Addison’s disease: An overview

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Reference: November 2025 | Issue 11 | Vol 11 | Page 8

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Addison’s disease (AD), or primary adrenal insufficiency (PAI), is a rare but serious endocrine disorder caused by destruction or dysfunction of the adrenal cortex, resulting in deficient production of glucocorticoids and mineralocorticoids.¹ Despite advances in diagnosis and treatment, AD remains potentially life-threatening, particularly when it presents as adrenal crisis.²

Aetiology

AD is caused by an inability of the adrenal cortices to produce adequate adrenocortical hormones. The condition is classified as primary or secondary adrenal insufficiency (SAI).³ PAI arises from direct injury to the adrenal cortex. This injury can result from a variety of causes, including autoimmune, infectious, haemorrhagic, infiltrative, and pharmacological factors. PAI is characterised by deficiencies in both glucocorticoids and mineralocorticoids.^1,4

Autoimmune destruction of the adrenal glands is the most frequent cause of PAI. This occurs through the development of antibodies targeting the adrenal cortex, leading to progressive glandular failure. Autoimmune adrenal insufficiency may occur as an isolated condition or as part of autoimmune polyglandular syndromes (APS).^1,5

Type 1 APS is characterised by autoimmune poly-endocrinopathy, chronic mucocutaneous candidiasis, and ectodermal dysplasia. The classical triad includes hypoparathyroidism, AD, and mucocutaneous candidiasis.^{1, 5}

Type 2 APS is associated with autoimmune thyroiditis (Schmidt syndrome), type 1 diabetes, and other autoimmune conditions such as pernicious anaemia, vitiligo, and alopecia. There are also documented associations between AD and coeliac disease.^{1, 5}

Infectious causes: Infections can damage the adrenal glands directly or through adrenal necrosis. Historical causes include tuberculosis and syphilis, while viral pathogens such as cytomegalovirus and human immunodeficiency virus (HIV) have become increasingly important. HIV is now recognised as a major contributor to adrenal insufficiency in adults. Fungal infections, including histoplasmosis and disseminated mycoses, and region-specific infections like blastomycosis in South America, are also implicated.^1,4

Adrenal haemorrhage: Bilateral adrenal haemorrhage can result from conditions such as disseminated intravascular coagulation, severe trauma, meningococcaemia, and neoplastic processes. Adrenal crisis secondary to meningococcaemia is classically known as Waterhouse-Friderichsen syndrome and occurs more frequently in children and patients with asplenia.¹

Infiltrative and genetic causes: Adrenal infiltration can occur in systemic disorders such as haemochromatosis, amyloidosis, sarcoidosis, and lymphoma, as well as from metastatic disease. Genetic and metabolic disorders, including congenital adrenal hyperplasia, adrenal leukodystrophy, and Wolman disease, can also compromise adrenal function.

Wolman disease, a rare inborn error of metabolism, presents with diarrhoea, hepatosplenomegaly, failure to thrive, and adrenal calcifications. Additionally, antiphospholipid antibody syndrome has been implicated in adrenal insufficiency.¹

Pharmacological causes: Certain medications may precipitate PAI by inhibiting adrenal steroidogenesis. For example, ketoconazole blocks adrenal enzyme activity, while etomidate selectively inhibits 11β-hydroxylase in a dose-dependent manner, reducing cortisol synthesis.¹

SAI results from impaired hypothalamic-pituitary function, leading to reduced adrenocorticotropic hormone (ACTH) production and consequent cortisol deficiency. Mineralocorticoid production, including aldosterone, is generally preserved due to intact renin-angiotensin regulation.¹

The most common cause of SAI is chronic exogenous glucocorticoid therapy, which suppresses ACTH synthesis. Symptoms typically manifest after withdrawal of steroid therapy. Compared with PAI, SAI is more prevalent, although it primarily affects glucocorticoid secretion rather than mineralocorticoid function.¹

Epidemiology

AD is a rare endocrine disorder, with an annual incidence of approximately 0.6 per 100,000 population. Its prevalence is estimated to range between four and 11 cases per 100,000 individuals. In Europe, prevalence estimates for AD vary, but are generally between 90 and 220 per million population.

Population studies indicate that autoimmune adrenalitis is the most frequent cause in high-income settings, while in lower-income countries or regions with less access to early diagnosis, infectious or infiltrative causes remain more represented.^6,7,8

The condition most commonly presents in adults aged 30 to 50 years and demonstrates a higher frequency in women. The autoimmune form of AD, which represents the predominant aetiology, is strongly associated with other autoimmune disorders.

