Addison’s Disease: Clinical Presentation, Pathophysiology, and Management

Addison’s disease, also known as primary adrenal insufficiency, is a rare but clinically significant endocrine disorder characterized by inadequate production of corticosteroids due to destruction or dysfunction of the adrenal cortex. Named after Dr. Thomas Addison, who first described the syndrome in 1855, the disease represents a failure of the adrenal glands to produce sufficient amounts of cortisol, and in many cases, aldosterone. Cortisol, the principal glucocorticoid, is essential for maintaining metabolic homeostasis, regulating immune responses, and mediating adaptation to stress. Aldosterone, a mineralocorticoid, plays a key role in electrolyte and fluid balance. A deficiency of these hormones has wide-ranging systemic effects, affecting cardiovascular, metabolic, and neurological function. This essay explores the etiology, pathophysiology, clinical manifestations, diagnostic features, and management of Addison’s disease, with an emphasis on understanding symptoms through the underlying hormonal deficits.

---

Anatomy and Function of the Adrenal Cortex

The adrenal glands are paired endocrine organs located atop the kidneys. Each gland comprises two anatomically and functionally distinct regions: the cortex and the medulla. The adrenal cortex is further divided into three zones, each responsible for producing distinct classes of steroid hormones. The zona glomerulosa synthesizes mineralocorticoids, primarily aldosterone, which regulates sodium and potassium balance. The zona fasciculata produces glucocorticoids, mainly cortisol, which regulate carbohydrate, protein, and fat metabolism, immune responses, and stress adaptation. The zona reticularis secretes adrenal androgens such as dehydroepiandrosterone (DHEA), which contribute modestly to circulating androgen levels, particularly in women. Destruction or dysfunction of the adrenal cortex in Addison’s disease impairs production of cortisol and often aldosterone, leading to systemic manifestations. The adrenal medulla, which secretes catecholamines such as epinephrine and norepinephrine, is usually spared in primary adrenal insufficiency.

---

Etiology of Addison’s Disease

Primary adrenal insufficiency arises from direct pathology of the adrenal glands. The most common cause in developed countries is autoimmune adrenalitis, wherein autoantibodies target adrenal cortical cells, gradually destroying the gland. This autoimmune destruction is often part of a broader spectrum of autoimmune polyendocrine syndromes, which may include thyroid disease, type 1 diabetes, and hypoparathyroidism. Infections historically were a common cause; for example, tuberculosis could infiltrate and destroy adrenal tissue. Other etiologies include adrenal hemorrhage, metastatic cancer, infiltrative diseases such as amyloidosis or sarcoidosis, genetic disorders affecting steroidogenesis, and certain medications that impair adrenal function. Rarely, surgical removal or bilateral infarction of the adrenal glands can precipitate Addison’s disease. Regardless of the cause, the end result is insufficient cortisol production, often accompanied by aldosterone deficiency.

---

Pathophysiology of Hormonal Deficiency

1. Cortisol Deficiency

Cortisol is vital for multiple physiological processes. It maintains blood glucose levels by promoting gluconeogenesis in the liver and by reducing peripheral glucose uptake. Cortisol enhances protein catabolism to provide substrates for glucose synthesis, mobilizes free fatty acids through lipolysis, and modulates vascular responsiveness to catecholamines, helping maintain blood pressure. It also exerts immunosuppressive effects, regulates circadian rhythms, and contributes to the body’s response to stress. In Addison’s disease, the lack of cortisol results in hypoglycemia, fatigue, hypotension, anorexia, weight loss, and impaired stress tolerance. Chronic cortisol deficiency disrupts the hypothalamic–pituitary–adrenal (HPA) axis. In primary adrenal insufficiency, low cortisol levels lead to loss of negative feedback at the pituitary, resulting in elevated adrenocorticotropic hormone (ACTH) secretion. ACTH shares a common precursor, pro-opiomelanocortin (POMC), with melanocyte-stimulating hormone (MSH), explaining the characteristic hyperpigmentation observed in patients with primary Addison’s disease.

