Updated: 12/10/2021

Primary Adrenal Insufficiency

Review Topic
  • Snapshot
    • A 15-year-old man is brought to his pediatrician by his father for complaints of fatigue, weight loss, and recurrent episodes of nausea and vomiting. His symptoms have been occurring for more than 2 weeks and he can’t recall any clear precipitating factors. He denies fever, symptoms of upper respiratory infection, chest pain, palpitations, abdominal pain, or urinary symptoms. A physical examination demonstrates hyperpigmentation of his oral mucosa. A basic metabolic panel reveals hyponatremia and hyperkalemia.
  • Introduction
    • Clinical definition
      • disorder characterized by the loss of adrenal gland function leading to the deficiency of aldosterone (mineralcorticoids) and cortisol
      • can be either acute or chronic depending of the etiology
    • Associated conditions
      • approximately ½ of patients with autoimmune adrenal insufficiency have other autoimmune endocrine disorders (e.g., hypothyroidism)
  • Epidemiology
    • Demographics
      • autoimmune causes (which accounts for 70-90% of cases in the U.S.) occur predominantly within the female population
    • Risk factors
      • other autoimmune endocrinopathies
    • Pathogenesis
      • any process that damages the adrenal cortices and leading to a deficiency of aldosterone and cortisol
      • autoimmune adrenalitis (Addison disease)
        • most common cause in the U.S.
        • both humoral and cell-mediated immune mechanisms targeting the adrenal cortex
        • a small percentage of patients may have polyglandular autoimmune syndrome
      • infectious adrenalitis
        • tuberculosis (most common cause in the developing world)
        • disseminated fungal infections (e.g., histoplasmosis)
        • HIV infection
      • hemorrhagic infarction
        • Waterhouse-Friderichsen syndrome associated with meningococcemia (Neisseria meningococcal)
        • anticoagulant drug or heparin therapy (e.g., heparin-induced thrombocytopenia)
      • metastatic disease
        • commonly associated with lung, breast, and melanoma cancers
  • Presentation
    • Symptoms
      • fatigue
      • weight loss
      • nausea/vomiting
      • abdominal pain
      • muscle/joint pain
      • salt craving
      • adrenal crisis
    • Physical exam
      • skin and mucosal hyperpigmentation (if longstanding)
        • due to increased production of proopiomelanocortin (POMC), a prohormone that is cleaved into ACTH and melanocyte-stimulating hormone (MSH)
      • hypotension
      • auricular-cartilage calcification
      • vitiligo
  • Studies
    • Diagnostic testing
      • diagnostic approach
        • chronic adrenal insufficiency is often more difficult to diagnose than acute adrenal insufficiency
        • diagnosis is based on clinical presentation and confirmed with an endocrine evaluation
      • imaging
        • computed tomography (CT)
          • may demonstrate bilateral adrenal injury, hemorrhage, or infarction
      • studies
        • serum cortisol concentration (e.g., morning serum cortisol)
          • best initial test
          • low serum cortisol (e.g., less than 5 ug/dL) strongly suggests adrenal insufficiency
        • plasma ACTH concentration
          • best initial test but often not quickly available
          • high plasma ACTH concentration with low serum cortisol suggests primary adrenal insufficiency
        • ACTH stimulation test
          • will have low response to ACTH stimulation
        • plasma aldosterone and renin levels
          • will have low aldosterone and high renin levels
        • laboratory abnormalities secondary to low aldosterone
          • hyperkalemia
          • hyponatremia
          • hypoglycemia
          • metabolic acidosis
  • Differential
    • Secondary adrenal insufficiency
      • distinguishing factors
        • will not have hyperpigmentation on physical examination
        • will have low levels of ACTH
  • Treatment
    • First-line
      • glucocorticoid replacement therapy
        • e.g., hydrocortisone or dexamethasone
        • stress doses indicated at times of stress (e.g., surgery)
        • significant adverse effects with chronic use (e.g., osteoporosis)
      • mineralcorticoid replacement therapy
        • e.g., fludrocortisone
        • prevents sodium loss, intravascular volume depletion, and hyperkalemia
      • androgen replacement therapy
        • e.g., dehydroepiandrosterone (DHEA)
        • appears to improve mood and psychological well-being
        • adverse effects include hirsutism, acne, and increased sweating/odor
  • Complications
    • Adrenal crisis
      • medical emergency managed with schedule IV glucocorticoid
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Questions (2)

(M2.EC.14.23) A 42-year-old Caucasian woman presents to the emergency department with complaints of progressive weight loss, dizziness, nausea, and vomiting over the last several months. She returned from a 2-week international business trip 6 months ago where she reports being ill with a fever, diarrhea, and a cough. Her temperature is 97.7°F (36.5°C), blood pressure is 114/64 mmHg, pulse is 105/min, respirations are 72/min, and oxygen saturation is 99% on room air. Physical exam is significant for the finding in Figure A. Initial laboratory studies are ordered as seen below.

Na+: 139 mEq/L
Cl-: 100 mEq/L
K+: 6.3 mEq/L
HCO3-: 15 mEq/L
BUN: 20 mg/dL
Glucose: 66 mg/dL
Creatinine: 1.1 mg/dL
Ca2+: 10.2 mg/dL

Which of the following is the most likely underlying etiology of this patient's symptoms?

QID: 104297




Autoimmune adrenalitis









Viral gastroenteritis



M 6 E

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(M2.OMB.4878) A 49-year-old man presents with 3 months of generalized weakness. He has had a chronic cough and a 20 pound unintentional weight loss over the past 6 months. He has a medical history significant for high blood pressure, hyperlipidemia, and seasonal allergies with no prior surgical history. He has no history of tobacco use. He moved from India 7 years prior to presentation. He currently lives in Oregon and has not left the west coast since moving. His temperature is 99°F (37.2°C), blood pressure is 100/70 mmHg, pulse is 76/min, and respirations are 16/min. His physical exam is significant for hyperpigmentation of the oral mucosa and temporal muscle wasting. Radiography of the abdomen demonstrates bilateral adrenal calcifications. Laboratory values are as follows:

Na+: 130 mEq/L
Cl-: 96 mEq/L
K+: 5.2 mEq/L
HCO3-: 24 mEq/L
Morning cortisol: 2 ug/dL
30-minute cortisol during cosyntropin test: 8 ug/dL (normal > 18 ug/dL)
Morning adrenocorticotropic hormone (ACTH) concentration (serum): 80 pg/mL (normal 10-60 pg/mL)

Which of the following is the most appropriate next step in management?

QID: 216385

Bilateral adrenalectomy, prednisone, and fludrocortisone






Hydrocortisone and immunoglobulin therapy



Prednisone taper



Rifamycin, isoniazid, pyrazinamide, ethambutol, and hydrocortisone therapy



M 11

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