Patients with autoimmune AD often have coexisting conditions such as type 1 diabetes mellitus, hypoparathyroidism, hypopituitarism, pernicious anaemia, Graves’ disease, chronic autoimmune thyroiditis, dermatitis herpetiformis, vitiligo, or myasthenia gravis. These associations highlight the tendency for autoimmune polyglandular involvement in affected individuals.^6,7,8

Clinical presentation and physical examination

AD typically presents with a gradual and insidious onset, often characterised by nonspecific symptoms that can delay diagnosis. The clinical course may evolve over weeks or months, making early recognition challenging. A high index of suspicion is important to avoid misdiagnosis.

Frequently, the condition is only identified when a patient experiences an acute adrenal crisis, which may manifest as hypotension, hyponatraemia, hyperkalaemia, and hypoglycaemia. Such crises are often precipitated by physiological stressors, including infection, trauma, surgery, or gastrointestinal disturbances such as vomiting or diarrhoea, which can unmask underlying cortisol and mineralocorticoid deficiency.^1,9

Early clinical features of AD include persistent fatigue, generalised weakness, unintentional weight loss, nausea, vomiting, abdominal discomfort, dizziness, tachycardia, and hypotension. Careful assessment should also include evaluation for loss of subcutaneous tissue.

The variability of presentation requires vigilance when assessing patients with nonspecific symptoms such as unexplained fatigue, poor appetite, chronic abdominal pain, or weight loss. Addisonian crisis is a life-threatening manifestation, characterised by severe dehydration, confusion, persistent hypotension, and shock, and is more commonly associated with PAI than secondary forms.^1,9

Physical examination should focus on skin and mucous membranes for evidence of hyperpigmentation, a hallmark of primary AD. This pigmentation is typically generalised, most pronounced in sun-exposed or pressure areas, and may appear as diffuse darkening or localised bronzing. Key sites for careful inspection include palmar creases, gingival mucosa, lips, particularly the vermilion border, elbows, knuckles, posterior neck, areolae, nipples, and nail beds.

Hyperpigmentation results from elevated levels of ACTH and melanocyte-stimulating hormone (MSH), which stimulate melanocyte receptors. It is almost universally present in PAI but is absent in secondary forms, where ACTH and MSH levels are low. Occasionally, patients may present without hyperpigmentation, which can delay recognition. Additional clinical features may include the development of multiple nevi, loss or thinning of axillary and pubic hair in female patients, and coexisting autoimmune conditions such as vitiligo.^1,9,10

Diagnosis

The diagnosis of AD is based on evidence of cortisol and aldosterone deficiency, elevated renin, and a blunted cortisol response to ACTH stimulation. Early recognition requires a structured and systematic approach to testing and interpretation.^1,9,10

Cortisol assessment: A low serum cortisol level is indicative of adrenal insufficiency. Cortisol secretion follows a diurnal rhythm, peaking in the early morning, making morning measurements preferred. A morning cortisol level greater than 18µg/dL usually excludes AD, whereas levels below 3µg/dL confirm adrenal insufficiency. Values between 3 and 18µg/dL are considered equivocal and warrant further evaluation.^1,9,10

ACTH and corticotropin stimulation: PAI is associated with elevated ACTH, while SAI  shows low or inappropriately normal ACTH levels. The ACTH stimulation test is the first-line diagnostic tool for confirming adrenal insufficiency. Serum cortisol is measured at baseline and again 30-60 minutes after ACTH administration.

In primary disease, ACTH rises further after corticotropin-releasing hormone stimulation, but cortisol fails to respond. In secondary disease, ACTH remains low, and cortisol response is inadequate. A peak cortisol above 18µg/dL (500-550 nmol/L) indicates normal adrenal function, whereas a peak below 18µg/dL confirms insufficiency.^1,9,10

Aldosterone and renin: Primary AD is characterised by low aldosterone levels accompanied by elevated plasma renin activity, reflecting mineralocorticoid deficiency. In SAI, aldosterone levels are usually preserved.^1,9,10

Laboratory findings: Common laboratory abnormalities in AD include hyponatraemia, hyperkalaemia, and hypoglycaemia. Hyponatraemia arises from both aldosterone deficiency and cortisol-mediated dysregulation of antidiuretic hormone. Hyperkalaemia occurs only in PAI due to aldosterone deficiency.

