What are the causes, clinical features, diagnostic criteria, and management of primary adrenal insufficiency (Addison disease)?

Addison Disease (Primary Adrenal Insufficiency): Comprehensive Overview

Definition and Pathophysiology

Addison disease is a life-threatening endocrine disorder caused by destruction of the adrenal cortex, resulting in deficiency of glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens. 1 The condition disrupts the hypothalamic-pituitary-adrenal axis, leading to cortisol deficiency that impairs metabolism, immune function, and stress responses, while aldosterone deficiency causes dysregulation of sodium and potassium homeostasis. 2

Causes and Etiology

Primary Causes by Frequency

• Autoimmune adrenalitis: Accounts for approximately 85% of cases in Western Europe and the United States, where the immune system destroys adrenal cortical cells 1, 3
• Infectious causes: Particularly tuberculosis (Mycobacterium tuberculosis), which can infiltrate and impair the adrenal glands 2
• Genetic disorders: Including adrenoleukodystrophy, IMAGE syndrome (CDKN1C mutations), MIRAGE syndrome (SAMD9 mutations), and nonclassic forms of STAR and CYP11A1 deficiency 4
• Hemorrhagic damage: Secondary to severe stress, trauma, coagulopathies, or anticoagulant therapy 5
• Metastatic neoplasms: Involving and destroying the adrenal glands 2
• Iatrogenic causes: Including checkpoint inhibitor immunotherapy, drugs affecting glucocorticoid synthesis or metabolism, and bilateral adrenalectomy 5

Diagnostic Algorithm for Etiology

Start with measurement of serum 21-hydroxylase (anti-adrenal) autoantibodies. 1 If antibodies are positive, the diagnosis is autoimmune Addison disease. 1

If antibodies are negative, proceed with: 1

• CT imaging of the adrenals to evaluate for hemorrhage, tumor, or tuberculosis
• In male patients: Assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy
• In children and young adults with hypoparathyroidism or candidiasis: Consider APS-1 (autoimmune polyglandular syndrome type 1), confirmed by anti-interferon omega antibodies or AIRE gene mutation analysis 1

Clinical Features

Chronic Presentation

The hallmark clinical features include fatigue, appetite loss, unintentional weight loss, hypotension, and hyponatremia. 6

Specific features of primary adrenal insufficiency (distinguishing from secondary): 6, 3

• Hyperpigmentation: Especially in areas subjected to friction, palmar creases, and mucous membranes
• Salt craving: Due to aldosterone deficiency
• Hyperkalemia: From mineralocorticoid deficiency
• Orthostatic hypotension: Due to volume depletion

Additional symptoms include: 1, 3

• Muscle and joint pain
• Nausea and vomiting
• Myasthenia (muscle weakness)

Neuropsychiatric Manifestations

Depression and psychosis can occur as part of the disease spectrum. 2

Acute Adrenal Crisis

An acute adrenal crisis is a life-threatening emergency requiring immediate treatment. 1 The frequency is 6-8 crises per 100 patient-years. 1

Precipitating events: 1

• Vomiting and/or diarrhea (patients cannot absorb oral medication when they need it most)
• Infections
• Surgical procedures
• Injuries
• Myocardial infarction
• Severe allergic reactions
• Severe hypoglycemia in diabetic patients
• Treatment failures in poorly educated or non-compliant patients

Crisis symptoms: 1

• Malaise and severe fatigue
• Nausea and vomiting
• Abdominal pain (sometimes with peritoneal irritation)
• Muscle pain or cramps
• Dehydration leading to hypotension and shock
• Impaired cognitive function, including confusion

Diagnostic Criteria

When to Suspect Addison Disease

Consider the diagnosis in all patients presenting with unexplained collapse, hypotension, vomiting, or diarrhea. 1 Hyperpigmentation, hyponatremia, hyperkalemia, acidosis, and hypoglycemia increase clinical suspicion. 1

Apply a low diagnostic threshold in: 7

• Acutely ill patients
• Patients with predisposing factors (autoimmune diseases, checkpoint inhibitor therapy)
• Pregnant women with unexplained persistent nausea, fatigue, and hypotension

