What are the signs and symptoms of adrenal insufficiency?

Signs and Symptoms of Adrenal Insufficiency

Adrenal insufficiency presents with a constellation of nonspecific symptoms that require high clinical suspicion, with fatigue (50-95%), nausea/vomiting (20-62%), and weight loss (43-73%) being the most common manifestations, while hyperpigmentation and salt craving specifically indicate primary adrenal insufficiency. 1

Cardinal Clinical Features

Common Symptoms (Present in Most Patients)

• Profound fatigue and lack of energy occur in 50-95% of patients and represent the most frequent complaint 1, 2
• Unintentional weight loss and anorexia affect 43-73% of patients 1, 2
• Nausea and vomiting occur in 20-62% of cases, often accompanied by poor appetite 3, 1
• Muscle weakness and generalized weakness are common presenting features 4
• Abdominal pain can be prominent, particularly during adrenal crisis 2, 5

Cardiovascular Manifestations

• Postural hypotension is a hallmark feature reflecting insufficient mineralocorticoid therapy and/or low salt intake 6, 2
• Hypotension requiring vasopressor support in severe cases 3
• Volume depletion due to loss of aldosterone in primary adrenal insufficiency 3

Features Specific to Primary Adrenal Insufficiency

• Hyperpigmentation of the skin develops due to elevated ACTH levels stimulating melanocytes; normal skin color is observed in patients on sufficient replacement therapy 6, 2
• Salt craving is a distinctive feature of primary adrenal insufficiency due to aldosterone deficiency 2
• Hyperpigmentation has uneven distribution when glucocorticoid under-replacement occurs 7

Laboratory Abnormalities

Electrolyte Disturbances

• Hyponatremia is present in 90% of newly diagnosed cases, though levels may be only marginally reduced 6, 3
• Hyperkalemia occurs in approximately 50% of patients at diagnosis—its absence does NOT rule out adrenal insufficiency 6, 3
• The classic combination of hyponatremia and hyperkalemia is not reliable for diagnosis as it occurs in only about half of cases 6
• Acidosis can be present 3

Other Laboratory Findings

• Hypoglycemia, particularly in children but rarely in adults 6, 3
• Mild to moderate hypercalcemia in 10-20% of patients at presentation 6, 3
• Anemia 3
• Mild eosinophilia and lymphocytosis 6, 3
• Elevated liver transaminases 6, 3
• Mildly elevated TSH (typically 4-10 IU/L) due to lack of cortisol's inhibitory effect on TSH production 6

Acute Presentation: Adrenal Crisis

Life-Threatening Features

• Unexplained collapse is a medical emergency requiring immediate treatment 6, 3
• Severe hypotension and shock that may be refractory to vasopressors 7, 3
• Severe abdominal pain mimicking an acute abdomen 3, 5
• Profound nausea and vomiting 3, 5
• Altered mental status 1
• Hyponatremia with potential for seizures 1

Precipitating Factors for Crisis

• Gastrointestinal illnesses are the most common trigger 5
• Other infectious diseases 5
• Stressful events including major pain, surgery, strenuous physical activity, heat exposure, and pregnancy 5
• Withdrawal or inadequate adjustment of glucocorticoid therapy during stress 5

Clinical Examination Findings

Physical Examination

• Normal blood pressure should be expected in adequately treated patients 6
• Postural hypotension indicates insufficient mineralocorticoid replacement or low salt intake 6
• Weight loss is a significant finding suggesting insufficient glucocorticoid dosing, stressful situations, or additional endocrine/non-endocrine disease 6
• Normal skin color in the majority of patients on sufficient replacement therapy 6

Important Clinical Pitfalls

Do Not Rely on "Classic" Presentations

• Hyponatremia may be marginal and hyperkalemia is absent in 50% of cases—do not exclude the diagnosis based on normal electrolytes 6
• Initial presentation is often nonspecific, leading to delayed diagnosis and increased risk of adrenal crisis 2
• Some patients present with hypokalaemia and alkalosis when severe vomiting is present 6

Distinguishing Primary from Secondary Adrenal Insufficiency

• Hyperpigmentation and salt craving occur ONLY in primary adrenal insufficiency due to elevated ACTH and aldosterone deficiency 2
• Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency, while hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 7
• Secondary adrenal insufficiency lacks mineralocorticoid deficiency since the renin-angiotensin-aldosterone system remains intact 7

High-Risk Scenarios Requiring Immediate Consideration

• Any patient with unexplained collapse, hypotension, vomiting, or diarrhea should be evaluated for adrenal insufficiency 6
• Patients taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develop unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 7
• Vasopressor-resistant hypotension in critically ill patients warrants screening for adrenal insufficiency 7

Associated Autoimmune Conditions

Screening Considerations

• Thyroid disease (both hypothyroidism and thyrotoxicosis) develops frequently and contributes to fatigue 6
• Type 1 diabetes mellitus 6
• Vitamin B12 deficiency due to autoimmune gastritis 6
• Celiac disease in patients with frequent or episodic diarrhea 6
• Premature ovarian insufficiency in women of reproductive age 6