What are the clinical features of adrenal hypofunction (Addison's disease)?

Clinical Features of Adrenal Hypofunction (Addison's Disease)

Addison's disease presents with a characteristic constellation of chronic symptoms including hyperpigmentation, profound fatigue, weight loss, orthostatic hypotension, and salt craving, along with laboratory findings of hyponatremia (90% of cases), hyperkalaemia (50% of cases), low cortisol, and markedly elevated ACTH. 1, 2

Chronic Clinical Manifestations

Constitutional Symptoms

• Profound fatigue and weakness are hallmark features, often developing insidiously over months to years 1, 3
• Unintentional weight loss occurs due to anorexia and metabolic derangements 1, 4
• Malaise and generalized weakness (myasthenia) are nearly universal complaints 5, 3

Dermatologic Features

• Hyperpigmentation is a distinguishing feature of primary adrenal insufficiency, with uneven distribution especially in sun-exposed areas, palmar creases, frictional surfaces (elbows, knees), vermilion border of lips, recent scars, genital skin, and oral mucosa 1, 4
• Normal skin color is observed in patients on sufficient replacement therapy 6

Cardiovascular Manifestations

• Orthostatic hypotension is a cardinal manifestation reflecting mineralocorticoid deficiency 2, 4
• Persistent hypotension even at rest may be present 1, 3
• Postural hypotension specifically reflects insufficient mineralocorticoid therapy and/or low salt intake 6

Gastrointestinal Symptoms

• Nausea occurs in 20-62% of patients 1
• Morning nausea and lack of appetite are particularly common 1
• Anorexia contributes to weight loss 7, 3
• Diarrhea may be present 4

Musculoskeletal Complaints

• Muscle pain or cramps, especially during acute crisis 1
• Joint and back pain are common complaints 4, 7

Specific Symptom

• Salt craving is a highly specific symptom reflecting mineralocorticoid deficiency 8, 1, 7

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 6, 1, 2
• Hyperkalaemia occurs in approximately 50% of cases at diagnosis, caused by aldosterone deficiency, impaired glomerular filtration, and acidosis 6, 1, 2
• Important caveat: The absence of hyperkalemia cannot rule out Addison's disease; in the presence of severe vomiting, hypokalaemia and alkalosis may be present 6, 1
• Mild to moderate hypercalcemia occurs in 10-20% of patients at presentation 6, 1

Hormonal Findings

• Low serum cortisol with markedly elevated plasma ACTH are characteristic 1, 2
• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH during acute illness is diagnostic 8, 2
• Elevated plasma renin activity (PRA) reflects mineralocorticoid deficiency 6
• Low DHEAS, androstenedione, and testosterone indicate androgen deficiency 1

Other Laboratory Findings

• Anemia, mild eosinophilia, and lymphocytosis may be present 6
• Increased liver transaminases can occur 6
• TSH levels in the range of 4-10 IU/L may be seen due to lack of cortisol's inhibitory effect on TSH production 6

Acute Adrenal Crisis Presentation

Acute adrenal crisis is a life-threatening emergency that must be recognized immediately and treated without delay. 6

Clinical Features of Crisis

• Severe malaise and profound fatigue 6, 1
• Nausea and vomiting 6, 1
• Severe abdominal pain, sometimes with peritoneal irritation 6
• Dehydration leading to hypotension and shock 6, 1
• Impaired cognitive function, including confusion, loss of consciousness, and coma 6, 1
• Fever may be present 4

Laboratory Findings in Crisis

• Hyponatraemia and hyperkalaemia are typical 6
• Increased creatinine due to prerenal renal failure 6, 1
• Hypoglycemia, particularly in children but rarely in adults 6

Precipitating Events

The frequency of acute adrenal crises is 6-8 per 100 patient-years, with common precipitating events including: 6

• Vomiting and/or diarrhea
• Infections (bacterial or viral)
• Surgical procedures
• Injuries
• Myocardial infarction
• Severe allergic reactions
• Severe hypoglycemia in diabetic patients
• Treatment failures in poorly educated or non-compliant patients

Critical Diagnostic Pitfalls

Delayed Diagnosis

• 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
• Many patients are not diagnosed until a life-threatening adrenal crisis develops 7, 9
• Diagnosis is often delayed even when biochemical proof is evident because the clinical presentation can be difficult to recognize 6

Electrolyte Misconceptions

• Do not rely solely on the classical combination of hyponatremia and hyperkalaemia for diagnosis, as serum sodium levels are often only marginally reduced and potassium is elevated in only approximately half of patients at diagnosis 6, 1
• Some patients may have normal electrolytes or only mild abnormalities at presentation 1

Cortisol Interpretation

• In some patients, serum cortisol levels may be within the normal range but are inappropriately low for the disease state, such as in patients with sepsis 6
• Exogenous steroid use (oral prednisolone or dexamethasone) and inhaled steroids (fluticasone) may confound interpretation of low serum cortisol levels 6

Associated Autoimmune Conditions

Approximately 50% of patients with autoimmune primary adrenal insufficiency develop another autoimmune disorder during their lifetime, requiring continuous surveillance. 8, 7

Polyendocrine Syndromes

• Autoimmune polyendocrine syndrome type-1 (APS-1): PAI with hypoparathyroidism and chronic mucocutaneous candidiasis 8
• Autoimmune polyendocrine syndrome type-2 (APS-2): PAI with primary hypothyroidism (most common), Graves' disease, type 1 diabetes, autoimmune gastritis with vitamin B12 deficiency 6, 8

Screening Requirements

• Thyroid dysfunction (both hypothyroidism and thyrotoxicosis) requires monitoring of TSH, FT4, and TPO antibodies every 12 months 6
• Type 1 diabetes mellitus requires screening with plasma glucose and HbA1c 6
• Pernicious anemia due to autoimmune gastritis requires annual B12 level monitoring 6
• Celiac disease should be screened with tissue transglutaminase 2 autoantibodies and total IgA in patients with frequent or episodic diarrhea 6
• Premature ovarian insufficiency (POI) risk, especially in the presence of anti-side-chain cleavage enzyme (SCC-Ab) antibodies 6