2. Aldosterone Deficiency

Aldosterone deficiency arises because the zona glomerulosa is also affected in primary adrenal insufficiency. Aldosterone promotes sodium reabsorption and potassium excretion in the distal nephron. Its deficiency leads to sodium loss, potassium retention, and volume depletion, producing hypotension, dehydration, salt craving, and, in severe cases, circulatory collapse. Aldosterone deficiency also contributes to metabolic acidosis due to impaired hydrogen ion excretion. Unlike cortisol, aldosterone secretion is mainly regulated by the renin-angiotensin-aldosterone system, which cannot compensate for adrenal destruction. Secondary adrenal insufficiency, caused by pituitary or hypothalamic dysfunction, typically spares aldosterone production because the renin-angiotensin system remains intact.

3. Adrenal Androgen Deficiency

The adrenal zona reticularis produces androgens, particularly DHEA. In women, adrenal androgens contribute significantly to circulating testosterone and the maintenance of libido, pubic and axillary hair, and overall androgenic tone. In Addison’s disease, androgen deficiency can result in decreased libido, loss of axillary and pubic hair, and general fatigue. In men, gonadal testosterone predominates, so adrenal androgen deficiency is less clinically evident.

---

Clinical Manifestations of Addison’s Disease

The symptoms of Addison’s disease are diverse, reflecting the systemic effects of cortisol, aldosterone, and androgen deficiency. They typically develop gradually due to the slow destruction of the adrenal cortex, although acute adrenal crises can occur in stress or illness.

1. Fatigue and Weakness

Fatigue is one of the most common early symptoms. Cortisol deficiency reduces gluconeogenesis, impairing energy supply to muscles and the brain. Protein catabolism further contributes to muscle weakness and decreased exercise tolerance. Patients often report profound tiredness despite adequate rest, reflecting the systemic impact of hypoglycemia, hypotension, and impaired metabolic regulation.

2. Weight Loss and Anorexia

Weight loss occurs due to a combination of decreased appetite, gastrointestinal discomfort, and catabolic effects of cortisol deficiency. Nausea, vomiting, and diarrhea are common, particularly in the early stages, contributing to reduced caloric intake and dehydration.

3. Hyperpigmentation

A hallmark of primary Addison’s disease is hyperpigmentation of the skin and mucous membranes. Elevated ACTH stimulates melanocytes via the shared POMC precursor, increasing melanin synthesis. Hyperpigmentation is often most noticeable in sun-exposed areas, palmar creases, elbows, knees, and oral mucosa. Secondary adrenal insufficiency, due to pituitary or hypothalamic dysfunction, does not produce hyperpigmentation because ACTH levels remain low or normal.

4. Hypotension and Salt Craving

Aldosterone deficiency results in impaired sodium reabsorption and extracellular fluid depletion. Patients frequently present with low blood pressure, dizziness, and orthostatic hypotension. The body responds with intense salt craving, a compensatory behavior aimed at restoring sodium balance. Persistent hypotension contributes to fatigue and reduced organ perfusion, especially during periods of stress or illness.

5. Electrolyte Disturbances

Aldosterone deficiency also leads to hyperkalemia and hyponatremia, which can have serious cardiac consequences. Hyperkalemia can prolong cardiac conduction and increase the risk of arrhythmias, while hyponatremia contributes to neurological symptoms, including confusion, lethargy, and in severe cases, seizures.

6. Hypoglycemia

Cortisol is critical for maintaining blood glucose, particularly during fasting or stress. Cortisol deficiency impairs gluconeogenesis and reduces peripheral insulin antagonism, resulting in hypoglycemia. Children and adolescents are particularly susceptible, with hypoglycemic episodes presenting as dizziness, weakness, and altered mental status.

7. Gastrointestinal Symptoms

Gastrointestinal manifestations include nausea, vomiting, abdominal pain, and diarrhea. These symptoms result from cortisol deficiency impairing gastrointestinal motility and the body’s response to stress. Chronic gastrointestinal symptoms contribute to weight loss and electrolyte imbalance.

8. Neuropsychiatric Symptoms

Cortisol deficiency affects mood, cognition, and general well-being. Patients may experience depression, irritability, apathy, and decreased concentration. Chronic fatigue and electrolyte disturbances exacerbate neuropsychiatric symptoms, often delaying diagnosis.