Diagnostic Testing Algorithm

Step 1: Initial screening (if acute crisis not suspected) 1

• Measure morning plasma ACTH and cortisol levels simultaneously
• Check basic metabolic panel (sodium, potassium, glucose)
• Measure plasma renin activity (PRA) - will be increased 1
• Check serum aldosterone (low) and DHEAS (low) 1

Diagnostic cortisol thresholds in acute illness: 1

• Serum cortisol <250 nmol/L (<9 μg/dL) with increased ACTH: Diagnostic of primary adrenal insufficiency
• Serum cortisol <400 nmol/L (<14.5 μg/dL) with increased ACTH: Strong suspicion of primary adrenal insufficiency

Important caveat: Approximately 10% of patients with primary adrenal insufficiency present with normal cortisol concentrations but clearly elevated ACTH (>300 pg/mL), representing early manifestation of Addison disease. 8 Normal to high basal cortisol with clearly elevated ACTH is indicative of primary adrenal insufficiency when clinical history is suggestive. 8

Step 2: Confirmatory testing (if initial results equivocal) 1, 7

• Short cosyntropin (synacthen/tetracosactide) stimulation test: Gold standard
• Administer 0.25 mg cosyntropin intramuscularly or intravenously
• Measure serum cortisol at 30 and/or 60 minutes
• Peak serum cortisol <500 nmol/L (<18 μg/dL) is diagnostic of primary adrenal insufficiency 1
• Normal response: One value should exceed 550 nmol/L 1

Critical principle: Treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures. 1 Secure blood samples for cortisol and ACTH before treatment if possible, but do not delay therapy. 1

Additional Laboratory Findings

• TSH levels may be mildly elevated (4-10 IU/L) due to lack of cortisol's inhibitory effect on TSH production 1
• Exogenous steroid use (prednisolone, dexamethasone) and inhaled fluticasone may confound interpretation of low cortisol levels 1

Management

Acute Adrenal Crisis Management

Adrenal crisis must be treated immediately with IV or IM hydrocortisone 100 mg, followed by 100 mg every 6-8 hours until recovered. 1

Fluid resuscitation: 1

• Administer isotonic (0.9%) sodium chloride solution
• Initial rate of 1 L/hour until hemodynamic improvement
• At least 2 L should be given 1

Seek the underlying precipitant (infection, etc.) once treatment has been initiated. 1

Taper stress-dose corticosteroids down to maintenance doses over 7-14 days after recovery. 1

Chronic Glucocorticoid Replacement

Most patients with primary adrenal insufficiency should take 15-25 mg of hydrocortisone daily in split doses. 1 The first dose should be taken immediately after waking, and the last dose not less than 6 hours before bedtime. 1

Typical dosing regimens for hydrocortisone: 1

• Three-dose regimen: 10 mg at 07:00 + 5 mg at 12:00 + 2.5-5 mg at 16:00
• Alternative: 15 mg + 5 mg + 5 mg, or 10 mg + 5 mg + 5 mg
• Two-dose regimen (for shift workers): 15 mg + 5 mg, or 10 mg + 10 mg

Alternative: Cortisone acetate 20-35 mg/day (equivalent to 25-37.5 mg in split doses) 1

Pediatric dosing: Hydrocortisone 6-10 mg/m² body surface area per day 1, 7

Principle: Use the lowest dose compatible with health and sense of well-being. 1

Drug Interactions Affecting Glucocorticoid Dosing

Medications requiring increased hydrocortisone doses: 1

• Anti-epileptic drugs and barbiturates
• Antituberculosis medications (rifampin)
• Etomidate
• Topiramate

Substances requiring decreased doses: 1

• Grapefruit juice (potentiates glucocorticoid effect)
• Liquorice (potentiates mineralocorticoid effect)

Antifungal drugs may require dose changes. 1

Mineralocorticoid Replacement

Most patients with primary adrenal insufficiency should take 50-200 μg fludrocortisone as a single daily dose upon awakening. 1 Children and younger adults may require higher doses (up to 500 μg daily). 1

Monitoring mineralocorticoid replacement: 1

• Ask about salt cravings or lightheadedness
• Measure blood pressure in supine and standing positions
• Check for peripheral edema
• Monitor serum electrolytes

Patients should be advised to take salt and salty foods ad libitum and avoid potassium-containing salts. 1 Unrestricted sodium intake is an important third component of substitution therapy. 1