Hypoglycaemia results from impaired gluconeogenesis and reduced oral intake, while hypercalcaemia may occur secondary to extracellular fluid loss. Mild elevation of thyroid-stimulating hormone (TSH) can occur due to altered cortisol feedback; persistent elevation should prompt evaluation for hypothyroidism.^1,9,10

Autoantibodies: The presence of anti-21-hydroxylase antibodies indicate autoimmune adrenal destruction. Testing for these antibodies helps determine the underlying aetiology and assess risk for other autoimmune disorders.^1,9,10

Imaging studies: Imaging is guided by biochemical results. Computed tomography (CT) can detect adrenal enlargement, haemorrhage, or calcification, whereas small adrenal glands suggest autoimmune destruction. Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region is indicated when ACTH levels are low, to evaluate for central causes of adrenal insufficiency.^1,9,10

Additional investigations: Further investigations are targeted to the suspected underlying cause. These may include: A purified protein derivative test for tuberculosis; serum very long-chain fatty acid analysis for adrenal leukodystrophy; full blood count to detect cytopenias; electrocardiogram to assess effects of hyperkalaemia; and histological examination for infiltrative disorders such as tuberculosis or sarcoidosis.^1,9,10

Differential diagnosis

Adrenal insufficiency can mimic several conditions that present with fatigue, hypotension, or shock. Sepsis shares features such as weakness, vomiting, and hypotension, but low cortisol response to ACTH confirms adrenal insufficiency. Shock from other causes may also lower cortisol levels, necessitating adrenal evaluation.

Chronic fatigue syndrome presents with persistent fatigue, but corticotropin-stimulated cortisol differentiates it. Infectious mononucleosis may cause fever, fatigue, and myalgias, but exudative pharyngitis and positive immunoglobulin M viral capsid antibodies distinguish it. Hypothyroidism also causes fatigue but is associated with weight gain, and cortisol measurement helps differentiate the two conditions.¹

Treatment and management of AD

AD requires lifelong hormone replacement to correct deficiencies in both glucocorticoids and mineralocorticoids. The cornerstone of therapy is glucocorticoid replacement, most commonly with hydrocortisone, which is administered to mimic the natural diurnal rhythm of cortisol secretion. Typical regimens involve a total daily dose of 15-25mg, divided into two or three doses, with the largest dose given in the morning to approximate physiological peak levels.

Alternative glucocorticoids, such as prednisolone or dexamethasone, may be considered in patients who experience adherence challenges or impaired absorption. During periods of physiological stress, including infection, surgery, or trauma, glucocorticoid doses should be increased to reduce the risk of adrenal crisis.^1,9,10

In addition to glucocorticoid therapy, patients with PAI require mineralocorticoid replacement. Fludrocortisone is the treatment of choice, with dosing individualised to maintain blood pressure, sodium balance, and potassium homeostasis. The typical daily dose ranges from 50-200µg, adjusted based on clinical response and monitoring of blood pressure, serum electrolytes, and plasma renin activity.^1,9,10

Patient education is central to effective long-term management. Patients should be taught to recognise early symptoms of adrenal insufficiency, carry medical alert identification, and understand ‘sick-day rules’, which include increasing glucocorticoid doses during febrile illnesses or other physiological stressors.

Routine follow-up should include assessment of electrolytes, renal function, blood pressure, and body weight. Long-term glucocorticoid therapy may adversely affect bone health, necessitating periodic evaluation. Given the frequent coexistence of autoimmune conditions in this patient population, screening for thyroid disease, type 1 diabetes, and coeliac disease is also recommended.^1,9,10

Management of Addisonian crisis

Addisonian crisis is a life-threatening complication of adrenal insufficiency that occurs due to acute cortisol deficiency. It is commonly precipitated by infection, surgery, trauma, or abrupt withdrawal of glucocorticoid therapy. Clinically, patients present with profound hypotension or shock, severe vomiting, and diarrhoea leading to dehydration, hypoglycaemia, electrolyte disturbances including hyponatraemia and hyperkalaemia, and altered mental status. Immediate recognition and treatment are essential to prevent morbidity and mortality.^9,11,12

The cornerstone of acute management is rapid fluid resuscitation. Intravenous administration of isotonic saline restores circulating volume, while dextrose-containing solutions are used if hypoglycaemia is present.

Prompt glucocorticoid replacement is required, typically with intravenous hydrocortisone administered as an initial bolus followed by continuous dosing until stabilisation. Dexamethasone can be used as an alternative in cases where cortisol measurement is necessary as it does not interfere with assay results. Electrolyte imbalances and hypoglycaemia should be corrected, and any precipitating causes, such as infection, must be identified and treated simultaneously.^9,11,12

Once the patient has stabilised, therapy is moved to oral glucocorticoids and fludrocortisone, with gradual adjustment to physiological replacement doses. Prevention of future crises relies heavily on patient education, including understanding the importance of stress-dose steroids, recognising early symptoms, and carrying injectable hydrocortisone along with medical alert identification. Regular follow-up with an endocrinologist ensures ongoing dose optimisation, monitoring for complications, and assessment of associated autoimmune conditions.^11,12