Quick Reference for Residents: Adrenal Insufficiency Soe Naing, MD, MRCP(UK), FACE Endocrinologist Associate Clinical Professor of Medicine Director of Division of Endocrinology Medical Director of Community Diabetes Care Center UCSF-Fresno Medical Education Program Version: SN/1-22-2018 1 PHYSIOLOGY 2 INTRODUCTION The symptoms and signs of adrenal insufficiency (AI) depend upon the rate and extent of loss of adrenal function, whether mineralocorticoid production is preserved, and the degree of stress. The onset of adrenal insufficiency is often very gradual, and it may go undetected until an illness or other stress precipitates adrenal crisis. ETIOLOGY OF ADRENAL INSUFFICIENCY Adrenal insufficiency is a hormone deficiency syndrome attributable to primary adrenal diseases or caused by a wide variety of pituitary-hypothalamic disorders (Table 1). Diseases causing primary adrenal insufficiency (PAI) usually destroy the total adrenal cortex, causing a combined deficiency of glucocorticoids and mineralocorticoids and adrenal androgens, and such diseases sometimes even cause adrenal medulla deficiency. The clinical symptoms are therefore usually more prominent than in cases of secondary insufficiency and can start as an acute crisis of adrenal insufficiency. Secondary adrenal insufficiency more selectively impairs glucocorticoid deficiency so that the mineralocorticoid function is better maintained and therefore less likely to cause an acute crisis. If such diseases (Table 1) evolve gradually over time, they rarely cause an abrupt-onset adrenal insufficiency crisis, whereas acute destruction of the adrenal or pituitary gland or acute interruption of glucocorticoid therapy is more likely to cause an acute onset adrenal failure crisis. 3 4 5 CLINICAL FEATURES 6 Diagnostic tests# # Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Feb; 101(2): 364–389. 1. We suggest the standard dose (250 μg for adults) iv corticotropin stimulation (30 or 60 min) test over other existing diagnostic tests to establish the diagnosis of adrenal insufficiency. Peak cortisol levels below 18 μg/dL at 30 or 60 minutes indicate adrenal insufficiency. 2. We suggest the low dose (1 μg) corticotropin test for diagnosis of PAI only when the substance itself is in short supply. 3. If a corticotropin stimulation test is not feasible, we suggest using a morning cortisol < 5 μg/dL in combination with ACTH as a preliminary test suggestive of adrenal insufficiency (until confirmatory testing with corticotropin stimulation is available). 4. We recommend measurement of plasma ACTH to establish PAI. The sample can be obtained at the same time as the baseline sample in the corticotropin test or paired with the morning cortisol sample. In patients with confirmed cortisol deficiency, a plasma ACTH >2 fold the upper limit of the reference range is consistent with PAI. 5. We recommend the simultaneous measurement of plasma renin and aldosterone in PAI to determine the presence of mineralocorticoid deficiency. 6. We suggest that the etiology of PAI should be determined in all patients with confirmed disease. AM Cortisol <5 and/or peak cortisol <18 at ACTH stimulation test 7 8 TREATMENT 9 10 ADRENAL CRISIS 11 12 Summary of evaluation for suspected hypoadrenalism (General) 13 Evaluation and management of adrenal insufficiency in critically ill patients Ref: Evaluation and management of adrenal insufficiency in critically ill patients: disease state review. Hamrahian et al. Endocr Pract. 2017 Jun;23(6):716-725. See page 15 for critical illness- related corticosteroid insufficiency (CIRCI) 14 Critical illness-related corticosteroid insufficiency (CIRCI) Ref: [1] Guidelines for the diagnosis and management of critical illness-related corticosteroid insufciency (CIRCI) in critically ill patients: Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med (2017) 43:1751–1763 [2] UpToDate: Glucocorticoid therapy in septic shock (last updated: Jan 19, 2018) Suboptimal cortisol production during septic shock has been termed "functional" adrenal insufficiency, "relative" adrenal insufficiency, or "critical illness-related corticosteroid insufficiency (CIRCI)." It is a concept to describe impairment of the hypothalamic pituitary axis (stress response) during critical illness. It is characterized by dysregulated systemic inflammation resulting from inadequate intracellular glucocorticoid-mediated anti-inflammatory activity for the severity of the patient’s critical illness. Diagnosis: Broadly accepted consensus about diagnostic criteria for this entity is lacking. Laboratory assays of plasma cortisol concentration and response to adrenocorticotropic hormone (ACTH) stimulation are likely unreliable in critically ill patients. With this caveat in mind, international guidelines support use of a change in baseline cortisol (delta cortisol) at 60 min of <9 mcg/dL after cosyntropin (250 mcg) administration and a random plasma cortisol of <10 mcg/dL. However, in general most clinicians do not rely on laboratory testing to initiate glucocorticoid replacement therapy. Recommendation on steroid use in CIRCI: We suggest using hydrocortisone in patients with severe septic shock (defined as a systolic blood pressure <90 mmHg for more than one hour despite adequate fluid resuscitation and vasopressor administration) regardless of cortisol level. If using hydrocortisone for septic shock, we suggest using long course and low dose (e.g., IV hydrocortisone <400 mg/day for at least 3 days and typically for 5-7 days at full dose) rather than high dose and short course in adult patients with septic shock and taper the dose as guided by the clinical response. 15 .