9. Acute Adrenal Crisis

In severe or acute Addisonian crisis, profound hypotension, hypovolemic shock, hyperkalemia, hyponatremia, and hypoglycemia can develop rapidly, often precipitated by stress, infection, surgery, or trauma. Symptoms include severe weakness, confusion, nausea, vomiting, abdominal pain, and collapse. This represents a life-threatening medical emergency requiring immediate intervention.

---

Diagnostic Evaluation

Diagnosis of Addison’s disease is based on clinical suspicion, biochemical testing, and imaging when indicated.

1. Hormone Assays: Baseline serum cortisol levels are low, particularly in the morning when cortisol should peak. Elevated ACTH levels distinguish primary from secondary adrenal insufficiency. Plasma renin activity is typically increased due to aldosterone deficiency, while serum electrolytes reveal hyponatremia and hyperkalemia.

2. Stimulation Tests: The ACTH stimulation (cosyntropin) test evaluates adrenal reserve. In Addison’s disease, cortisol fails to rise appropriately after exogenous ACTH administration.

3. Autoantibody Testing: Detection of 21-hydroxylase antibodies confirms autoimmune adrenalitis as the etiology.

4. Imaging: CT or MRI may be indicated to assess adrenal morphology, particularly in infectious, infiltrative, or neoplastic causes.

---

Management of Addison’s Disease

The primary goal of treatment is to replace deficient hormones, manage symptoms, and prevent adrenal crises.

1. Glucocorticoid Replacement

Hydrocortisone is the preferred glucocorticoid due to its balance of glucocorticoid and mineralocorticoid activity. Typical replacement therapy mimics physiological circadian rhythms with divided doses, often two-thirds in the morning and one-third in the afternoon. Alternatives include prednisone or dexamethasone in select patients. Education about stress-dose adjustments during illness, surgery, or trauma is critical to prevent adrenal crises.

2. Mineralocorticoid Replacement

Fludrocortisone is used to replace aldosterone, maintaining sodium and water balance, correcting hypotension, and normalizing electrolytes. Dose titration is guided by blood pressure, plasma renin activity, and serum electrolytes.

3. Androgen Replacement

In women with fatigue or loss of libido due to adrenal androgen deficiency, low-dose DHEA supplementation may be considered, although its use is individualized and less well established than glucocorticoid or mineralocorticoid therapy.

4. Lifestyle and Education

Patients should receive education on medication adherence, recognizing early signs of adrenal insufficiency, and carrying medical alert identification. Sick-day rules include doubling or tripling glucocorticoid doses during intercurrent illness and prompt medical attention during severe stress.

5. Acute Adrenal Crisis Management

Acute adrenal crises require intravenous hydrocortisone, aggressive fluid and electrolyte replacement, and monitoring of blood glucose and hemodynamic status. Early recognition and rapid intervention are critical for survival.

---

Prognosis

With appropriate hormone replacement and patient education, individuals with Addison’s disease can lead normal, active lives. Lifelong adherence to therapy, vigilance during illness or surgery, and routine follow-up are essential to prevent morbidity and mortality associated with adrenal crises. Advances in understanding autoimmune adrenalitis and improved diagnostic tools have significantly reduced disease-related mortality.

---

Conclusion

Addison’s disease is a disorder of primary adrenal insufficiency marked by cortisol and often aldosterone deficiency. Its pathophysiology reflects the systemic consequences of inadequate glucocorticoid and mineralocorticoid action, manifesting as fatigue, hypotension, electrolyte disturbances, hypoglycemia, gastrointestinal symptoms, hyperpigmentation, and, in severe cases, life-threatening adrenal crises. Diagnosis relies on clinical suspicion, biochemical testing, and stimulation tests, with autoantibody detection and imaging providing etiologic clarity. Management focuses on physiologic hormone replacement, patient education, and prompt intervention during stress or acute crises. Understanding the hormonal basis of Addison’s disease is crucial for recognizing its diverse clinical features and implementing effective treatment strategies, ultimately enabling affected individuals to achieve normal quality of life and longevity.