Adrenal Insufficiency


Primary Adrenal Insufficiency

Adrenal Hemorrhage/Infarction/Loss

  • Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]])
  • Bilateral Adrenalectomy: after bilateral nephrectomy or in the management of Cushing syndrome
  • Heparin-Induced Thrombocytopenia (HIT) (see Heparin, [[Heparin]])
  • Waterhouse-Friderichsen Syndrome (Bilateral Adrenal Hemorrhage)
    • Abdominal Trauma/Tumors
    • Cancer
    • Coagulopathy (due to heparin, etc): major risk factor
    • Gastrointestinal Perforation
    • Hypotension/Sepsis
    • Idiopathic Spontaneous Adrenal Hemorrhage: some cases
    • Intracranial Trauma/Tumors
    • Major Surgery: major risk factor
    • Corticosteroids (see Corticosteroids, [[Corticosteroids]])
    • Syphilis (see Syphilis, [[Syphilis]])
    • Thromboemboli to Adrenals: major risk factor

Autoimmune Disease

  • Addison’s Disease


  • Aminoglutethimide (Cytadren) (see Aminoglutethimide, [[Aminoglutethimide]])
  • Abiraterone (Zytiga) (see Abiraterone, [[Abiraterone]])
    • Pharmacology
      • Inhibits CYP17A1 enzyme in testicles, adrenal glands, and prostatic cancer -> decreases circulating testosterone levels
      • Produces mineralocorticoid excess -> side effects of hypokalemia/hypertension
  • Etomidate (see Etomidate, [[Etomidate]]): inhibits adrenal steroidogenesis
  • Heparin (see Heparin, [[Heparin]]): the latter three mechanisms below may contribute to the development of hyperkalemia, but heparin does not typically cause adrenal insufficiency (in the absence of adrenal hemorrhage or HIT)
    • Potential Pharmacologic Mechanisms of Action on Adrenal Gland/Kidney
      • Adrenal hemorrhage (see above under “Adrenal Hemorrhage/Infarction”)
      • Decreased aldosterone synthesis
      • Atrophy of the adrenocortical zona glomerulosa
      • Decreased in number and affinity of aldosterone II receptors
  • Ketoconazole (see Ketoconazole, [[Ketoconazole]])
  • Mifepristone (RU-486) (see Mifepristone, [[Mifepristone]])
  • Mitotane
  • Suramin
  • Trilostane


  • Adrenal Hypoplasia Congenita (AHC)
  • Adrenoleukodystrophy (ALD)/Adrenomyeloneuropathy (AMN)
  • Autoimmune Polyglandular Syndrome 1 (APS1): involves the AIRE gene
  • Autoimmune Polyglandular Syndrome 2 (APS2)
  • Congenital Adrenal Hyperplasia (CAH)
  • Congenital Lipoid Adrenal Hyperplasia (CLAH)
  • Familial Glucocorticoid Deficiency
  • IMAGe Syndrome
  • Kearns-Sayre Syndrome
  • Smith-Lemli-Opitz Syndrome
  • Triple A Syndrome



Secondary Adrenal Insufficiency

Drug-Induced Adrenal Insufficiency

  • Glucocorticoid Excess (see Corticosteroids, [[Corticosteroids]]): endogenous or exogenous

Pituitary Tumors

Pituitary Metastases

Mass Affecting Hypothalamic-Pituitary Region

  • Craniopharyngioma
  • Ependymoma
  • Meningioma (see Meningioma, [[Meningioma]])
  • Metastases

Pituitary Infiltration


  • Autoimmune Hypophysitis
  • Combined Pituitary Hormone Deficiency (CPHD)
  • Congenital Isolated ACTH Deficiency
  • Pituitary Apoplexy/Hemorrhage
    • Sheehan’s Syndrome (Post-Partum Pituitary Necrosis)
  • Pituitary Irradiation
  • Proopiomelanocortin Deficiency (POMC)

Isolated Hypoaldosteronism

Isolated Adrenomedullary Insufficiency

  • Adrenal Metastases
  • Congenital Inherited Dysautonomia
  • Surgery
  • Tuberculosis (see Tuberculosis, [[Tuberculosis]])


Features of Adrenal Dysfunction in Critical Illness [MEDLINE]

  • Suppressed Expression/Activity of Cortisol-Metabolizing Enzymes, Resulting in Decreased Cortisol Degradation
  • Hypercortisolemia: elevated total and free cortisol
  • Corticotropin Suppression


  • Cortrosyn Stimulation Test
    • Performed at any time of day/can be performed at least 24 hrs after HC dose, but not after prednisone dose
    • Baseline Cortisol -> Cortrosyn 250 ug IV (25 U) -> Cortisol 1hr later
    • Normal Response: Cortisol >18 µg/dL (Surviving Sepsis Campaign and Am Coll Crit Care Med suggest adequacy with increment >9 µg/dL)
    • Depressed responses may be seen in critically ill patients

