Symptoms of Addison's Disease
Addison's disease presents with a characteristic constellation of chronic symptoms including profound fatigue, hyperpigmentation (especially in sun-exposed areas and palmar creases), weight loss, orthostatic hypotension, salt craving, nausea, and laboratory findings of hyponatremia (90% of cases), hyperkalemia (50% of cases), low cortisol, and markedly elevated ACTH. 1, 2
Chronic Symptoms Developing Over Months to Years
Cardinal Clinical Features
- Profound fatigue and weakness that develops insidiously and is often the most debilitating symptom 1, 3
- Hyperpigmentation with characteristic uneven distribution, particularly prominent in:
- Unintentional weight loss and malaise 1, 3
- Orthostatic hypotension reflecting mineralocorticoid deficiency 1
- Salt craving - a highly specific symptom of aldosterone deficiency 1, 2
Gastrointestinal Symptoms
- Nausea occurs in 20-62% of patients 1, 2
- Morning nausea and lack of appetite are particularly common 1
- Vomiting and diarrhea may occur 5
- Poor appetite contributing to weight loss 6
Musculoskeletal Symptoms
Neuropsychiatric Manifestations
- Depression and psychosis can occur as part of the disease spectrum 3
- Lethargy when under-replaced with glucocorticoids 6, 7
Laboratory Abnormalities in Chronic Disease
Electrolyte Disturbances
- Hyponatremia present in 90% of newly diagnosed cases, caused by sodium loss in urine and impaired free water clearance 1, 7, 2
- Hyperkalemia occurs in approximately 50% of cases at diagnosis, caused by aldosterone deficiency 1, 7, 2
- Mild to moderate hypercalcemia in 10-20% of patients at presentation 2
Hormonal Findings
- Low serum cortisol with markedly elevated plasma ACTH are characteristic 1, 7, 2
- Elevated plasma renin activity reflecting mineralocorticoid deficiency 1
- Low DHEAS, androstenedione, and testosterone indicating androgen deficiency 1, 2
Acute Adrenal Crisis Presentation
Acute adrenal crisis is a life-threatening emergency requiring immediate recognition and treatment without delay. 6, 1
Clinical Features of Crisis
- Severe malaise and profound fatigue 6, 2
- Nausea and vomiting 6, 2, 8
- Severe abdominal pain (sometimes with peritoneal irritation) 6
- Dehydration leading to hypotension and shock 6, 2
- Impaired cognitive function including confusion, loss of consciousness, and coma 6, 2
- Fever and seizures (unusual but reported presentations) 5
Laboratory Findings in Crisis
- Hyponatremia and hyperkalemia are typical 6, 1
- Increased creatinine due to prerenal renal failure 6, 1, 2
- Hypoglycemia, particularly in children 6, 1, 2
- Sometimes mild hypercalcemia 6
Critical Diagnostic Pitfalls
Recognition Challenges
- The insidious nature of symptom development over months to years often leads to delayed diagnosis, and symptoms are frequently non-specific in early stages 1, 2, 9
- Many patients are not diagnosed until a life-threatening adrenal crisis develops 9
- Symptoms often mimic more prevalent diseases such as syncope, gastroenteritis, or chronic fatigue syndrome 8
Laboratory Interpretation Errors
- Do not rely solely on the classical combination of hyponatremia and hyperkalemia for diagnosis, as serum sodium levels are often only marginally reduced and potassium is elevated in only approximately half of patients at diagnosis 1, 2
- The absence of hyperkalemia cannot rule out Addison's disease 2
- Normal inflammatory markers (ESR, CRP) do not exclude the diagnosis 1
Associated Autoimmune Conditions
- Approximately 50% of patients with autoimmune primary adrenal insufficiency develop another autoimmune disorder during their lifetime, requiring continuous surveillance 1, 7
- Autoimmune polyendocrine syndrome type-1 (APS-1) is defined by any two of: primary adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis 1, 7
- Autoimmune polyendocrine syndrome type-2 (APS-2) most commonly includes primary adrenal insufficiency with primary hypothyroidism, and may also include Graves' disease, type 1 diabetes mellitus, and pernicious anemia 1, 7