What are the diagnostics, presentation, and treatment for adrenal insufficiency?

Adrenal Insufficiency: Diagnostics, Presentation, and Treatment

Clinical Presentation

Adrenal insufficiency should be suspected in any patient presenting with unexplained collapse, hypotension, vomiting, or diarrhea, particularly when accompanied by hyponatremia, hyperkalemia, or hyperpigmentation. 1

Chronic Symptoms

• Fatigue (50-95% of patients) is the most common presenting symptom 2
• Nausea and vomiting (20-62% of patients) 2
• Anorexia and weight loss (43-73% of patients) 2
• Salt craving due to aldosterone deficiency (specific to primary adrenal insufficiency) 1
• Postural hypotension leading to dizziness, syncope, or unexplained collapse 1
• Muscle and joint pain 3

Physical Examination Findings Specific to Primary Adrenal Insufficiency

• Hyperpigmentation in sun-exposed areas, skin creases, and mucous membranes due to elevated ACTH levels 1, 4
• Postural hypotension reflecting insufficient mineralocorticoid therapy 5
• Weight loss indicating insufficient glucocorticoid dosing 5

Adrenal Crisis Presentation

• Severe hypotension or shock not responsive to fluid resuscitation 1, 4
• Altered mental status including confusion, loss of consciousness, and coma 1, 4
• Severe dehydration 4
• Abdominal pain (often mimicking acute abdomen) 4
• Fever especially if triggered by infection 1

Diagnostic Approach

Initial Laboratory Testing

Draw early-morning (approximately 8 AM) serum cortisol, ACTH, and DHEAS before initiating treatment, but never delay treatment waiting for results if adrenal crisis is suspected. 4, 2

Primary Adrenal Insufficiency Laboratory Pattern

• Low morning cortisol (<5 µg/dL or <138 nmol/L) 2
• Elevated plasma ACTH 4, 2
• Low DHEAS levels 2
• Hyponatremia (present in ~90% of newly presenting cases) 4
• Hyperkalemia (present in ~50% of patients) 4
• Mild hypercalcemia (10-20% of patients) 1, 4

Secondary Adrenal Insufficiency Laboratory Pattern

• Low or intermediate morning cortisol (5-10 µg/dL) 2
• Low or low-normal ACTH 2
• Low or low-normal DHEAS 2
• Hyponatremia may be present, but hyperkalemia is absent (no mineralocorticoid deficiency) 2

Confirmatory Testing

• Cosyntropin stimulation test for patients with intermediate early-morning cortisol levels (5-10 µg/dL): measure cortisol before and 60 minutes after administration of cosyntropin 250 µg 2, 3
• Serum cortisol <250 nmol/L with increased ACTH is diagnostic of primary adrenal insufficiency 4

Etiologic Workup

• Test for 21-hydroxylase autoantibodies (21OH-Ab) which are positive in autoimmune Addison disease (approximately 85% of cases in Western Europe) 4
• CT scan of the adrenals if 21OH-Ab is negative, to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative processes 4
• Very long chain fatty acids (VLCFA) if adrenoleukodystrophy is suspected 4

Associated Autoimmune Conditions Screening

• Thyroid function tests (TSH, FT4, TPO-Ab) every 12 months, as hypothyroidism or thyrotoxicosis frequently develops 5, 6
• Vitamin B12 levels annually to screen for autoimmune gastritis 5, 6
• Plasma glucose and HbA1c to screen for type 1 diabetes 5, 6
• Complete blood count to screen for anemia 5, 6
• Tissue transglutaminase 2 autoantibodies and total IgA in patients with frequent or episodic diarrhea to screen for coeliac disease 5

Treatment

Acute Adrenal Crisis Management

Administer hydrocortisone 100 mg IV bolus immediately upon clinical suspicion of adrenal crisis, followed by rapid IV administration of isotonic saline at 1 L/hour. 6, 4