Clinical Syndromes

  • Primary Adrenal Insufficiency Syndromes: manifest signs of both glucocorticoid deficiency + mineralocorticoid deficiency
    • Manifests adrenal androgen deficiency
    • Skin Findings: hyperpigmentation is characteristic of primary adrenal insufficiency (due to excess ACTH stimulation of melanocytes)
    • Acute adrenal insufficiency is more common in primary adrenal insufficiency (due to loss of both glucocorticoids + mineralocorticoids)
  • Secondary Adrenal Insufficiency Syndromes: manifest signs of only glucorticoid deficiency (since the adrenal gland itself is intact and capable of responding to stimulation from the renin-angiotensin-aldosterone axis)
    • Manifests adrenal androgen deficiency
    • Skin Findings: alabaster-like paleness of skin (due to lack of ACTH stimulation of melanocytes)
    • In cases with hypotahalamic-pituitary disease, patients may also manifest clinical signs associated with other endocrine axes (thyroid, gonadal, growth hormone, prolactin) or visual impairment due to pituitary tumor compressing the optic chiasm
  • Exogenous Glucocorticoid Administration Syndrome
    • Patients present with manifestions of glucocorticoid deficiency (if glucocorticoids are discontinued abruptly) + Cushingoid appearance (due to prior exposure to glucocorticoids)

Clinical Manifestations

Symptoms/Signs of Glucocorticoid Deficiency

  • Anorexia (see Anorexia, [[Anorexia]])
  • Arthralgias (see Arthralgias, [[Arthralgias]])
  • Fatigue/Lack of Energy (see Fatigue, [[Fatigue]])
  • Fever (see Fever, [[Fever]])
  • Hematologic Abnormalities
  • Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]]): more common in children
  • Hyponatremia (see Hyponatremia, [[Hyponatremia]])
    • Epidemiology: found in 80% of primary adrenal insufficiency cases at initial presentation
    • Mechanism: loss of cortisol feedback inhibition of AVP release (resulting in mild SIADH)
  • Hypotension/Postural Hypotension (see Hypotension, [[Hypotension]])
  • Mildly Increased Thyroid Stimulating Hormone (TSH): due to loss of feedback inhibition of TSH release
    • Usually normalizes within weeks after glucocorticoid replacement therapy
  • Myalgias (see Myalgias, [[Myalgias]])
  • Weight Loss (see Weight Loss, [[Weight Loss]])

Symptoms/Signs of Mineralcorticoid Deficiency

  • Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])
  • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])
  • Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])
    • Epidemiology: found in 40% of primary adrenal insufficiency cases at initial presentation
  • Hyponatremia (see Hyponatremia, [[Hyponatremia]])
    • Epidemiology: found in 80% of primary adrenal insufficiency cases at initial presentation
    • Mechanism: primariliy caused by mineralocorticoid deficiency
  • Hypotension/Postural Hypotension (see Hypotension, [[Hypotension]])
  • Hypovolemia (see Hypovolemic Shock, [[Hypovolemic Shock]])
  • Salt-Craving


  • Hydrocortisone: 100 mg q8 hrs
    • 2006 Cochrane review: in relative adrenal insufficiency, if used for at least 5 days (with at least 200 mg/day), there is a 20% decrease in mortality (with no increased risk of superinfection, GI bleeding, or hyperglycemia)
  • Fludrocortisone (Florinef): 50 ug PO QD
    • 2002 JAMA study (Annane, et al): Fludro+HC had lower 28-day mortality than HC alone
    • However, randomized trial is needed to determine if fludro is necessary
  • 2008 Surviving Sepsis Guidelines
    • Use Hydrocortisone (<300 mg qday) for septic shock, only if unresponsive to fluids/pressors
      • Don’t use cort stim testing to determine who should get steroids (unless another reason to suspect adrenal insufficiency exists)
      • Hydrocortisone is preferred over dexamethasone
    • Wean steroids with wean of pressors
    • Fludrocortisone is optional, if HC is used


  • Hyperreninemic hypoaldosteronism in the critically ill: a new entity. J Clin Endocrinol Metab. 1981 Oct;53(4):867-73 [MEDLINE]
  • Reduced cortisol metabolism during critical illness. N Engl J Med. 2013 Apr 18;368(16):1477-88. doi: 10.1056/NEJMoa1214969. Epub 2013 Mar 19 [MEDLINE]
  • Adrenal dysfunction in critically ill patients. N Engl J Med 2013;368(16):1547-1548 [MEDLINE]