Adrenal Insufficiency for the ABIM
Start your One-Week Free Trial
Already subscribed? Log in »
Adrenal Insufficiency for the American Board of Internal Medicine Exam
- Pathophysiology
- Primary Adrenal Insufficiency (Addison’s Disease): Results from the destruction or dysfunction of the adrenal cortex, leading to decreased production of glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens. In primary adrenal insufficiency, both cortisol and aldosterone are affected.
- Glucocorticoid Deficiency: Leads to impaired metabolism of carbohydrates, fats, and proteins, causing hypoglycemia and fatigue.
- Mineralocorticoid Deficiency: Causes impaired sodium reabsorption and potassium excretion, leading to hyponatremia, hyperkalemia, and hypotension.
- Adrenal Androgen Deficiency: Decreased production of adrenal androgens leads to reduced hair growth, especially in women.
- Secondary Adrenal Insufficiency: Caused by inadequate secretion of adrenocorticotropic hormone (ACTH) from the pituitary, which results in decreased cortisol production but preserved aldosterone secretion, as aldosterone is regulated by the renin-angiotensin-aldosterone system (RAAS). Most cases are secondary to chronic exogenous glucocorticoid use, which suppresses the hypothalamic-pituitary-adrenal (HPA) axis.
- Tertiary Adrenal Insufficiency: Results from dysfunction of the hypothalamus, leading to reduced corticotropin-releasing hormone (CRH) and subsequent reduction in ACTH and cortisol production. It is also often related to chronic glucocorticoid therapy.
- Etiology
- Primary Adrenal Insufficiency:
- Autoimmune Destruction: The most common cause in developed countries, known as autoimmune adrenalitis, where the body’s immune system attacks the adrenal cortex.
- Infectious Causes: Tuberculosis (most common worldwide), fungal infections (e.g., histoplasmosis), HIV, and CMV infections can destroy the adrenal glands.
- Metastasis: Adrenal metastases from cancers, especially lung and breast cancers, can result in adrenal insufficiency.
- Adrenal Hemorrhage: Seen in Waterhouse-Friderichsen syndrome, often secondary to meningococcal sepsis, or in anticoagulant use.
- Congenital Adrenal Hyperplasia (CAH): A genetic disorder resulting in enzyme deficiencies that impair cortisol production.
- Secondary Adrenal Insufficiency:
- Chronic Exogenous Glucocorticoid Use: Long-term use of glucocorticoids suppresses ACTH production, leading to adrenal atrophy.
- Pituitary Disorders: Pituitary tumors, surgery, or radiation that damage ACTH-secreting cells.
- Tertiary Adrenal Insufficiency: Often due to hypothalamic tumors, surgery, or chronic glucocorticoid use.
- Clinical Features
- Primary Adrenal Insufficiency (Addison's Disease):
- Fatigue, Weakness, and Anorexia: Common symptoms due to glucocorticoid deficiency.
- Hypotension: Resulting from both glucocorticoid and mineralocorticoid deficiencies.
- Hyponatremia and Hyperkalemia: Caused by aldosterone deficiency, leading to decreased sodium reabsorption and potassium excretion.
- Hyperpigmentation: Occurs due to increased ACTH, which shares a precursor with melanocyte-stimulating hormone (MSH), leading to increased pigmentation, particularly in the skin creases, gums, and areas exposed to friction.
- Salt Craving: Due to aldosterone deficiency, causing sodium loss.
- Hypoglycemia: Results from cortisol deficiency and impaired gluconeogenesis.
- Secondary and Tertiary Adrenal Insufficiency:
- Similar to primary adrenal insufficiency, except no hyperpigmentation and no significant hyperkalemia since aldosterone secretion is preserved.
- Symptoms are often less severe and more insidious in onset compared to primary adrenal insufficiency.
- Hypoglycemia and hypotension can still occur due to cortisol deficiency.
- Diagnosis
- Initial Testing:
- Morning Serum Cortisol: A low cortisol level (<5 µg/dL) in the morning suggests adrenal insufficiency.
- ACTH Level:
- Elevated ACTH in primary adrenal insufficiency.
