We start this Wednesday’s Pharm and Cheese off with something unappetizing: emesis. You’re rounding on Red Team and meet a patient with a history of cholangiocarcinoma on chemotherapy who isn’t tolerating PO pending a CT scan. He has normal vitals and a benign exam, but he tells you that for the past two weeks he’s had intractable emesis, even when not eating or drinking. He initially thought it was just from chemo, but his last round was 3 weeks ago and he hasn’t improved.
You consider a broad differential that’s all refuted by normal labs and an unchanged CT scan with no signs of obstruction or worsening disease. He gets admitted as multiple rounds of antiemetics fail to improve his symptoms. You follow up a few days later and read a note from an astute GI consultant who suggests the possibility of adrenal insufficiency.
ADRENAL INSUFFICIENCY OFFENDERS
Adrenal insufficiency (AI) is often elusive, an entity that is missed in over 60% of initial cases.1 AI comes in three flavors. Primary AI, where the adrenal gland itself is the issue, most commonly from autoimmune disorders in the US (Addison’s disease), but also from trauma, malignancy, congenital adrenal hyperplasia, and infection (always think TB in our population and globally).
Secondary and tertiary AI comes from issues in the pituitary and hypothalamus glands, respectively, both leading to impaired signaling of the adrenal gland. The most common culprit of AI in general is from exogenous steroid use, as exposure gradually renders endogenous cortisol production obsolete.
Importantly, this isn’t limited to PO steroids; An estimated 5-7% of those taking chronic inhaled steroids and upwards of 50% of those receiving intra-articular steroid injections experience some degree of adrenal suppression.1 Opioids are another underappreciated perpetrator, with cortisol deficiency estimated at 10-30% in those with chronic opioid use.5-7 Other medications that interfere with adrenal function or cortisol metabolism include phenytoin, ketoconazole, rifampin, levothyroxine, and the notorious etomidate.
As cancer prevalence continues to rise, an increasingly relevant group of medications are immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Up to 10% of patients taking these medications develop endocrinopathies, most commonly thyroiditis and hypophysitis, but even isolated ACTH deficiencies are seen.2 Though less common, tyrosine kinase inhibitors can also lead to AI.3
EVASIVE AI
The reason AI so often slips past us is because the initial symptoms are vague and may include fatigue, inability to tolerate PO, abdominal pain, weight loss, muscle and joint pain. Remember the adrenal gland secretes mineralocorticoids (aldosterone) and glucocorticoids (cortisol). A lack of cortisol can cause mild hyponatremia and hypoglycemia. In primary AI, the additional lack of aldosterone can lead to hyperkalemia, hypercalcemia, and more pronounced hyponatremia; however, electrolytes may be entirely normal making this a challenging diagnosis. Cortisol also decreases eosinophils and lymphocytes, so consider AI in ill patients with eosinophilia > 300/uL or with low neutrophil:lymphocyte ratios.8
Diagnostic testing for AI includes costropin (ACTH) stimulation testing or morning cortisol levels. In the ED, one option is obtaining a random cortisol level. Though not diagnostic, a cortisol level > 20 μg/dL suggests that AI is unlikely.
SAVE A LIFE
Adrenal crisis presents as hypotension often with emesis, abdominal/flank pain, fever, and somnolence or confusion. During times of stress, cortisol becomes essential for optimal cardiac function and vascular tone, working synergistically with catecholamines, and with a half life of only 90 minutes, a lack of cortisol in critical moments can lead to rapid decompensation.4,7 This shock is often refractory to vasopressors.
During a crisis, give 100mg IV hydrocortisone up front, followed by 50mg q6 hours. In pediatric patients the dosing is 50mg/m2, but for ease, give 2-3 mg/Kg x 1 dose for children <1month, 25mg to children >1 month and <1 years, 50mg for 1-6 years, and 100mg to those >6 years. Follow this with 50mg/m2 daily in divided doses q6 hours. You should expect to see drastic improvement in hypotension and symptoms within the first 1-2 hours.7 For those not in crisis but sick with primary AI, the recommendation is to double or triple the daily hydrocortisone dose. Note that prednisone and dexamethasone have little to no mineralocorticoid activity, thus they are not recommended for known primary AI, however their glucocorticoid effects will improve symptoms if hydrocortisone isn’t available.
Start fluid resuscitation, correct glucose as needed and monitor electrolytes. Note that glucose repletion may be refractory until steroids are given, and be cautious in children and neonates who are particularly susceptible to hypoglycemia.9 Importantly, address the underlying cause of the crisis. Any type of stressor can precipitate AI, the most common being infection, however pregnancy, exercise, emotional stressors, and medications can all prompt a crisis.
CONCLUSION
Your patient was admitted to the floor where AM cortisol was < 5 μg/dL and confirmatory ACTH stim test revealed AI. The patient was started on hydrocortisone and finally started tolerating PO and was discharged home.
The main point here is to consider AI, as symptoms are often vague, and the traditional electrolyte derangements may be missed or not even present. Consider opioids, exogenous steroids, TB, check point inhibitors, cancers, auto-immune, and congenital conditions. Keep a wide differential for vomiting, including endocrinopathies like AI and DKA. In AI crisis, give 100mg hydrocortisone or 50mg/m2 in pediatric patients right away and give fluids as liberally as tolerated.
SOURCES
Lentz, S., Collier, K. C., Willis, G., & Long, B. (2022). Diagnosis and Management of Adrenal Insufficiency and Adrenal Crisis in the Emergency Department. The Journal of Emergency Medicine, 63(2), 212–220. https://doi.org/10.1016/j.jemermed.2022.06.005
Lee JH. Immune Checkpoint Inhibitor-Related Hypophysitis: A Call for Vigilance. Endocrinol Metab. 2025;40(3):391-393.
Raschi E, Fusaroli M, Giunchi V, Repaci A, Pelusi C, Mollica V, Massari F, Ardizzoni A, Poluzzi E, Pagotto U, Di Dalmazi G. Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System. Cancers (Basel). 2022 Sep 22;14(19):4610. doi: 10.3390/cancers14194610. PMID: 36230533; PMCID: PMC9559636.
Elshimy G, Chippa V, Kaur J, et al. Adrenal Crisis. [Updated 2025 Feb 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499968/?utm_source=eblast&utm_medium=email&utm_campaign=multiview_dedicatedblast_AAEM
Rice D, Yoshida H. Opioid-Induced Adrenal Insufficiency. JAMA Intern Med. 2024;184(7):830–831. doi:10.1001/jamainternmed.2024.0687
Kilincalp, S. and Papachrysos, N. (2022), Letter: a hidden cause of chronic abdominal pain—opioid-induced adrenal insufficiency. Aliment Pharmacol Ther, 56: 1304-1304. https://doi.org/10.1111/apt.17172
Simcoe S, Simcoe RA. Emergency Department Evaluation and Management of Patients With Adrenal Insufficiency. Emergency Medicine Practice. 2025;27(10). EB Medicine.
Farkas J. Adrenal crisis (IBCC chapter). EMCrit Project. Published September 23, 2025. Accessed April 21, 2026. Adrenal crisis IBCC chapter
Lee SC, Baranowski ES, Sakremath R, Saraff V, Mohamed Z. Hypoglycaemia in adrenal insufficiency. Front Endocrinol (Lausanne). 2023 Nov 20;14:1198519. doi: 10.3389/fendo.2023.1198519. PMID: 38053731; PMCID: PMC10694272.
Authored by Samson Frendo MD and Eric Leser MD