What is the approach to diagnose and manage adrenal insufficiency?

How to Identify Adrenal Insufficiency

Clinical Presentation: When to Suspect the Diagnosis

Consider adrenal insufficiency in any patient presenting with unexplained collapse, hypotension, vomiting, diarrhea, or profound fatigue—these are the hallmark presentations that should immediately trigger diagnostic evaluation. 1

Key Clinical Features That Raise Suspicion

• Cardiovascular: Hypotension (especially postural), vasopressor-resistant shock, unexplained collapse 1, 2
• Gastrointestinal: Nausea and vomiting (20-62% of cases), anorexia, weight loss (43-73%), abdominal pain 2, 3
• Constitutional: Profound fatigue (50-95% of cases), muscle weakness 2, 3
• Dermatologic (Primary AI only): Hyperpigmentation of skin and mucous membranes, salt craving 1, 3

Laboratory Clues

• Hyponatremia is present in 90% of newly diagnosed cases and is the most common electrolyte abnormality 4
• Hyperkalemia occurs in only ~50% of cases, so its absence does NOT rule out adrenal insufficiency 1, 4
• Hypoglycemia, acidosis, and elevated TSH (4-10 IU/L range) may be present 1

High-Risk Populations Requiring Heightened Vigilance

• Patients taking ≥20 mg/day prednisone (or equivalent) for ≥3 weeks who develop unexplained hypotension 4
• Recent tapering or discontinuation of supraphysiological glucocorticoid doses 2
• Patients on chronic opioid therapy (suppresses ACTH production) 2
• History of pituitary/hypothalamic disease, surgery, or radiation 2

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Diagnostic Algorithm: Step-by-Step Approach

Step 1: Initial Laboratory Testing (Morning 8 AM Samples)

Obtain paired measurement of serum cortisol and plasma ACTH as the first-line diagnostic test—this single test combination can often establish the diagnosis without further testing. 1, 5

• Draw blood at approximately 8 AM for serum cortisol, plasma ACTH, and DHEAS 2, 6
• Simultaneously obtain basic metabolic panel (sodium, potassium, CO2, glucose) 4, 5

Step 2: Interpret Initial Results

Primary Adrenal Insufficiency Pattern:

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic 1, 4, 5
• Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH in acute illness raises strong suspicion 1, 5
• Low DHEAS levels support primary adrenal insufficiency 1, 2

Secondary/Glucocorticoid-Induced Adrenal Insufficiency Pattern:

• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH 4, 2
• Low or low-normal DHEAS levels 2

Clearly Normal:

• Morning cortisol >550 nmol/L (>18-20 μg/dL) effectively rules out adrenal insufficiency 4, 2

Step 3: Confirmatory Testing (When Initial Results Are Equivocal)

For intermediate cortisol values (140-400 nmol/L or 5-14.5 μg/dL), perform the cosyntropin (Synacthen) stimulation test to definitively confirm or exclude the diagnosis. 1, 4

Cosyntropin Stimulation Test Protocol:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 4
• Measure serum cortisol at baseline and at 30 and/or 60 minutes post-administration 1, 4
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 4, 5
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and excludes the diagnosis 4, 2

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Determining the Underlying Cause

For Confirmed Primary Adrenal Insufficiency

Step 1: Measure 21-hydroxylase (anti-adrenal) autoantibodies first—this identifies autoimmune etiology in ~85% of cases in Western populations. 1, 4, 5

Step 2: If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for:

• Adrenal hemorrhage
• Tumors or metastases
• Tuberculosis or fungal infections
• Structural abnormalities 1, 4, 5

Step 3: In male patients with negative antibodies, measure very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 4, 5

For Confirmed Secondary Adrenal Insufficiency

• Evaluate for pituitary/hypothalamic pathology with MRI imaging 2
• Assess other pituitary hormone axes (TSH, LH/FSH, prolactin, IGF-1) 2
• Review medication history for opioids, glucocorticoids, or other ACTH-suppressing agents 2

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Critical Pitfalls and How to Avoid Them

Pitfall #1: Delaying Treatment While Awaiting Test Results

NEVER delay treatment of suspected acute adrenal crisis for diagnostic procedures—this is the most dangerous mistake and can be fatal. 1, 4, 5

• If the patient is hemodynamically unstable with suspected adrenal crisis, immediately administer:
  • IV hydrocortisone 100 mg bolus, followed by 100 mg every 6-8 hours 1, 5, 7
  • 0.9% sodium chloride solution at 1 L/hour until hemodynamic improvement 1, 5, 7
• Draw blood for cortisol and ACTH before treatment if possible, but do NOT delay treatment 4, 5

Pitfall #2: Using Hydrocortisone When You Still Need Diagnostic Testing

If you need to treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone—dexamethasone does not interfere with cortisol assays. 4, 8

Pitfall #3: Relying on Electrolyte Abnormalities to Make or Exclude the Diagnosis

• Hyperkalemia is present in only ~50% of cases, so normal potassium does NOT rule out adrenal insufficiency 1, 4
• Some patients have completely normal electrolytes at presentation 4
• 10-20% of patients may have mild or moderate hypercalcemia 4

Pitfall #4: Misinterpreting Cortisol Levels in Patients on Exogenous Steroids

Oral prednisolone, dexamethasone, and inhaled steroids (fluticasone) can suppress the HPA axis and confound interpretation of cortisol levels. 1, 4

• Document all steroid use (including inhaled and topical) before testing 1
• Consider that chronic glucocorticoid use is a common cause of iatrogenic secondary adrenal insufficiency 4, 2

Pitfall #5: Diagnosing SIADH Without Excluding Adrenal Insufficiency

Adrenal insufficiency can present with a clinical picture nearly identical to SIADH—both show euvolemic hypo-osmolar hyponatremia with inappropriately high urine osmolality and elevated urinary sodium. 4

• The cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia 4
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 4

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Special Considerations

Hyponatremia Workup

When evaluating hyponatremia with hypo-osmolality, adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present with:

• Serum sodium <134 mEq/L
• Plasma osmolality <275 mOsm/kg
• Inappropriately high urine osmolality
• Elevated urinary sodium concentration 4

Screening for Associated Autoimmune Conditions

Once primary adrenal insufficiency is diagnosed, annual screening should include:

• Thyroid function (TSH, FT4, TPO antibodies) every 12 months 1
• Plasma glucose and HbA1c for diabetes mellitus 1
• Complete blood count for anemia 1
• Vitamin B12 levels for autoimmune gastritis 1
• Tissue transglutaminase antibodies and total IgA for celiac disease if diarrhea present 1
• Consider screening for premature ovarian insufficiency in women of reproductive age, especially if SCC antibodies present 1