MD Notes

creation date: 2026-06-12 22:33
tags: Pathologies

Primary Adrenal Insufficiency

Background

Definitions

Adrenal insufficiency refers to a deficiency in the hormones produced by the adrenal glands.

Primary adrenal insufficiency: pathology affecting the adrenal gland itself
Secondary adrenal insufficiency: pathology results in reduced ACTH from pituitary gland
Tertiary adrenal insufficiency: pathology results in reduced CRH from the hypothalamus

Adrenal insufficiency can also be categorized by acute vs. chronic. Acute insufficiency is referred to as adrenal crisis.

Etiology & Pathogenesis

Autoimmune adrenalitis
Autoimmune disease is responsible for 70-90% of cases. Epidemiology is as follows:

  • Age 0-20: 70% male
  • Age 20-30: equal male-to-female ratio
  • Age >30: 80% female

Genetics predispose patient to autoantibody generation against steroidogenic enzymes (commonly 21-hydroxylase) in all three zones of the adrenal cortex.

Autoimmune adrenalitis is not strongly associated with common autoimmune endocrine disorders (eg. type 1 diabetes, chronic autoimmune thyroiditis, Graves’ disease). Associated autoimmune syndromes consist of:

  • Polyglandular autoimmune syndrome (PAS) type 1: hypoparathyroidism, chronic mucocutaneous candidiasis, adrenal insufficiency
  • PAS type 2: adrenal insufficiency with endocrine and nonendocrine autoimmune disorder without PAS type 1 conditions

Infectious adrenalitis
Infection can destroy the adrenal glands. Causative agents include:

  • Tuberculosis (predominantly medulla)
  • Disseminated fungal infection
  • HIV infection
  • Syphilis
  • African trypanosomiasis

Hemorrhagic infarction
Infarction due to hemorrhage or adrenal vein thrombosis results in destruction of the gland. Hemorrhage is hypothesized to be due to:

  • Increased adrenal blood flow stimulated by stress-response ACTH secretion
  • Anticoagulation/heparin use
  • Thrombocytopenia

Bilateral adrenal injury
Blunt trauma to the lower torso can result adrenal insufficiency. Additionally, sudden, bilateral adrenal necrosis can occur from hemorrhage, emboli, or sepsis.

Metastatic disease
Infiltration of the adrenal gland by metastatic cancer is common due to their rich blood supply. Common sources are:

  • Lung or breast cancer
  • Melanoma
  • Stomach or colon cancer

Iatrogenic (medication-induced)
A number of drugs are associated with adrenal insufficiency:

  • Checkpoint inhibitor immunotherapy
  • Cortisol biosynthesis inhibitors (usually not clinically significant)
  • Drugs that accelerate metabolism of cortisol
    • Phenytoin
    • Barbiturates
    • Rifampin
  • Mitotane (used to treat adrenal tumours)
  • CRH/ACTH production suppressors
    • Glucocorticoids
    • Megestrol acetate
    • Opioids

Pathophysiology of Clinical Findings

In the setting of primary adrenal insufficiency, both mineralocorticoids and glucocorticoids are deficient. This is contrasted to central insufficiency, in which mineralocorticoid production is often preserved due to alternative regulatory pathways outside the HPA axis.

Adrenal crisis occurs due to mineralocorticoid and glucocorticoid deficiency.

  • Aldosterone promotes sodium retention and enhance vasoconstriction
  • Glucocorticoids are important to vascular responsiveness, synthesis of renin, and synthesis of epinephrine

The loss of adrenal products results in a loss in ability to maintain blood pressure. Precipitating factors for adrenal crisis typically involve a recent abrupt change in glucocorticoid exposure:

  • Serious infection or major stress in setting of chronic primary adrenal insufficiency
  • Under-replacement of glucocorticoid in setting of known adrenal insufficiency
  • Acute destruction of adrenal glands

Clinical Presentation

Signs & Symptoms

Adrenal Crisis

Adrenal crisis from primary adrenal insufficiency presents with:

  • Hypotension with cardiovascular collapse
  • Abdominal tenderness (generalized, on deep palpation)
  • Fever (caused by infection and exaggerated by hypocortisolemia)

Evidence of a precipitating factor (eg. blunt trauma) may be seen. There may also be signs of chronic adrenal insufficiency.

Chronic Adrenal Insufficiency

A number of nonspecific symptoms relating to adrenal insufficiency are usually present. It should be noted that onset if often insidious and thus not evidently due to adrenal insufficiency.

