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

Signs and Symptoms of Addison's Disease

Addison's disease presents with a characteristic constellation of chronic symptoms including profound fatigue, hyperpigmentation, weight loss, orthostatic hypotension, and salt craving, along with laboratory findings of hyponatremia, hyperkalemia (in ~50% of cases), low cortisol, and markedly elevated ACTH. 1

Chronic Clinical Manifestations

Cardinal Symptoms

• Profound fatigue and weakness develop insidiously over months to years and represent the most common presenting complaint 1
• Hyperpigmentation is the distinguishing feature of primary adrenal insufficiency, with uneven distribution especially in sun-exposed areas, skin creases, scars, and mucous membranes—this reflects markedly elevated ACTH levels 1, 2
• Unintentional weight loss occurs progressively as the disease advances 1, 3
• Salt craving is a highly specific symptom reflecting mineralocorticoid deficiency and should immediately raise suspicion for primary adrenal insufficiency 1, 4
• Orthostatic hypotension is a cardinal manifestation reflecting mineralocorticoid deficiency and inadequate sodium retention 1, 2

Gastrointestinal Symptoms

• Nausea occurs in 20-62% of patients, with morning nausea and lack of appetite being particularly common 1, 2
• Vomiting can be present in chronic disease and is especially prominent during acute crisis 3, 5
• Abdominal pain may occur, sometimes with peritoneal irritation mimicking an acute abdomen 2

Musculoskeletal Symptoms

• Muscle pain or cramps are common complaints, especially during acute crisis 1, 2
• Myasthenia (muscle weakness) is a frequent manifestation 6

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 1, 2, 4
• Hyperkalemia occurs in approximately 50% of cases at diagnosis—the absence of hyperkalemia cannot rule out adrenal insufficiency 1, 2, 4
• Mild hypercalcemia occurs in 10-20% of patients at presentation 2

Hormonal Findings

• Low serum cortisol with markedly elevated plasma ACTH are characteristic of primary adrenal insufficiency 1, 4
• Elevated plasma renin activity (PRA) reflects mineralocorticoid deficiency 1
• Low DHEAS, androstenedione, and testosterone indicate androgen deficiency 1

Acute Adrenal Crisis Presentation

Acute adrenal crisis is a life-threatening emergency that must be recognized immediately and treated without delay. 1

Clinical Features of Crisis

• Severe malaise and profound fatigue progressing to altered mental status 1
• Severe vomiting and/or diarrhea are common precipitating events and presenting symptoms 2
• Severe abdominal pain with peritoneal irritation 1, 2
• Hypotension and shock with dehydration are hallmark features 2, 5
• Confusion, altered mental status, loss of consciousness, or coma are not uncommon 2
• Unexplained collapse should immediately raise suspicion for adrenal crisis 2

Laboratory Findings in Crisis

• Hyponatremia and hyperkalemia are typical but not universal 1
• Increased creatinine due to prerenal renal failure is common 1, 2
• Hypoglycemia, particularly in children, can occur during acute crisis 1, 2

Critical Diagnostic Pitfalls

Delayed Recognition

• The insidious nature of symptom development often leads to delayed diagnosis, with symptoms being non-specific in early stages 1, 7
• Symptoms often mimic more prevalent diseases such as chronic fatigue syndrome, depression, or gastrointestinal disorders 3
• Diagnosis is often delayed even when biochemical proof is evident because the clinical presentation can be difficult to recognize 1

Common Misinterpretations

• Do not rely solely on the classical combination of hyponatremia and hyperkalemia for diagnosis—serum sodium levels are often only marginally reduced and potassium is elevated in only approximately half of patients at diagnosis 1, 2
• Normal cortisol concentrations do not exclude early Addison's disease—approximately 10% of patients with confirmed primary adrenal insufficiency present with normal basal cortisol levels when ACTH is clearly elevated 8
• The absence of hyperpigmentation cannot rule out primary adrenal insufficiency, especially in early disease 1

High-Risk Scenarios Requiring Immediate Consideration

• Unexplained syncope, vomiting, weight loss, or hypoglycemia should prompt immediate suspicion of Addison's disease 3
• Unexplained collapse, hypotension, and gastrointestinal symptoms (vomiting or diarrhea) should immediately raise suspicion for adrenal crisis 2
• Vasopressor-resistant hypotension in critically ill patients warrants consideration of adrenal insufficiency 2

Associated Autoimmune Conditions

• Approximately 50% of patients with autoimmune primary adrenal insufficiency develop another autoimmune disorder during their lifetime, requiring continuous surveillance 1, 4
• Autoimmune polyendocrine syndrome type-1 (APS-1) is defined as the combination of two of the following: PAI, hypoparathyroidism, and chronic mucocutaneous candidiasis 9, 1, 4
• Autoimmune polyendocrine syndrome type-2 (APS-2) most commonly involves PAI with primary hypothyroidism, but can include Graves' disease, type 1 diabetes, autoimmune gastritis with vitamin B12 deficiency, and pernicious anemia 9, 1, 4
• Patients should be screened for thyroid dysfunction, type 1 diabetes mellitus, pernicious anemia, and celiac disease 1, 2

Neuropsychiatric Manifestations

• Depression and psychosis can occur as neuropsychiatric manifestations of Addison's disease 6
• Cognitive impairment and altered mental status may be present, particularly during crisis 2, 6