Addison’s disease (AD), also known as primary adrenal insufficiency, is a disorder where the adrenal glands fail to produce sufficient levels of certain steroid hormones. These small, triangular glands sit atop the kidneys and produce two primary hormones necessary for life: cortisol and aldosterone. Cortisol regulates the body’s response to stress, maintains blood pressure, and manages blood sugar, while aldosterone balances sodium and potassium levels, which affects blood volume. When the adrenal glands are damaged, the resulting deficiency in these hormones can lead to a potentially life-threatening condition if left untreated.
The Leading Cause: Autoimmune Destruction
The vast majority of Addison’s disease cases in developed countries, estimated to be between 70% and 90%, result from an autoimmune response. This occurs when the body’s immune system mistakenly identifies the cells of the adrenal cortex as foreign invaders and slowly destroys them. Autoantibodies, specifically those targeting the steroid 21-hydroxylase enzyme, are often present in the blood, serving as a marker for this autoimmune form of the disease.
While autoimmune destruction is the direct cause, a general genetic predisposition increases the likelihood of this immune malfunction. Specific variations in the human leukocyte antigen (HLA) complex, particularly the HLA-DR3 and HLA-DR4 alleles, are strongly associated with an elevated risk of developing autoimmune Addison’s disease. The HLA complex genes are involved in presenting antigens to T-cells, and certain types may make the immune system more prone to attacking the body’s own tissues.
Specific Genetic Syndromes Linked to Addison’s
In a smaller number of cases, Addison’s disease is a feature of a defined, inherited genetic syndrome rather than an acquired autoimmune condition. Autoimmune Polyendocrine Syndrome Type 1 (APS-1) is a rare, monogenic disorder caused by mutations in the AIRE (Autoimmune Regulator) gene. A defect in this gene results in widespread autoimmune attacks on various endocrine glands. APS-1 is inherited in an autosomal recessive pattern, meaning a child must inherit a copy of the defective AIRE gene from both parents to develop the syndrome, which often presents with Addison’s disease alongside chronic candidiasis and hypoparathyroidism.
Another specific inherited cause is X-linked Adrenoleukodystrophy (ALD), a progressive neurodegenerative condition caused by a mutation in the ABCD1 gene located on the X chromosome. This gene defect impairs the body’s ability to break down very long-chain fatty acids (VLCFAs), which then accumulate in the nervous system and the adrenal cortex. The accumulation of these fatty acids in the adrenal glands often causes Addison’s disease, sometimes presenting as the first or even the only symptom, particularly in young males. Because ALD is X-linked, it primarily affects males, although female carriers can experience milder symptoms.
Non-Autoimmune Causes of Adrenal Failure
Addison’s disease can also result from physical damage to the adrenal glands caused by factors other than autoimmunity or inherited syndromes. Globally, the most common non-autoimmune cause is infectious disease, primarily tuberculosis (TB), which can physically destroy the adrenal cortex tissue. Though rare in developed nations where it accounts for about 7% to 20% of cases, TB was the leading cause historically and remains so in many developing countries.
Other rare causes involve physical compromise of the adrenal tissue, such as fungal infections or the spread of cancer, known as metastasis, to the glands. Adrenal hemorrhage, or bleeding into the adrenals, can also acutely destroy the tissue, often occurring during periods of severe shock, sepsis, or after trauma. It is important to distinguish primary AD from secondary adrenal insufficiency, which is a separate disorder caused by a lack of ACTH (adrenocorticotropic hormone) from the pituitary gland. Secondary adrenal insufficiency is not typically genetic and does not involve damage to the adrenal glands themselves.
How Addison’s Disease is Diagnosed
The definitive test for diagnosing Addison’s disease is the ACTH stimulation test, which assesses the adrenal glands’ capacity to produce cortisol. A synthetic version of ACTH is injected into the patient, and blood cortisol levels are measured before and 30 to 60 minutes after the injection. In a healthy person, the synthetic ACTH prompts a significant rise in cortisol; however, in a patient with Addison’s disease, the damaged adrenal glands show little to no increase in cortisol production.
Supporting blood tests are also conducted to check for characteristic hormone and electrolyte imbalances. These tests measure the levels of sodium and potassium, which are often low and high, respectively, due to aldosterone deficiency. Measuring native ACTH level is useful, as a high level indicates primary adrenal insufficiency, meaning the pituitary gland is attempting to stimulate the failing adrenal glands. If a specific genetic syndrome is suspected, such as in a young male presenting with AD, specialized genetic testing for mutations like those in the ABCD1 or AIRE genes can be used to confirm the underlying cause.