What is adrenal insufficiency?

What is Adrenal Insufficiency

Adrenal insufficiency is a syndrome of cortisol deficiency caused by inadequate production of glucocorticoids by the adrenal cortex (primary), insufficient ACTH secretion from the pituitary (secondary), or suppression of the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoids (tertiary/iatrogenic). 1, 2

Classification and Pathophysiology

Adrenal insufficiency is categorized into three distinct types based on the anatomical level of dysfunction:

Primary Adrenal Insufficiency (Addison's Disease)

• The underlying pathology lies within the adrenal gland itself, resulting in deficiency of cortisol, aldosterone, and adrenal androgens. 1
• Autoimmune destruction accounts for approximately 85% of cases in Western populations, with other causes including congenital adrenal hyperplasia (1 in 15,000 live births), tuberculosis, fungal infections, adrenal hemorrhage, metastatic disease, and pharmacological inhibition from high-dose azole antifungals. 1, 2
• Prevalence is 10-15 per 100,000 population, affecting approximately 1 in 8,000-10,000 individuals. 1

Secondary Adrenal Insufficiency

• The defect originates in the pituitary gland with inadequate ACTH production, resulting in cortisol deficiency while aldosterone secretion remains intact through the renin-angiotensin system. 1
• Causes include pituitary tumors, hemorrhage, inflammatory conditions (hypophysitis, sarcoidosis, hemochromatosis), surgery, radiation therapy, or medications that suppress ACTH production such as opioids. 2

Tertiary/Iatrogenic Adrenal Insufficiency

• This results from suppression of the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoid therapy across all routes of administration (oral, inhaled, topical, intranasal, intra-articular). 1, 3
• Approximately 7 in 1,000 people are prescribed long-term oral corticosteroids—roughly 100 times the number with intrinsic adrenal disease—creating a large at-risk population. 1
• Inhaled corticosteroids at commonly prescribed doses can cause dose-dependent HPA axis suppression, contrary to earlier beliefs. 1

Clinical Presentation

Common Symptoms

• Fatigue occurs in 50-95% of patients, nausea and vomiting in 20-62%, and anorexia with weight loss in 43-73% of cases. 2
• Morning nausea, lack of appetite, lethargy, and poor energy are particularly characteristic of glucocorticoid under-replacement. 4
• Salt craving is a specific clinical clue for primary adrenal insufficiency due to aldosterone deficiency. 4
• Hyperpigmentation occurs in primary adrenal insufficiency from elevated ACTH levels stimulating melanocytes. 1

Laboratory Findings at Presentation

• Hyponatremia is present in 90% of newly diagnosed cases, but hyperkalemia occurs in only approximately 50% of patients with primary adrenal insufficiency. 1, 4
• The classic combination of hyponatremia and hyperkalemia is not reliable for diagnosis because sodium levels are often only marginally reduced. 1
• Between 10-20% of patients have mild or moderate hypercalcemia at presentation. 1
• Anemia, mild eosinophilia, lymphocytosis, and increased liver transaminases may be present. 1
• Children are particularly prone to hypoglycemia and hypoglycemic seizures, though this is rare in adults. 1, 5

Life-Threatening Complications

Adrenal Crisis

• Prior to the 1940s synthesis of corticosteroids, primary adrenal insufficiency was always fatal; premature death from adrenal crises remains a problem today despite available treatment. 1
• Adrenal crisis presents with hypovolemic shock, severe hypotension, altered mental status, vomiting, diarrhea, and can cause death if untreated. 2, 6
• All steroid-dependent patients are at risk of adrenal crisis during acute illness, physical stress, or inadequate glucocorticoid therapy. 1, 2

Mortality Risk

• In a Swedish cohort of 1,675 patients with adrenal insufficiency, the risk ratio for all-cause mortality was 2.19 for men and 2.86 for women. 1

Associated Conditions

Autoimmune Polyendocrine Syndromes

• Approximately one-half of patients with primary adrenal insufficiency have co-existing autoimmune diseases. 1
• Common associations include autoimmune thyroid disease, autoimmune gastritis with vitamin B12 deficiency, type 1 diabetes mellitus, premature ovarian insufficiency, vitiligo, and celiac disease. 1
• Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by AIRE gene mutations and defined by two of three components: primary adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis. 1
• Autoimmune polyendocrine syndrome type-2 (APS-2) most commonly involves primary adrenal insufficiency with primary hypothyroidism, plus other conditions like Graves' disease or type 1 diabetes. 1

Long-Term Health Impacts

• Patients face increased risk of therapy-related osteoporosis and cardiovascular complications. 1
• Quality of life and ability to work is reduced in many patients. 1
• Women have concerns about fertility due to increased risk of autoimmune premature ovarian insufficiency and sexual dysfunction from androgen deficiency. 1

Diagnostic Principles

Initial Testing

• The diagnosis requires paired measurement of early morning (8 AM) serum cortisol and plasma ACTH, with additional measurement of DHEAS to distinguish primary from secondary causes. 1, 4, 2
• Primary adrenal insufficiency: low morning cortisol (<5 µg/dL or <140 nmol/L), high ACTH, and low DHEAS. 4, 2
• Secondary adrenal insufficiency: low or intermediate cortisol (5-10 µg/dL or 140-275 nmol/L), low or inappropriately normal ACTH, and low DHEAS. 4, 2

Confirmatory Testing

• The ACTH stimulation test (cosyntropin/Synacthen test) is the gold standard for confirming adrenal insufficiency when initial results are indeterminate. 1, 4
• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously, with cortisol measurements at baseline and 30 and/or 60 minutes. 1, 4
• Peak cortisol <500 nmol/L (<18 µg/dL) is diagnostic of adrenal insufficiency; >550 nmol/L (>18-20 µg/dL) is normal. 1, 4

Critical Diagnostic Pitfall

• Treatment of suspected acute adrenal insufficiency should NEVER be delayed by diagnostic procedures—if the patient is clinically unstable, give 100 mg IV hydrocortisone immediately. 1, 4

Treatment Fundamentals

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) or prednisone 3-5 mg daily is the standard maintenance therapy. 4, 2
• Hydrocortisone is preferred over long-acting steroids because it allows recreation of the diurnal cortisol rhythm. 4

Mineralocorticoid Replacement (Primary AI Only)

• Fludrocortisone 0.05-0.3 mg daily is required for primary adrenal insufficiency to replace aldosterone deficiency. 4, 6, 2
• Secondary adrenal insufficiency does NOT require mineralocorticoid replacement because the renin-angiotensin-aldosterone system remains intact. 4

Patient Education Requirements

• All patients must receive instruction on stress dosing (doubling or tripling doses during illness), wear a medical alert bracelet, and be prescribed injectable hydrocortisone 100 mg IM with self-injection training. 1, 4, 2