Addison’s Disease

Addison’s disease is a form of primary adrenal insufficiency in which dysfunction or destruction of the adrenal cortex results in inadequate production of adrenal cortical hormones. Cortisol deficiency is fundamental, and mineralocorticoid production, particularly aldosterone, is also commonly impaired.

The disorder originates within the adrenal glands themselves. Because cortisol concentrations fall, negative feedback inhibition of the hypothalamus and anterior pituitary decreases. This leads to increased secretion of corticotropin-releasing hormone and adrenocorticotropic hormone (ACTH). Elevated ACTH and related proopiomelanocortin-derived peptides contribute to the characteristic hyperpigmentation associated with primary adrenal insufficiency.

Aldosterone deficiency produces additional disturbances that distinguish primary adrenal insufficiency from many central forms of adrenal insufficiency. Reduced renal sodium conservation and impaired potassium and hydrogen ion excretion can result in sodium loss, volume depletion, hypotension, hyperkalemia, and metabolic acidosis.

Primary Adrenal Insufficiency

Addison’s disease is specifically associated with failure of the adrenal cortex.

This distinguishes it from secondary adrenal insufficiency caused by inadequate pituitary ACTH secretion and tertiary adrenal insufficiency associated with inadequate hypothalamic stimulation or prolonged suppression of the hypothalamic-pituitary-adrenal axis.

Adrenal Cortex

The adrenal cortex forms the outer portion of the adrenal gland and consists of three major histological zones.

Adrenal Cortical Zone	Major Hormonal Products
Zona glomerulosa	Mineralocorticoids, particularly aldosterone
Zona fasciculata	Glucocorticoids, particularly cortisol
Zona reticularis	Adrenal androgens

Hormonal Deficiencies

Extensive adrenal cortical dysfunction can impair production of hormones from all three cortical zones.

The most physiologically important deficiencies involve cortisol and aldosterone.

Cortisol Deficiency

Cortisol is the principal glucocorticoid produced by the adrenal cortex.

Deficiency impairs normal metabolic adaptation, vascular responsiveness, immune regulation, and the physiological response to stress.

Aldosterone Deficiency

Aldosterone is the principal mineralocorticoid produced by the zona glomerulosa.

Its deficiency reduces renal sodium reabsorption while decreasing potassium and hydrogen ion secretion.

Adrenal Androgen Deficiency

Primary adrenal insufficiency can also reduce production of adrenal androgens such as dehydroepiandrosterone (DHEA) and DHEA sulfate.

The physiological consequences vary because gonadal androgen production can compensate for much of this loss, particularly in men.

Hypothalamic-Pituitary-Adrenal Axis

Cortisol production is regulated through the hypothalamic-pituitary-adrenal (HPA) axis.

The hypothalamus secretes corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to secrete ACTH. ACTH then stimulates cortisol-producing cells of the adrenal cortex.

Normal HPA Axis

A simplified pathway is:

Hypothalamus → CRH → Anterior pituitary → ACTH → Adrenal cortex → Cortisol

Loss of Negative Feedback

Normally, cortisol inhibits further secretion of CRH and ACTH through negative feedback.

In Addison’s disease, cortisol production remains inadequate despite increased ACTH stimulation because the adrenal cortex itself is dysfunctional.

ACTH Elevation

Reduced cortisol-mediated negative feedback results in increased ACTH secretion from anterior pituitary corticotrophs.

High ACTH concentrations are therefore characteristic of primary adrenal insufficiency and help distinguish it from central adrenal insufficiency.

Proopiomelanocortin

ACTH is produced from the precursor molecule proopiomelanocortin (POMC).

POMC processing also gives rise to peptides related to melanocortin signaling. Increased POMC production during primary adrenal insufficiency contributes to increased pigmentation.

Hyperpigmentation

Hyperpigmentation is a characteristic clinical feature of primary adrenal insufficiency.

It results from increased melanocortin activity associated with elevated ACTH and other POMC-derived peptides.

Distribution of Hyperpigmentation

Hyperpigmentation may be particularly noticeable in areas exposed to friction or normally increased pigmentation.

Commonly affected locations can include:

• Palmar creases
• Knuckles
• Elbows
• Knees
• Scars
• Oral mucosa
• Areas exposed to pressure or friction

Causes of Addison’s Disease

Addison’s disease can result from any process that causes sufficient bilateral destruction or dysfunction of the adrenal cortex.

Major etiological categories include autoimmune disease, infection, hemorrhage, infiltration, metastatic disease, and selected genetic disorders.

Autoimmune Adrenalitis

Autoimmune adrenalitis is an important cause of primary adrenal insufficiency.

Immune-mediated destruction progressively damages the adrenal cortex and eventually reduces its ability to produce sufficient steroid hormones.