Medications to Avoid with Fludrocortisone

The following should be avoided: 1

• Diuretics
• Acetazolamide
• Carbenoxolone and liquorice
• NSAIDs

Drospirenone-containing contraceptives may require increased fludrocortisone doses. 1

If essential hypertension develops, treat by adding a vasodilator, not by stopping mineralocorticoid replacement (though dose reduction should be considered). 1

Adrenal Androgen Replacement

There is insufficient evidence of benefit to recommend routine replacement of adrenal androgens. 1

Pragmatic approach for women: 1

• Offer a 6-month trial of DHEA 25 mg daily to female patients with persistent lack of libido and/or low energy despite optimized glucocorticoid and mineralocorticoid replacement
• Continue if clinically effective
• Monitor serum DHEAS, androstenedione, and testosterone levels (maintain in normal range)
• Use with caution due to unknown long-term effects 1

Stress Dosing for Surgery and Procedures

Major surgery with long recovery time: 1

• Preoperative: 100 mg hydrocortisone IM just before anesthesia
• Postoperative: Continue 100 mg hydrocortisone IM every 6 hours until able to eat and drink, then double oral dose for 48+ hours, then taper to normal dose

Major surgery with rapid recovery: 1

• Preoperative: 100 mg hydrocortisone IM just before anesthesia
• Postoperative: Continue 100 mg hydrocortisone IM every 6 hours for 24-48 hours, then double oral dose for 24-48 hours, then taper

Minor surgery and major dental surgery: 1

• Preoperative: 100 mg hydrocortisone IM just before anesthesia
• Postoperative: Double oral dose for 24 hours, then return to normal dose

Dental procedures: 1

• Extra morning dose 1 hour prior to surgery
• Double oral dose for 24 hours, then return to normal dose

Minor procedures: 1

• Usually not required
• Extra dose (e.g., 20 mg hydrocortisone) if symptoms develop

Management During Pregnancy

Small adjustments to hydrocortisone and fludrocortisone doses may be needed during pregnancy, particularly during the last trimester. 1 Free cortisol levels rise during the third trimester, requiring an increase in hydrocortisone by 2.5-10 mg daily. 1 Serum progesterone has anti-mineralocorticoid effects, often necessitating increased fludrocortisone doses during late pregnancy. 1

During delivery: 1

• Give bolus parenteral dose of 100 mg hydrocortisone IM at onset of labor
• Repeat if necessary every 6 hours
• Double oral dose for 24-48 hours postpartum, then taper to normal dose

Monitor using salt cravings, blood pressure, and serum electrolytes (PRA is not useful during pregnancy as it normally increases). 1

Physical Activity Adjustments

Regular, accustomed, and time-limited physical activity does not generally require dose adjustment. 1

For unaccustomed, intense, or prolonged exercise: 1

• May require increased hydrocortisone and salt intake
• For marathon running: Take extra 5 mg hydrocortisone before the race
• In hot conditions or intense activity: Additional fluid and salt intake to replace sweat losses
• Test proposed replacement regimen before the event

Patient Education and Safety

All patients with adrenal insufficiency must: 1

• Wear Medic Alert identification jewelry
• Carry a steroid/alert card
• Receive sufficient education to manage daily medications and situations of minor to moderate concurrent illnesses
• Have supplies for self-injection of parenteral hydrocortisone 1

Critical teaching point: Even mild upset stomach may precipitate a crisis, as patients do not absorb their medication when they need it most. 1

Follow-Up and Monitoring

Patients with primary adrenal insufficiency should be reviewed at least annually with: 1

• Assessment of health and well-being
• Measurement of weight
• Blood pressure measurement (supine and standing)
• Serum electrolytes
• Occasional monitoring for development of new autoimmune disorders, particularly hypothyroidism (up to 50% develop another autoimmune disorder during their lifetime) 3
• Assessment for complications of glucocorticoid therapy
• Bone mineral density monitoring every 3-5 years 1

Common Pitfalls

Under-replacement of mineralocorticoids is common and sometimes compensated for by over-replacement of glucocorticoids, possibly predisposing patients to recurrent adrenal crises. 1

Diagnosis is frequently delayed due to nonspecific symptoms early in the disease course, which poses significant challenges to early detection prior to an adrenal crisis. 6, 5

Normal cortisol levels do not exclude early Addison disease - approximately 10% of patients present with normal cortisol but elevated ACTH. 8