- Low or inappropriately normal ACTH in secondary or tertiary adrenal insufficiency.
- Confirmatory Testing:
- ACTH Stimulation Test (Cosyntropin Test): Synthetic ACTH (cosyntropin) is administered, and cortisol levels are measured at baseline and 30–60 minutes after administration.
- Primary Adrenal Insufficiency: Cortisol fails to rise adequately (<18 µg/dL).
- Secondary/Tertiary Adrenal Insufficiency: A delayed or blunted rise in cortisol occurs, but cortisol may still increase somewhat depending on the degree of adrenal atrophy.
- Other Tests:
- Electrolytes: Hyponatremia and hyperkalemia are common in primary adrenal insufficiency.
- Imaging: Abdominal CT to evaluate adrenal glands for tumors, hemorrhage, or calcification (especially in TB). MRI of the pituitary may be needed in secondary adrenal insufficiency.
- Management
- Primary Adrenal Insufficiency:
- Glucocorticoid Replacement: Hydrocortisone or prednisone is used to replace cortisol. Dosing is typically split, with a higher dose in the morning and a lower dose in the evening to mimic the natural diurnal rhythm.
- Mineralocorticoid Replacement: Fludrocortisone is given to replace aldosterone and help control blood pressure, sodium levels, and potassium balance.
- Androgen Replacement: DHEA (dehydroepiandrosterone) may be considered in some women to improve well-being, libido, and energy levels.
- Secondary and Tertiary Adrenal Insufficiency:
- Glucocorticoid Replacement: Hydrocortisone or prednisone. Mineralocorticoid replacement is not needed since aldosterone production is intact.
- Tapering Exogenous Glucocorticoids: For those with glucocorticoid-induced adrenal insufficiency, glucocorticoids should be tapered slowly to allow the HPA axis to recover.
- Acute Adrenal Crisis:
- This is a life-threatening emergency, often precipitated by infection, surgery, or trauma in individuals with adrenal insufficiency.
- Symptoms: Severe hypotension, vomiting, abdominal pain, fever, and confusion.
- Treatment:
- Immediate IV administration of high-dose hydrocortisone.
- Aggressive fluid resuscitation with normal saline.
- Correction of electrolyte abnormalities (e.g., hyponatremia, hyperkalemia).
- Complications
- Adrenal Crisis: Can occur in both primary and secondary adrenal insufficiency, precipitated by stress, trauma, or infection. It is characterized by hypotension, shock, and electrolyte disturbances.
- Chronic Adrenal Insufficiency: If untreated, leads to fatigue, weakness, weight loss, and decreased quality of life. Even with treatment, careful monitoring of glucocorticoid dosing is essential to avoid complications like osteoporosis or Cushingoid features from overtreatment.
Key Points
- Pathophysiology: Primary adrenal insufficiency involves destruction of the adrenal cortex, leading to cortisol and aldosterone deficiencies. Secondary and tertiary adrenal insufficiency result from reduced ACTH or CRH, causing cortisol deficiency with preserved aldosterone secretion.
- Etiology: Primary adrenal insufficiency is most commonly autoimmune. Other causes include infections, metastases, and adrenal hemorrhage. Secondary causes include chronic glucocorticoid use and pituitary disorders.
- Clinical Features: Primary adrenal insufficiency presents with hyperpigmentation, fatigue, hypotension, hyponatremia, hyperkalemia, and hypoglycemia. Secondary/tertiary forms lack hyperpigmentation and typically preserve aldosterone function.
- Diagnosis: Low morning cortisol, elevated ACTH in primary insufficiency, and an ACTH stimulation test help confirm the diagnosis. Electrolytes may show hyponatremia and hyperkalemia in primary disease.
- Treatment: Glucocorticoid and mineralocorticoid replacement in primary adrenal insufficiency, while only glucocorticoids are needed in secondary and tertiary forms. Acute adrenal crisis requires urgent IV hydrocortisone and fluid resuscitation.
- Complications: Untreated adrenal insufficiency can lead to adrenal crisis, which is a life-threatening emergency characterized by shock and severe electrolyte imbalances.