21-Hydroxylase Autoantibodies

Autoantibodies directed against 21-hydroxylase can be detected in many patients with autoimmune primary adrenal insufficiency.

Their presence can support an autoimmune etiology in the appropriate clinical context.

Autoimmune Polyglandular Syndromes

Autoimmune adrenal insufficiency can occur together with other autoimmune endocrine disorders as part of an autoimmune polyglandular syndrome.

Associated disorders vary according to the specific syndrome.

Tuberculosis

Tuberculosis can involve both adrenal glands and cause progressive destruction of adrenal cortical tissue.

Historically, tuberculosis was a major cause of Addison’s disease and remains clinically important in regions where tuberculosis is prevalent.

Other Infections

Other infectious processes can damage the adrenal glands, particularly in immunocompromised individuals.

Potential causes include selected fungal, bacterial, and opportunistic infections.

Adrenal Hemorrhage

Severe bilateral adrenal hemorrhage can rapidly destroy functional adrenal tissue and cause acute primary adrenal insufficiency.

This may occur in association with severe systemic illness, coagulopathy, trauma, or other conditions predisposing to adrenal bleeding.

Adrenal Infarction

Bilateral adrenal infarction can impair adrenal cortical function and produce adrenal insufficiency.

The clinical presentation depends on the extent and speed of tissue loss.

Metastatic Disease

Malignant tumors can metastasize to the adrenal glands.

Adrenal insufficiency generally requires extensive bilateral destruction because the adrenal glands possess considerable functional reserve.

Infiltrative Disorders

Infiltrative diseases can replace or damage adrenal cortical tissue.

Examples include selected granulomatous, storage, and infiltrative disorders.

Adrenoleukodystrophy

X-linked adrenoleukodystrophy is a genetic disorder involving abnormal metabolism of very-long-chain fatty acids.

Adrenal cortical dysfunction can be an important component of the disease.

Pathophysiology

The manifestations of Addison’s disease arise primarily from glucocorticoid deficiency, mineralocorticoid deficiency, and compensatory elevation of ACTH.

Abnormality	Major Consequences
Cortisol deficiency	Impaired stress response, weakness, metabolic abnormalities and reduced vascular responsiveness
Aldosterone deficiency	Sodium loss, volume depletion, hyperkalemia and hypotension
Elevated ACTH/POMC activity	Hyperpigmentation

Sodium Loss

Reduced aldosterone activity decreases sodium reabsorption in the distal nephron.

Increased renal sodium loss contributes to reduced extracellular fluid volume.

Hyponatremia

Hyponatremia is common in primary adrenal insufficiency.

Mineralocorticoid deficiency promotes renal sodium loss, while cortisol deficiency can also contribute through increased antidiuretic hormone activity and impaired free-water excretion.

Volume Depletion

Loss of sodium and water decreases extracellular and intravascular volume.

This contributes to weakness, orthostatic symptoms, and hypotension.

Hypotension

Hypotension can result from both volume depletion and reduced vascular responsiveness associated with cortisol deficiency.

Blood pressure abnormalities may become particularly severe during adrenal crisis.

Orthostatic Hypotension

Reduced circulating volume can impair maintenance of arterial pressure when standing.

Patients may therefore develop orthostatic hypotension, dizziness, or presyncope.

Hyperkalemia

Loss of aldosterone reduces potassium secretion by principal cells of the distal nephron.

This can produce hyperkalemia, particularly when mineralocorticoid deficiency is substantial.

Hydrogen Ion Retention

Reduced mineralocorticoid activity can impair distal hydrogen ion secretion.

The resulting acid retention can contribute to a metabolic acidosis.

Electrolyte Effects

Variable	Typical Tendency	Major Mechanism
Sodium	Decreased	Renal sodium loss and altered water balance
Potassium	Increased	Reduced aldosterone-mediated potassium secretion
Hydrogen ions	Retention	Reduced distal acid secretion
Extracellular volume	Decreased	Sodium and water loss

Glucose Homeostasis

Cortisol supports hepatic glucose production and normal metabolic adaptation during fasting and physiological stress.

Cortisol deficiency can therefore predispose susceptible patients to hypoglycemia, particularly during fasting, illness, or increased metabolic demand.

Weakness and Fatigue

Persistent fatigue and weakness are common manifestations of adrenal insufficiency.

They reflect the combined effects of cortisol deficiency, electrolyte disturbances, volume depletion, altered metabolism, and systemic illness.

Weight Loss

Unintentional weight loss can occur because of reduced appetite, gastrointestinal symptoms, dehydration, and chronic hormonal deficiency.

Gastrointestinal Manifestations

Primary adrenal insufficiency can produce gastrointestinal symptoms including:

• Anorexia
• Nausea
• Vomiting
• Abdominal discomfort
• Diarrhea or altered bowel function in some patients

Salt Craving

Some patients develop a pronounced craving for salt.

