Addison's disease

Addison’s disease

_{^{is a specific type of adrenal insufficiency where the problem lies entirely within the adrenal cortex itself.}}

• Primary Adrenal Insufficiency: The adrenal glands are physically destroyed or dysfunctional.

• Most Common Cause: Autoimmune adrenalitis (in developed nations). Globally, tuberculosis remains a major infectious cause.

• The Deficit: The adrenal cortex fails to produce all three classes of cortical hormones (Mnemonic: Sugar, Salt, S*x):

Glucocorticoids (Cortisol)

Made in the Zona Fasciculata. Lack of cortisol impairs gluconeogenesis, reduces vascular tone, and removes the negative feedback on the pituitary.

Mineralocorticoids (Aldosterone)

Made in the Zona Glomerulosa. Lack of aldosterone prevents sodium reabsorption and potassium excretion in the kidneys.

Androgens (DHEA)

Made in the Zona Reticularis. Lack of androgens primarily affects women, causing loss of axillary/pubic hair and decreased libido.

Secondary adrenal insufficiency

(caused by pituitary disease or abrupt withdrawal of exogenous steroids) results in low cortisol and low ACTH, but aldosterone levels remain normal (because aldosterone is regulated by the Renin-Angiotensin System, not ACTH). Therefore, hyperkalemia and profound hypotension are rare in secondary insufficiency.

Clinical Presentation & Electrolyte Derangements

Skin: Hyperpigmentation

Cardiovascular: Hypotension and postural (orthostatic) dizziness

Gastrointestinal

Metabolic/Laboratory Hallmarks

Skin: Hyperpigmentation

(palmar creases, buccal mucosa, scars). As discussed, this is due to high ACTH/POMC and alpha-MSH due to lack of negative feedback from cortisol.

Cardiovascular: Hypotension and postural (orthostatic) dizziness

This is a direct result of sodium/water loss (lack of aldosterone) and decreased vascular sensitivity to catecholamines (lack of cortisol).

Gastrointestinal

Anorexia, weight loss, nausea, vomiting, and non-specific abdominal pain.

Metabolic/Laboratory Hallmarks:

• Hyponatremia (low sodium)

• Hyperkalemia (high potassium)

• Hypoglycemia (low glucose)

• Metabolic Acidosis (mild, non-anion gap)

Diagnostic Testing

Morning Serum Cortisol

Basal Plasma ACTH

The Gold Standard (Cosyntropin Stimulation Test)

Morning Serum Cortisol

A low 8:00 AM cortisol level (< 3 mcg/dL) strongly suggests insufficiency.

Basal Plasma ACTH

In primary disease (Addison’s), ACTH will be markedly elevated (> 100 pg/mL) because the pituitary is screaming at the adrenal glands to work. In secondary disease, ACTH is low or inappropriately normal.

The Gold Standard (Cosyntropin Stimulation Test)

• Administer 250 mcg of synthetic ACTH (Cosyntropin) IV or IM.

• Measure cortisol at baseline, 30 minutes, and 60 minutes.

• Interpretation: In a healthy patient, cortisol will rise robustly. In Addison’s disease, the damaged adrenal glands cannot respond, and cortisol remains low (< 18 mcg/dL).

Glucocorticoid Replacement

• First-Line Agent: Hydrocortisone (15–25 mg/day). It is preferred because it most closely mimics endogenous cortisol and possesses some inherent mineralocorticoid activity.

• Dosing Regimen: Must simulate the natural diurnal rhythm (highest upon waking, lowest at night).

Dosing Regimen in glucocorticoid replacement

Typical split: Two-thirds (e.g., 15 mg) given immediately upon waking in the morning, and one-third (e.g., 5-10 mg) given in the early afternoon (around 2:00 PM - 4:00 PM). Avoid giving late in the evening to prevent insomnia.

alternative for glucocorticoid replacement

Prednisone (3-5 mg once daily) or Dexamethasone (0.5-0.75 mg once daily) are longer-acting and easier for adherence, but hydrocortisone remains the gold standard.

Mineralocorticoid Replacement

• First-Line Agent: Fludrocortisone (0.05–0.2 mg once daily in the morning).

• Monitoring: Efficacy is monitored by checking blood pressure (specifically looking for orthostatic hypotension), serum sodium, serum potassium, and plasma renin activity (aiming for the upper half of the normal reference range).

Stress Dosing

The body normally produces massive amounts of cortisol during physical stress. Addisonian patients cannot do this.

Minor Stress (Fever > 38°C, minor infection, tooth extraction)

Double or triple the daily glucocorticoid dose until recovery (usually 2-3 days). (Do NOT adjust the fludrocortisone dose).

Major Stress (Surgery, severe trauma, childbirth)

Requires IV hydrocortisone (typically 50-100 mg every 6-8 hours).

Emergency Precautions

• Patients must wear a Medical Alert bracelet or necklace.

• Patients must carry a Glucocorticoid Emergency Kit (e.g., injectable hydrocortisone sodium succinate 100 mg vial or dexamethasone 4 mg pre-filled syringe) and know how to self-inject IM if they begin vomiting and cannot tolerate oral medications.

Acute Adrenal Crisis (Medical Emergency)

Severe hypotension refractory to pressors, acute abdominal pain (often mimicking an acute surgical abdomen), intractable vomiting, fever, and altered mental status.

Management Protocol (The 3 Pillars): adrenal crisis

Immediate Volume Resuscitation: Aggressive IV fluids. 0.9% Normal Saline to correct severe hypovolemia and hyponatremia. If the patient is hypoglycemic, use 5% Dextrose in Normal Saline (D5NS).

• Immediate IV Glucocorticoids:

  • Hydrocortisone 100 mg IV bolus immediately.

  • Followed by continuous IV infusion (200 mg/24 hours) OR 50 mg IV every 6 hours.

  • PhLE Pearl: High-dose IV hydrocortisone (>50 mg) provides sufficient mineralocorticoid cross-reactivity, so fludrocortisone is not needed during the acute resuscitation phase.

• Identify and Treat the Precipitating Cause: Empiric antibiotics for suspected infection.