow up outpatient with endocrinologist and gastroenterologist. Hepatoadrenal syndrome is an important differential to consider in patients with liver disease presenting with hypoglycemia and hyponatremia. It is a potentially life-threatening condition requiring immediate treatment and appropriate work up. The condition improves with corticosteroid replacement therapy. Reference: Anastasiadis SN, Giouleme OI, Germanidis GS, Vasiliadis TG. Relative adrenal insufficiency in cirrhotic patients. Clin Med Insights Gastroenterol. 2015;8:13–17. Published 2015 Mar 2. doi:10.4137/CGast.S18127

STUDY OF ADRENAL INSUFFICIENCY IN SEVERE FALCIPARUM MALARIA WITH SHOCK KEY WORDS: Falciparum Malaria, Shock, Adrenal

Malaria remains a serious health problem in South East Asian Region (SEAR) with nearly 290 million people are estimated to be at high risk.India accounts for 77% of the regional total malarial cases.Most of deaths in malaria are due to severe falciparum malaria. Odisha is a unique state in the eastern region of India, which contributes 4% of the population and counting up to >40% of total falciparum malaria cases of India. Malaria is one of the most important public health disease in Odisha. In spite of such an important disease, there are many areas on severe falciparum malarias where research work is scanty. One among of them is detection of relative adrenal insufficiency in severe falciparum malaria. As there is limited work about the relative adrenal insufficiency in severe falciparum malaria with shock and its relation to mortality. This study has been undertaken with the following aims and objectives, firstly detection of relative adrenal insufficiency in severe falciparum malaria with shock and secondly to establish the relation of mortality with or without adrenal insufficiency in severe falciparum malaria.The present study has established that relative adrenal insufficiency is an important cause contributing to shock and increased mortality. Thus addition of corticosteroid saves life and must be used in the relative adrenal insufficiency. However the firm diagnosis of relative adrenal insufficiency depends upon estimation of basal serum cortisol level & post ACTH serum cortisol level. As corticosteroid reduces the mortality rate, it should be empirically used in critically ill severe falciparum malaria cases with shock.

The Adrenal Cortex, an Underestimated Site of SARS-CoV-2 Infection

BackgroundThe majority of the critically ill patients may have critical illness-related corticosteroid insufficiency (CIRCI). The therapeutic effect of dexamethasone may be related to its ability to improve cortical function. Recent study showed that dexamethasone can reduce COVID-19 deaths by up to one third in critically ill patients. The aim of this article is to investigate whether SARS-CoV-2 can attack the adrenal cortex to aggravate the relative adrenal insufficiency.MethodsWe summarized the clinical features of COVID-19 reported in currently available observational studies. ACE2 and TMPRSS2 expression was examined in human adrenal glands by immunohistochemical staining. We retrospectively analyzed serum cortisol levels in critically ill patients with or without COVID-19.ResultsHigh percentage of critically ill patients with SARS-COV-2 infection in the study were treated with vasopressors. ACE2 receptor and TMPRSS2 serine protease were colocalized in adrenocortical cells in zona fasciculata and zona reticularis. We collected plasma cortisol concentrations in nine critically ill patients with COVID-19. The cortisol levels of critically ill patients with COVID-19 were lower than those in non-COVID-19 critically ill group. Six of the nine COVID-19 critically ill patients had random plasma cortisol concentrations below 10 µg/dl, which met the criteria for the diagnosis of CIRCI.ConclusionWe demonstrate that ACE2 and TMPRSS2 are colocalized in adrenocortical cells, and that the cortisol levels are lower in critically ill patients with COVID-19 as compared to those of non-COVID-19 critically ill patients. Based on our findings, we recommend measuring plasma cortisol level to guide hormonal therapy.