What are the manifestations and treatment of low serum cortisol levels in patients?

Clinical Manifestations and Treatment of Low Serum Cortisol

Clinical Manifestations

Low serum cortisol presents with nonspecific symptoms that can easily be missed, making a high index of suspicion essential for diagnosis.

Common Symptoms

• Fatigue occurs in 50-95% of patients and is often the most prominent presenting complaint 1
• Nausea and vomiting affect 20-62% of patients, frequently accompanied by poor appetite and unintentional weight loss 2, 1
• Anorexia and weight loss occur in 43-73% of cases, with morning nausea being particularly characteristic of glucocorticoid under-replacement 2, 1
• Salt craving is a specific clinical clue for primary adrenal insufficiency due to concurrent mineralocorticoid deficiency 2

Cardiovascular Manifestations

• Unexplained hypotension is a critical red flag, especially when requiring high-dose vasopressors or multiple vasopressor agents that remain refractory to treatment 2
• Orthostatic hypotension and lightheadedness suggest inadequate mineralocorticoid replacement in primary adrenal insufficiency 2
• Vasopressor-resistant hypotension may respond to stress-dose hydrocortisone alone, potentially avoiding high doses of other lymphocytotoxic corticosteroids 2

Metabolic and Electrolyte Abnormalities

• Hyponatremia is present in 90% of newly diagnosed cases and can be clinically indistinguishable from SIADH 2
• Hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases, so its absence cannot rule out the diagnosis 2
• Mild hypoglycemia with tendency towards low blood glucose is common, particularly during fasting or stress 3
• Between 10-20% of patients present with mild to moderate hypercalcemia, and some may have completely normal electrolytes 2

Life-Threatening Presentation: Adrenal Crisis

• Unexplained collapse, severe hypotension, and gastrointestinal symptoms (vomiting or diarrhea) should immediately raise suspicion for adrenal crisis 2
• Altered mental status, shock, and death can occur if untreated 1
• Treatment should NEVER be delayed for diagnostic procedures when adrenal crisis is suspected 2, 4

Diagnostic Approach

Initial Laboratory Testing

• Morning (8 AM) serum cortisol and plasma ACTH measured simultaneously are the first-line diagnostic tests 2, 1
• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 2
• Morning cortisol <250 nmol/L with low or inappropriately normal ACTH indicates secondary adrenal insufficiency 5, 4
• Basic metabolic panel should be obtained to assess for hyponatremia, hyperkalemia, and hypoglycemia 2

Confirmatory Testing

• The ACTH stimulation test (cosyntropin 0.25 mg IM or IV) is the gold standard when morning cortisol is indeterminate (5-10 μg/dL) 2, 1
• Measure serum cortisol at baseline and 30 and/or 60 minutes post-administration 2
• A peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and rules out adrenal insufficiency 2, 6
• A peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 2, 1

Distinguishing Primary from Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: high ACTH with low cortisol, often with hyponatremia AND hyperkalemia 2
• Secondary adrenal insufficiency: low or inappropriately normal ACTH with low cortisol, hyponatremia WITHOUT hyperkalemia 5, 4
• Primary AI requires both glucocorticoid and mineralocorticoid replacement; secondary AI requires only glucocorticoids 2, 5

Etiologic Workup for Primary Adrenal Insufficiency

• Measure 21-hydroxylase autoantibodies first, as autoimmunity accounts for ~85% of cases in Western populations 2
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 2
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 2

Critical Pitfall to Avoid

• Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound diagnostic testing 2
• If you need to treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 2, 4

Treatment

Emergency Management: Adrenal Crisis

If clinically unstable with suspected adrenal crisis, give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour (at least 2L total)—do NOT delay for diagnostic testing 2, 4

• Draw blood for cortisol and ACTH before treatment if possible, but never delay treatment 2
• Continue hydrocortisone 50-100 mg IV every 6-8 hours or 200 mg continuous infusion for 24-48 hours 2
• Aggressive fluid resuscitation with 0.9% saline is essential 2

Chronic Glucocorticoid Replacement

For Primary and Secondary Adrenal Insufficiency

• Hydrocortisone 15-25 mg daily in divided doses is the preferred glucocorticoid replacement 2, 1
• Typical regimens: 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM to approximate physiological cortisol secretion 2
• Alternative effective regimens include 15+5 mg, 10+10 mg, or 10+5+5 mg depending on individual response 2
• Alternative glucocorticoid: prednisone 3-5 mg daily or prednisolone 4-5 mg daily 2, 1

Timing Adjustments for Symptom Control

• For morning nausea and lack of appetite, have the patient wake earlier to take the first dose and return to sleep 2
• Adjust timing based on when symptoms occur during the day, with detailed questioning about energy dips 2

Mineralocorticoid Replacement (Primary AI Only)

• Fludrocortisone 0.05-0.1 mg daily is required for primary adrenal insufficiency 2, 1
• Typical dosing range is 50-200 µg daily, but doses up to 500 µg daily may be needed in younger adults 2
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, and peripheral edema 2
• Unrestricted sodium salt intake is essential alongside glucocorticoid and mineralocorticoid replacement 2
• Secondary adrenal insufficiency does NOT require mineralocorticoid replacement 5, 1

Stress Dosing Protocol

• All patients must be educated to double or triple their dose during illness, fever, or physical stress 2
• Minor stress: double the usual daily dose for 1-2 days 2
• Moderate stress (e.g., gastroenteritis, fever >38°C): hydrocortisone 50-75 mg daily or prednisone 20 mg daily 2
• Major stress (e.g., surgery, severe illness): hydrocortisone 100-150 mg daily 2
• Patients should be prescribed a hydrocortisone 100 mg IM injection kit with self-injection training 2

Drug Interactions and Considerations

• Medications that increase hydrocortisone requirements: anti-epileptics, antituberculosis drugs, antifungal medications, etomidate, topiramate 2
• Medications that interfere with fludrocortisone: diuretics, acetazolamide, NSAIDs 2
• Grapefruit juice and liquorice decrease hydrocortisone requirements and should be avoided 2

Special Consideration: Concurrent Hypothyroidism

When treating both adrenal insufficiency and hypothyroidism, corticosteroids MUST be started several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 2, 4

Mandatory Patient Education and Safety Measures

• All patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency 2, 1
• Patients need instruction on warning signs of impending adrenal crisis 2
• Endocrine consultation is mandatory for newly diagnosed patients, pre-operative planning, and any patient with recurrent adrenal crises 2

Monitoring for Under-Replacement

• Lethargy, nausea, poor appetite, weight loss, and increased pigmentation (in primary AI) suggest glucocorticoid under-replacement 2
• Persistent hypotension, salt cravings, or orthostatic symptoms suggest mineralocorticoid under-replacement in primary AI 2

Annual Screening (Primary AI)

• Patients with primary adrenal insufficiency should undergo annual screening for associated autoimmune conditions: thyroid function, diabetes, pernicious anemia, and celiac disease 2