This is associated with chronic sodium depletion resulting from mineralocorticoid deficiency.

Clinical Features

Feature	Physiological Basis
Fatigue	Cortisol deficiency and systemic metabolic effects
Weight loss	Reduced appetite and chronic illness
Hypotension	Volume depletion and reduced vascular responsiveness
Hyperpigmentation	Elevated ACTH and melanocortin activity
Hyponatremia	Sodium loss and altered water balance
Hyperkalemia	Aldosterone deficiency
Salt craving	Chronic sodium depletion
Hypoglycemia	Reduced glucocorticoid support of glucose homeostasis

Adrenal Crisis

An adrenal crisis is an acute, potentially life-threatening manifestation of severe adrenal insufficiency.

It occurs when glucocorticoid availability is critically inadequate for the physiological demands of the body.

Precipitating Factors

Adrenal crisis can be precipitated by major physiological stress in a person with established or unrecognized adrenal insufficiency.

Potential triggers include:

• Severe infection
• Surgery
• Trauma
• Major gastrointestinal illness with vomiting or diarrhea
• Interruption of required glucocorticoid replacement

Features of Adrenal Crisis

Clinical abnormalities can include:

• Severe hypotension
• Circulatory shock
• Volume depletion
• Vomiting
• Abdominal pain
• Weakness
• Hyponatremia
• Hyperkalemia in primary adrenal insufficiency
• Hypoglycemia
• Altered mental status

Why Adrenal Crisis Is Dangerous

Cortisol is required for appropriate cardiovascular and metabolic adaptation during severe physiological stress.

When cortisol is severely deficient, vascular responsiveness and metabolic homeostasis can deteriorate rapidly. Concurrent mineralocorticoid deficiency can worsen volume depletion and electrolyte abnormalities.

Diagnosis

Evaluation of suspected Addison’s disease involves assessment of adrenal glucocorticoid production and the regulatory HPA axis.

Laboratory findings are interpreted together with clinical features and the suspected underlying cause.

Morning Serum Cortisol

Cortisol normally follows a circadian rhythm, with concentrations generally highest around the early morning and awakening period.

A morning serum cortisol concentration can therefore provide useful initial information when adrenal insufficiency is suspected, although intermediate values may require dynamic testing.

Plasma ACTH

Measurement of plasma ACTH helps distinguish primary adrenal insufficiency from central causes.

In primary adrenal insufficiency, cortisol is low while ACTH is typically elevated.

ACTH Stimulation Test

The ACTH stimulation test assesses the ability of the adrenal cortex to produce cortisol after administration of synthetic ACTH.

An inadequate cortisol response supports adrenal insufficiency when interpreted using the appropriate assay and clinical context.

Renin and Aldosterone

Assessment of renin and aldosterone can help evaluate mineralocorticoid function.

Primary adrenal insufficiency commonly produces reduced aldosterone activity with compensatory activation of renin secretion.

Typical Hormonal Pattern

Hormone or Variable	Typical Finding in Primary Adrenal Insufficiency
Cortisol	Decreased
ACTH	Increased
Aldosterone	Often decreased
Renin	Usually increased when mineralocorticoid deficiency is present

Determining the Cause

Once primary adrenal insufficiency is established, additional investigation may be required to determine its etiology.

The evaluation can include adrenal autoantibodies, imaging, infectious investigations, or testing for selected genetic and infiltrative disorders depending on the clinical context.

Adrenal Autoantibodies

Detection of antibodies against 21-hydroxylase can support the diagnosis of autoimmune adrenalitis.

Adrenal Imaging

CT or other imaging of the adrenal glands can provide anatomical information when infection, hemorrhage, infiltration, malignancy, or another structural adrenal disorder is suspected.

The imaging appearance depends on the underlying disease and its stage.

Primary Versus Secondary Adrenal Insufficiency

Feature	Primary Adrenal Insufficiency	Secondary Adrenal Insufficiency
Site of dysfunction	Adrenal cortex	Pituitary or central ACTH pathway
Cortisol	Low	Low
ACTH	High	Low or inappropriately normal
Aldosterone	Often low	Usually relatively preserved
Hyperkalemia	Can occur	Not typically caused by the adrenal insufficiency itself
Hyperpigmentation	Can occur	Not characteristic
Renin	Can be elevated	Usually not elevated because of ACTH deficiency alone

Why Aldosterone Is Preserved in Secondary Adrenal Insufficiency

Aldosterone secretion is controlled predominantly by the renin-angiotensin system and extracellular potassium concentration rather than ACTH.

Therefore, loss of pituitary ACTH primarily reduces cortisol production while mineralocorticoid secretion generally remains comparatively preserved.