Immediate Emergency Steps

• Hydrocortisone 100 mg IV bolus immediately (this dose saturates 11β-hydroxysteroid dehydrogenase type 2 to provide mineralocorticoid effect) 4, 7
• Isotonic saline (0.9%) at 1 liter over the first hour, followed by 3-4 L over 24 hours with frequent hemodynamic monitoring 6, 4
• Draw blood for cortisol, ACTH, electrolytes, creatinine, and glucose before treatment, but do not delay therapy 4

Subsequent Management

• Continue hydrocortisone 100-300 mg/day as continuous IV infusion or divided IV/IM doses every 6 hours 6, 4
• Monitor serum electrolytes frequently to guide fluid management 4
• Do not add separate mineralocorticoid (fludrocortisone) during acute crisis, as high-dose hydrocortisone provides adequate mineralocorticoid activity 4
• Taper parenteral glucocorticoids over 1-3 days to oral maintenance therapy as the patient's condition improves 6, 4

Maintenance Therapy

Hydrocortisone 15-25 mg daily in divided doses (2-3 times daily) is the preferred glucocorticoid for replacement therapy, with fludrocortisone 50-200 µg daily required for primary adrenal insufficiency. 6, 2

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily divided into 2-3 doses 6, 2
• Common dosing schedule: 10 mg + 5 mg + 2.5 mg (morning, midday, afternoon) 6
• First dose immediately upon waking, last dose at least 6 hours before bedtime to avoid sleep disturbances 6
• Cortisone acetate 18.75-31.25 mg daily can be used as an alternative 6

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 50-200 µg once daily 6, 2
• Higher doses (up to 500 µg daily) may be needed in children, younger adults, or during the last trimester of pregnancy 6
• Patients should consume salt and salty foods without restriction 6

Stress Dosing

Minor Illness with Fever

• Double or triple the usual glucocorticoid dose 6

Major Surgery

• Hydrocortisone 100 mg IM before anesthesia, followed by 100 mg IM every 6 hours until able to take oral medications 6

Minor Surgery

• Hydrocortisone 100 mg IM before anesthesia, then double oral dose for 24 hours 6

Prevention of Adrenal Crisis

All patients must wear medical alert identification jewelry and be educated on increasing steroid doses during intercurrent illnesses, vomiting, injuries, or other stressors. 6, 1

Patient Education Essentials

• Increase glucocorticoid doses during intercurrent illness to prevent crisis 6, 4
• Carry emergency injectable hydrocortisone (100 mg IM) and know how to self-administer 1, 2
• Seek medical help before reaching a state of inability to self-care 5
• Even mild upset stomach may precipitate crisis as patients cannot absorb oral medication when needed most 4

Common Precipitating Factors to Avoid

• Gastrointestinal illness with vomiting/diarrhea (most common trigger) 6, 4
• Infections of any type 6, 4
• Surgical procedures without adequate steroid coverage 6, 4
• Physical injuries or trauma 6, 4
• Severe allergic reactions 6, 4

Follow-up and Monitoring

Annual Assessment

• Evaluate symptoms, weight, and blood pressure 6
• Serum sodium, potassium, glucose, HbA1c, and complete blood count 6
• Thyroid function tests (TSH, FT4, TPO-Ab) 6
• Vitamin B12 levels 6

Signs of Inadequate Replacement

• Weight loss, fatigue, postural hypotension, salt craving, hyperpigmentation (in primary adrenal insufficiency) 6

Signs of Excessive Replacement

• Weight gain, hypertension, and edema 6

Critical Pitfalls and Caveats

• Never delay treatment for diagnostic procedures when adrenal crisis is suspected, as mortality increases with delayed intervention 1, 4
• Under-replacement with mineralocorticoids is common and can predispose to recurrent adrenal crises 6, 4
• Never start thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies, as this can trigger adrenal crisis 4
• Anti-epileptic drugs and barbiturates may increase hydrocortisone requirements by accelerating cortisol clearance 6, 4
• Essential hypertension should be treated with vasodilators rather than stopping mineralocorticoid replacement 6
• Absence of hyperkalemia does not exclude adrenal crisis, as it is present in only 50% of cases 4
• Chronic under-replacement with fludrocortisone combined with low salt consumption contributes to recurrent crises 5, 4