Addison’s disease is a rare endocrine disorder resulting from the adrenal glands’ inability to produce sufficient amounts of the steroid hormones cortisol and aldosterone. Cortisol regulates the body’s response to stress and metabolism, while aldosterone manages salt and water balance in the blood. This deficiency, known as primary adrenal insufficiency, can affect individuals at any age, typically manifesting with symptoms like persistent fatigue, unintentional weight loss, and chronically low blood pressure. While the condition is not usually passed directly from parent to child, a person’s genetic background significantly influences their susceptibility to developing the disease.
The Primary Cause of Adrenal Gland Destruction
The primary reason for the onset of Addison’s disease in the developed world is Autoimmune Adrenalitis (AAA), accounting for approximately 80 to 90 percent of all cases. This process involves the body’s own immune system mistakenly launching a sustained attack against the healthy cells of the adrenal cortex, identifying them as foreign invaders.
Specifically, the immune cells target an enzyme called 21-hydroxylase, which is necessary for the final steps in the production of cortisol and aldosterone. The resulting chronic inflammation and destruction of the adrenal tissue leads to the gradual, irreversible decline in hormone production. The presence of autoantibodies directed against 21-hydroxylase in the blood is a strong indicator of this underlying autoimmune destruction.
The autoimmune attack is a slow, progressive process, meaning symptoms often develop subtly over months or years before a diagnosis is reached. This common form of the disease is considered acquired, though the underlying predisposition is strongly influenced by inherited genetic makeup. The condition often clusters in families, suggesting a shared genetic risk for autoimmune conditions in general, such as Type 1 diabetes or thyroid disease.
Other factors can also cause adrenal destruction, showing that not all cases of Addison’s disease involve an inherited component. Infections such as tuberculosis, which can physically damage the adrenal glands, remain a major cause in many regions of the world. Non-genetic causes also include bleeding into the adrenal glands (hemorrhage) or the spread of cancerous cells from a different primary tumor.
Genetic Risk Factors in Autoimmune Addison’s Disease
The genetic component underlying Autoimmune Adrenalitis is not due to a single faulty gene, but rather a complex inheritance pattern known as polygenic risk. This means multiple genes, each contributing a small amount of risk, combine to create an individual’s overall susceptibility to the autoimmune attack. The strongest genetic association for this common form of Addison’s disease lies within the Major Histocompatibility Complex (MHC) on chromosome six.
The MHC region contains the Human Leukocyte Antigen (HLA) genes, which are responsible for coding proteins that display foreign and self-peptides to T-cells. These HLA proteins effectively instruct the immune system what to target or ignore. Certain variants of the HLA genes are far more common in individuals who develop Autoimmune Adrenalitis. Specifically, the HLA-DR3 and HLA-DR4 alleles are highly associated with increased risk, often in combination with certain HLA-DQ alleles.
An individual who inherits both the HLA-DR3 and HLA-DR4 alleles carries an especially pronounced risk profile for developing the autoimmune form of Addison’s disease. This combination of alleles appears to create an immune environment particularly prone to misidentifying the adrenal gland’s 21-hydroxylase enzyme as an invading foreign protein. The risk is not a guarantee that a person will develop the condition, but it significantly elevates the probability compared to the general population who lack these specific variants.
Beyond the HLA region, scientists have identified other genes that contribute to the overall autoimmune susceptibility profile. These are known as non-HLA susceptibility genes and they often regulate various aspects of immune cell function. One example is the CTLA4 gene, which helps put the brakes on an activated T-cell response, acting as a negative regulator of immune activity.
Variations in this gene can impair the immune system’s ability to halt the self-destructive attack against adrenal tissue, allowing the autoimmune process to continue unchecked. Another gene of interest is CIITA, which is involved in regulating the expression of the HLA proteins themselves, further influencing how the immune system presents self-antigens. Autoimmune disease arises from a cumulative effect of numerous small genetic vulnerabilities, requiring a specific combination of variants and an environmental trigger to manifest.
Specific Inherited Disorders Linked to Adrenal Failure
While the polygenic risk factors for Autoimmune Adrenalitis are inherited, some rare forms of adrenal failure are caused by a single gene mutation, establishing a clear Mendelian inheritance pattern. These single-gene disorders mean the condition is a highly likely outcome of inheriting the mutation. Autoimmune Polyendocrine Syndrome Type 1 (APS-1) is one such example, which is inherited in an autosomal recessive manner.
APS-1 is caused by mutations in the AIRE gene, which stands for Autoimmune Regulator. The protein produced by AIRE is normally expressed in the thymus gland, where it presents the body’s own proteins, called self-antigens, to developing T-cells. This process is known as central immune tolerance, and it is designed to ensure that self-reactive T-cells are destroyed before they can leave the thymus.
A defective AIRE gene means that the self-antigens are not properly presented, allowing destructive T-cells to escape into the bloodstream and attack multiple endocrine glands. Addison’s disease is one of the three primary components of APS-1, alongside hypoparathyroidism and chronic mucocutaneous candidiasis. Adrenal insufficiency usually develops in childhood or adolescence for individuals with this specific inherited mutation.
Another single-gene disorder linked to adrenal failure is X-linked Adrenoleukodystrophy (ALD), which is caused by a mutation in the ABCD1 gene. This gene is located on the X chromosome, meaning the inheritance pattern is X-linked, and the disease is typically more severe in males. The ABCD1 gene is responsible for transporting very long-chain fatty acids (VLCFAs) into peroxisomes for breakdown.
When the gene is mutated, VLCFAs accumulate in the body, specifically damaging the myelin sheath in the nervous system and the cells of the adrenal cortex. Adrenal insufficiency is often the first symptom of ALD, sometimes preceding the severe neurological decline by several years.