  • Fatigue
  • Weight loss (due to anorexia and dehydration)
  • Gastrointestinal complaints (eg. nausea, vomiting, abdominal pain, diarrhea/constipation)
  • Amenorrhea (may be due to weight loss/chronic illness)
  • Diffuse myalgia and arthralgia
  • Psychiatric symptoms
    • Mild-to-moderate neurocognitive disorders
    • Impairment of memory (may progress to confusion, delirium, stupor)
    • Depression, anxiety, mania
    • Psychosis
  • Auricular-cartilage calcification

More specific findings to primary adrenal insufficiency include:

  • Postural hypotension (volume depletion due to aldosterone deficiency)
  • Salt craving
  • Hyperpigmentation (generalized but most notable in areas exposed to light)
  • Vitiligo

History & Physical Exam

History should include:

  • Symptom progression and time
  • History of autoimmune disorders
  • History of malignancy
  • History of infiltrative disorders (eg. hemochromatosis, sarcoidosis, or primary amyloidosis)
  • Anticoagulation or hypercoagulable states
  • Immunocompromise status
  • History of chronic glucocorticoid therapy (and abrupt cessation/reduction)
  • Neurologic symptoms (in males, suggests X-linked adrenoleukodystrophy)
  • Medications

Risk Factors

Diagnosis

Criteria

Diagnosis of adrenal insufficiency requires demonstration of inappropriately low cortisol production.

  • Serum cortisol in cases of adrenal crisis
    • Diagnosis if cortisol <500 nmol/L
    • Note, in cases of increased corticosteroid-binding globulin (CBG), such as in pregnancy, cortisol values may appear normal
  • Early morning serum cortisol
    • Within 3 hours of waking
    • Diagnosis if cortisol ≤80 nmol/L in absence of CBG deficiency
    • Inconclusive if cortisol between 80-500 nmol/L (proceed to ACTH stimulation)
  • ACTH stimulation test
    • Serum cortisol peak <390 nmol/L
    • Inconclusive if cortisol between 390-500 nmol/L (proceed to DHEAS)
  • Dehydroepiandrosterone sulfate (DHEAS)
    • Based on age/sex specific reference range; normal rules out adrenal insuffiency

Following diagnosis of adrenal insufficiency, serum aldosterone and renin can differentiate between primary vs. central insufficiency. Findings of primary insufficiency are:

  • Low aldosterone
  • Elevated renin

Clinical history can also determine primary etiology in some cases.

Work-up

Additional evaluation for cause
If the etiology is not clear from history, additional testing can be done.

  • Antibodies to 21-hydroxylase
  • Contrast CT abdomen pelvis

Differential

The primary differential are:

  • Secondary adrenal insufficiency (normal aldosterone, decreased ACTH, elevated CRH)
  • Tertiary adrenal insufficiency (normal aldosterone, decreased ACTH, decreased CRH)

Red Flags / Complications

Adrenal crisis can result in shock which may be life threatening.

Management

Emergency Management of Adrenal Crisis

Initial treatment consist of:

  1. Establishing IV access
  2. Isotonic fluid infusion
  3. Glucocorticoid therapy

Laboratory tests for electrolytes, glucose levels, and hormone measurements for diagnosis (if needed) should be ordered prior to glucocorticoid therapy.

Fluid is administered as at least 1 L (within first hour) followed by at least 2-3 L (first 12-24 hours) of:

  • 0.9% saline
  • 5% dextrose in 0.9% saline

Glucocorticoid therapy:

  • Hydrocortisone 100 mg IV bolus followed by 50 mg IV q6h OR 200 mg/24 hour IV infusion (preferred for both glucocorticoid and mineralocorticoid activity)
  • Methylprednisolone 40 mg IV (in two divided daily doses)
  • Dexamethazone 4-6 mg IV daily

Management of Chronic Adrenal Insufficiency

Mainstay of primary adrenal insufficiency management is glucocorticoid and mineralocorticoid replacement.

Hydrocortisone is preferred for glucocorticoid replacement as it is short-acting and thus dosing can be modulated.

  • Initial dose of 15-25 mg daily divided into 2-3 doses (first dose upon waking, last dose 4-8h before bedtime)
  • Titrate dose to lowest total daily dose that alleviates symptoms; adjust in 2.5-5 mg increments

Monitoring for glucocorticoid use is done clinically:

  • Undertreatment: lethargy, subjective weakness, low BP, nausea, weight loss
  • Overtreatment: body weight gain, increased BP, impaired sleep, edema, other manifestations of Cushing syndrome

Fludrocortisone is used for mineralcorticoid replacement. Note that a deficiency should be confirmed with serum aldosterone and renin levels.

  • If taking hydrocortisone or cortisone acetate, start with 0.05 mg daily
  • If taking other glucocorticoids, start with 0.1 mg daily

Dose should be adjusted for salt losses or primary hypertension. For example, in warmer climates, fludrocortisone dose may be need to be increased by 50-100% to make up for increased prespiration.

Monitoring for mineralocorticoid use is done clinically:

  • Undertreatment: fatigue, lightheadedness, nausea, salt craving
  • Overtreatment: hypertension, edema

Androgen replacement may be indicated for females with significant symptoms of depression or anxiety, low libido or energy, or impaired sense or well-being, despite optimized glucocorticoid and mineralocorticoid therapy.

  • DHEA 25-50 mg daily in morning; adjust to serum level and clinical response

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