What are the typical signs and symptoms of primary adrenal insufficiency (Addison's disease)?

Addison's Disease: Clinical Presentation and Symptoms

Addison's disease presents with a characteristic constellation of chronic symptoms including profound fatigue, hyperpigmentation, weight loss, orthostatic hypotension, and salt craving, along with hyponatremia in 90% of cases—though the insidious nature often leads to delayed diagnosis until adrenal crisis occurs. 1

Chronic Manifestations

Cardinal Symptoms

• Profound fatigue and weakness are the most common presenting complaints, developing insidiously over months to years and often dismissed as nonspecific until other features emerge 1, 2
• Hyperpigmentation is the distinguishing feature of primary adrenal insufficiency, with uneven distribution especially prominent in sun-exposed areas, skin creases, palmar creases, knuckles, elbows, knees, and mucosal surfaces (buccal mucosa, gums) 1, 3
• Unintentional weight loss occurs in the majority of patients, typically accompanied by anorexia and poor appetite 1, 4
• Salt craving is a highly specific symptom reflecting mineralocorticoid deficiency and should immediately raise suspicion for primary adrenal insufficiency 1

Cardiovascular Manifestations

• Orthostatic hypotension is a cardinal manifestation reflecting mineralocorticoid deficiency, with blood pressure dropping significantly from supine to standing positions 1
• Chronic hypotension is present even at rest in many patients 4, 3

Gastrointestinal Symptoms

• Nausea occurs in 20-62% of patients, with morning nausea and lack of appetite being particularly common 1
• Vomiting and diarrhea may be present, especially during periods of decompensation 5, 2
• Abdominal pain can occur, sometimes mimicking acute abdomen 6

Musculoskeletal Complaints

• Muscle pain or cramps are common complaints, especially during acute crisis 1
• Generalized weakness and myasthenia affect daily functioning 2, 4

Laboratory Abnormalities in Chronic Disease

Electrolyte Disturbances

• Hyponatremia is present in 90% of newly diagnosed cases, caused by sodium loss in urine and impaired free water clearance 7, 1
• Hyperkalemia occurs in approximately 50% of cases at diagnosis—its absence does NOT rule out Addison's disease 1
• The classical combination of hyponatremia and hyperkalemia is NOT reliable for diagnosis, as sodium levels are often only marginally reduced and potassium is elevated in only half of patients 7, 1

Hormonal Findings

• Low serum cortisol with markedly elevated plasma ACTH are characteristic of primary adrenal insufficiency 1
• Elevated plasma renin activity reflects mineralocorticoid deficiency 1
• Low DHEAS, androstenedione, and testosterone indicate androgen deficiency, particularly affecting women 1

Other Laboratory Findings

• Mild hypercalcemia sometimes occurs, though the mechanism is unclear 1
• Elevated creatinine may be present due to prerenal azotemia from volume depletion 1

Acute Adrenal Crisis Presentation

Acute adrenal crisis is a life-threatening emergency requiring immediate recognition and treatment without delay for diagnostic procedures. 1, 6

Crisis Features

• Severe malaise and profound fatigue progressing rapidly 1
• Severe nausea and vomiting with inability to tolerate oral intake 1, 6
• Severe abdominal pain, often periumbilical, that can mimic surgical abdomen 1, 6
• Profound hypotension and shock with dehydration 1, 8
• Impaired cognitive function, confusion, altered mental status, or even coma 1
• Hypoglycemia, particularly in children 1

Precipitating Factors

• Infection, trauma, surgery, or other physiologic stress 1
• Abrupt withdrawal of corticosteroids in patients with iatrogenic adrenal suppression 6
• Gastrointestinal illness with vomiting or diarrhea 1

Neuropsychiatric Manifestations

• Depression and psychosis can occur as manifestations of Addison's disease 2
• Cognitive impairment and altered mental status, especially during crisis 1, 2
• Seizures have been reported as an unusual presenting feature 5

Associated Autoimmune Conditions

Approximately 50% of patients with autoimmune primary adrenal insufficiency develop another autoimmune disorder during their lifetime, requiring continuous surveillance. 1

Common Associations

• Autoimmune thyroid disease (hypothyroidism or Graves' disease) is the most common association 7
• Type 1 diabetes mellitus frequently coexists 7
• Autoimmune gastritis with vitamin B12 deficiency and pernicious anemia 7
• Premature ovarian insufficiency in women 7
• Vitiligo and celiac disease 7

Polyendocrine Syndromes

• Autoimmune polyendocrine syndrome type-1 (APS-1) is defined by two of three components: primary adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis 7
• Autoimmune polyendocrine syndrome type-2 (APS-2) most commonly involves primary adrenal insufficiency with primary hypothyroidism 7

Critical Diagnostic Pitfalls

Why Diagnosis Is Delayed

• The insidious nature of symptom development leads to delayed diagnosis, with symptoms being nonspecific in early stages and often attributed to other conditions 1, 4
• Diagnosis is frequently delayed even when biochemical proof is evident because the clinical presentation can be difficult to recognize 1
• Many patients are not diagnosed until a life-threatening adrenal crisis develops 4

Common Mistakes to Avoid

• Do NOT rely solely on the presence of hyponatremia and hyperkalemia for diagnosis—sodium is often only marginally reduced and potassium is elevated in only approximately half of patients 7, 1
• Do NOT exclude Addison's disease based on absence of hyperkalemia—it is present in only ~50% of cases 1
• Do NOT dismiss hyperpigmentation as sun exposure—in the context of fatigue, weight loss, and hypotension, it is pathognomonic for primary adrenal insufficiency 1, 8, 3
• Do NOT delay treatment of suspected adrenal crisis for diagnostic testing—mortality is high if untreated 1, 6

Key Distinguishing Features from Secondary Adrenal Insufficiency

• Hyperpigmentation is ONLY present in primary adrenal insufficiency due to elevated ACTH stimulating melanocytes—it is absent in secondary adrenal insufficiency where ACTH is low 1
• Salt craving and mineralocorticoid deficiency (hyperkalemia, severe hypotension) occur only in primary adrenal insufficiency, as the renin-angiotensin-aldosterone system remains intact in secondary disease 1
• Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency, while hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 1