Addison’s Disease Versus Cushing Syndrome

Feature	Addison’s Disease	Cushing Syndrome
Glucocorticoid state	Deficiency	Excess
Blood pressure	Often decreased	Often increased
Body weight	Weight loss is common	Central weight gain is common
Glucose tendency	Hypoglycemia can occur	Hyperglycemia or glucose intolerance can occur
Skin findings	Hyperpigmentation can occur in primary disease	Skin thinning, bruising and broad striae can occur

Treatment Principles

Management of Addison’s disease requires replacement of deficient adrenal cortical hormones.

The specific regimen is individualized according to the degree of glucocorticoid and mineralocorticoid deficiency and the patient's physiological requirements.

Glucocorticoid Replacement

Glucocorticoid replacement substitutes for deficient endogenous cortisol.

Hydrocortisone or other appropriate glucocorticoid preparations can be used to reproduce essential glucocorticoid activity.

Mineralocorticoid Replacement

Patients with significant aldosterone deficiency generally require mineralocorticoid replacement.

Fludrocortisone is commonly used to provide mineralocorticoid activity and support sodium balance, extracellular volume, and potassium homeostasis.

Stress Dosing

Healthy adrenal glands increase cortisol secretion during substantial physiological stress.

Patients with adrenal insufficiency cannot generate this normal endogenous increase and therefore require appropriately increased glucocorticoid replacement during significant illness, surgery, trauma, or other major physiological stress according to clinical guidance.

Emergency Treatment of Adrenal Crisis

Adrenal crisis requires urgent treatment.

Management includes prompt administration of glucocorticoid replacement and correction of circulatory volume, electrolyte, and glucose abnormalities as clinically indicated.

Effects of Treatment on ACTH

Adequate glucocorticoid replacement restores negative feedback to the hypothalamus and pituitary.

This reduces excessive ACTH stimulation and can gradually decrease hyperpigmentation associated with untreated primary adrenal insufficiency.

Anatomical Changes in Addison’s Disease

The anatomical appearance of the adrenal glands varies according to the underlying cause.

Autoimmune destruction can eventually produce small or atrophic adrenal glands, while infection, hemorrhage, infiltration, or metastatic disease may produce enlargement or other structural abnormalities.

Adrenal Reserve

The adrenal cortex possesses substantial functional reserve.

Clinical adrenal insufficiency generally becomes evident only after a considerable loss of functional cortical capacity, which explains why destructive processes can progress before overt hormonal deficiency becomes apparent.

Relationship to the Adrenal Medulla

Addison’s disease primarily involves the adrenal cortex, not the adrenal medulla.

However, cortical dysfunction can influence medullary physiology because cortisol delivered from the cortex normally promotes expression of PNMT, the enzyme responsible for conversion of norepinephrine into epinephrine.

Key Features of Addison’s Disease

Feature	Key Point
Disorder type	Primary adrenal insufficiency
Primary anatomical site	Adrenal cortex
Cortisol	Decreased
ACTH	Increased
Aldosterone	Often decreased
Renin	Often increased
Sodium	Often decreased
Potassium	Can be increased
Blood pressure	Often decreased
Characteristic skin finding	Hyperpigmentation
Major acute complication	Adrenal crisis

Clinical Associations

Finding or Condition	Relationship to Addison’s Disease
Autoimmune adrenalitis	Important cause of primary adrenal insufficiency
Hyperpigmentation	Results from elevated ACTH and melanocortin activity
Hyperkalemia	Can result from aldosterone deficiency
Hyponatremia	Related to sodium loss and altered water balance
Hypotension	Related to volume depletion and cortisol deficiency
Adrenal crisis	Acute life-threatening manifestation of severe adrenal insufficiency

Anatomical and Physiological Importance

Addison’s disease illustrates the systemic importance of the adrenal cortex. Although the adrenal glands are relatively small organs, destruction of their cortical tissue can disrupt cardiovascular regulation, electrolyte balance, glucose metabolism, and the physiological response to stress.

The combination of cortisol and aldosterone deficiency explains many of the characteristic manifestations. Cortisol deficiency impairs metabolic and cardiovascular adaptation, while aldosterone deficiency promotes renal sodium loss, potassium retention, extracellular volume depletion, and hypotension. Loss of cortisol negative feedback simultaneously increases ACTH secretion, producing the characteristic hyperpigmentation of primary adrenal insufficiency.

The hormonal pattern also provides an important anatomical distinction between primary and central adrenal insufficiency. In Addison’s disease, the defect lies within the adrenal cortex, so ACTH rises in an attempt to stimulate a failing gland and mineralocorticoid production can also be impaired. In secondary adrenal insufficiency, the primary defect lies upstream in the pituitary ACTH pathway, so ACTH is reduced and aldosterone is usually relatively preserved.