What are the signs and symptoms of adrenal insufficiency in patients?

Signs and Symptoms of Adrenal Insufficiency

Adrenal insufficiency presents with a constellation of nonspecific symptoms that often delay diagnosis, but key clinical features include profound fatigue (50-95% of cases), unexplained weight loss and anorexia (43-73%), gastrointestinal symptoms including nausea and vomiting (20-62%), and postural hypotension, with hyponatremia present in 90% of newly diagnosed cases. 1, 2, 3

Constitutional and General Symptoms

• Profound fatigue is the most common presenting symptom, occurring in 50-95% of patients, and represents inadequate glucocorticoid replacement 2, 3
• Unintentional weight loss occurs in 43-73% of patients, often accompanied by poor appetite and anorexia 2, 3
• Muscle weakness and generalized malaise are frequent complaints that significantly impact daily activities 3, 4

Gastrointestinal Manifestations

• Nausea and vomiting occur in 20-62% of patients and can be particularly prominent in the morning, often representing glucocorticoid under-replacement 5, 2
• Diarrhea is a recognized gastrointestinal symptom that may be present at diagnosis 1, 5
• Abdominal pain can occur, and when severe, may indicate impending adrenal crisis 5, 3
• Morning nausea and lack of appetite are particularly characteristic of primary adrenal insufficiency 6

Cardiovascular Signs

• Postural hypotension is a hallmark feature caused by mineralocorticoid deficiency and volume depletion in primary adrenal insufficiency 5, 3
• Unexplained hypotension should immediately raise suspicion for adrenal insufficiency, especially in patients taking ≥20 mg/day prednisone or equivalent for at least 3 weeks 6, 7
• Hypotension and collapse may represent the initial presentation, particularly in acute adrenal crisis 1, 7, 5

Skin and Pigmentation Changes (Primary Adrenal Insufficiency Only)

• Hyperpigmentation develops in primary adrenal insufficiency due to elevated ACTH levels, with darkening of skin in sun-exposed areas, skin creases, scars, and mucous membranes 1, 3
• Increased pigmentation with uneven distribution may indicate chronic glucocorticoid under-replacement 6
• This feature is absent in secondary adrenal insufficiency because ACTH levels are low rather than elevated 3

Salt Craving (Primary Adrenal Insufficiency Only)

• Salt craving is a specific clinical clue for primary adrenal insufficiency caused by aldosterone deficiency 6, 3
• This symptom does not occur in secondary adrenal insufficiency where the renin-angiotensin-aldosterone system remains intact 6

Laboratory Abnormalities as Clinical Clues

• Hyponatremia is present in 90% of newly presenting cases and is the most common electrolyte abnormality, though serum sodium levels are often only marginally reduced 1, 7, 5
• Hyperkalemia occurs in only approximately 50% of patients at diagnosis, so its absence does not rule out adrenal insufficiency 1, 7
• Hypoglycemia is more common in children but can occur in adults, particularly during acute illness or stress 1, 8
• Mild to moderate hypercalcemia is present in 10-20% of patients at presentation 1, 5
• Anemia, mild eosinophilia, lymphocytosis, and elevated liver transaminases may be present 1, 5

Adrenal Crisis: Life-Threatening Presentation

Adrenal crisis is a medical emergency that requires immediate treatment without waiting for diagnostic confirmation. 1, 7

• Severe abdominal pain, intractable nausea and vomiting are cardinal features 5
• Unexplained collapse with profound hypotension or shock 1, 7, 5
• Altered mental status progressing to coma if untreated 2
• Severe hyponatremia and hyperkalemia (though hyperkalemia may be absent if severe vomiting causes hypokalaemia and alkalosis) 1

Important Clinical Pitfalls

• The classical combination of hyponatremia and hyperkalemia is not reliable for diagnosis because serum sodium is often only marginally reduced and potassium is elevated in only about half of patients 1, 7
• Symptoms are often nonspecific and may be attributed to other conditions, leading to delayed diagnosis 2, 3, 9
• In the presence of severe vomiting, hypokalaemia and alkalosis may be present rather than the expected hyperkalemia 1
• Patients with sepsis or acute illness may have cortisol levels within the normal range that are inappropriately low for the disease state 1

Distinguishing Primary from Secondary Adrenal Insufficiency

• Hyperpigmentation, salt craving, and hyperkalemia suggest primary adrenal insufficiency 1, 6, 3
• Hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 6
• Primary adrenal insufficiency involves deficiency of all adrenocortical hormones (glucocorticoids, mineralocorticoids, and androgens) 2
• Secondary adrenal insufficiency involves only glucocorticoid deficiency, as the renin-angiotensin-aldosterone system remains intact 6, 2

High-Risk Clinical Scenarios Requiring Immediate Evaluation

• Any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks who develops unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 6, 7
• Patients presenting with unexplained collapse, hypotension, vomiting or diarrhea should have adrenal insufficiency considered in the differential diagnosis 1, 7
• Vasopressor-resistant hypotension in critically ill patients, particularly those with cirrhosis, should prompt evaluation for adrenal insufficiency 6