Addison’s disease is caused by damage to the adrenal glands, the small organs sitting on top of your kidneys that produce cortisol and other essential hormones. In about 80% of cases in developed countries, the damage comes from your own immune system attacking the glands. The remaining cases result from infections, cancer, bleeding, genetic conditions, or other physical destruction of adrenal tissue. The condition is rare, affecting roughly 4 to 11 people per 100,000.
Autoimmune Destruction of the Adrenal Glands
The most common cause is autoimmune adrenalitis, where the body’s immune system mistakes adrenal cells for a threat and gradually destroys them. Specifically, a type of white blood cell called CD8+ T cells targets a key enzyme in the adrenal cortex called 21-hydroxylase. This enzyme is essential for producing cortisol and aldosterone. As these immune cells infiltrate the gland and kill hormone-producing cells, your adrenal output slowly declines.
Most people also develop antibodies against 21-hydroxylase, which show up on blood tests and serve as a useful diagnostic marker. Interestingly, these antibodies themselves don’t appear to drive the destruction. The actual damage is done by the T cells. The immune attack is slow and progressive, which is why symptoms often develop over months or years. By the time most people notice something is wrong, roughly 90% of the adrenal cortex has already been destroyed.
Certain genetic profiles make this autoimmune attack more likely. People who carry specific immune system gene variants, particularly HLA-A2 and HLA-C7, show higher frequencies of adrenal-targeting T cells. The immune response in autoimmune Addison’s disease is comparable in magnitude to the T cell attacks seen in type 1 diabetes, another autoimmune condition that destroys hormone-producing cells.
Autoimmune Polyendocrine Syndromes
Addison’s disease sometimes appears alongside other autoimmune conditions in recognized patterns. In autoimmune polyendocrine syndrome type 1 (APS-1), a mutation in a gene called AIRE on chromosome 21 disrupts how the immune system learns to distinguish the body’s own tissues from foreign invaders. This gene normally ensures that developing immune cells are exposed to proteins from various organs, so they learn not to attack them. When AIRE doesn’t work properly, the immune system can target multiple organs. People with APS-1 typically develop chronic fungal infections of the mouth and skin, low calcium from parathyroid damage, and adrenal failure, often beginning in childhood. They may also develop liver inflammation, thyroid disease, type 1 diabetes, or fertility problems.
Autoimmune polyendocrine syndrome type 2 (APS-2) is more common and involves a different set of genes on chromosome 6 in the HLA region. It typically appears in adulthood and combines adrenal insufficiency with thyroid disease and type 1 diabetes. People with APS-2 may also develop celiac disease, vitiligo (patchy loss of skin color), or pernicious anemia. If you’re diagnosed with Addison’s disease from an autoimmune cause, your doctor will often screen for these related conditions because they tend to cluster together.
Tuberculosis and Other Infections
Before autoimmune testing existed, tuberculosis (TB) was the most recognized cause of Addison’s disease. It remains the leading cause of adrenal insufficiency in parts of the world where TB is widespread. The bacteria can spread through the bloodstream and settle in the adrenal glands, gradually replacing functional tissue with infection and scar tissue.
HIV significantly raises the risk of adrenal problems through several pathways. Opportunistic infections that come with advanced HIV can directly infiltrate the adrenal glands. Certain antifungal medications used to treat those infections can block the enzymes needed to produce cortisol. Rifampicin, a cornerstone drug for treating TB, speeds up the breakdown of cortisol in the body, effectively lowering levels even when the glands are still partially functional. HIV-related inflammation itself can also disrupt adrenal function. When TB and HIV occur together, the combined assault on the adrenal glands is particularly damaging. Some studies have found signs of adrenal insufficiency in up to 75% of HIV-positive patients, though many of these cases are subclinical, meaning hormone levels are low but symptoms haven’t fully developed.
Fungal infections, including histoplasmosis and coccidioidomycosis, can also destroy adrenal tissue in people with weakened immune systems.
Cancer That Spreads to the Adrenal Glands
The adrenal glands are a common landing site for cancer that has spread from other organs. Lung cancer is the most frequent culprit, accounting for roughly half of adrenal metastases in surgical studies. Kidney cancer, liver cancer, breast cancer, and melanoma also commonly spread there.
However, metastatic cancer in the adrenal glands does not automatically cause Addison’s disease. Both glands need to be extensively destroyed before hormone production drops enough to cause symptoms. In one study of 47 patients with adrenal metastases, all had normal cortisol and aldosterone levels despite having tumors in the glands. Symptoms like fatigue and weight loss in cancer patients are more often caused by the cancer itself than by adrenal failure. Still, when large tumors replace tissue in both glands, full adrenal insufficiency can develop.
Adrenal Hemorrhage
Sudden bleeding into both adrenal glands can cause rapid, life-threatening adrenal failure. This is known as Waterhouse-Friderichsen syndrome when it occurs during severe bacterial infections. It was first described in children with meningococcal sepsis but has since been linked to infections from many different bacteria, including those that cause pneumonia, urinary tract infections, and skin infections.
Bleeding into the adrenals can also happen outside of infection. Blood-thinning medications are a recognized risk factor, though the complication is uncommon. In one 25-year study, only about 2% of adrenal hemorrhage cases were linked to anticoagulant therapy alone. A more significant risk comes from heparin-induced thrombocytopenia, a paradoxical clotting disorder triggered by the blood thinner heparin, which accounted for nearly 10% of cases in the same study. Almost all of those patients developed bilateral hemorrhage and acute adrenal insufficiency, most often in the days following surgery.
How the Diagnosis Is Confirmed
Regardless of the underlying cause, the diagnosis comes down to measuring how well your adrenal glands respond to a signal telling them to produce cortisol. The standard test involves injecting a synthetic version of the pituitary hormone that normally stimulates cortisol production, then checking blood cortisol levels 30 and 60 minutes later. A normal adrenal gland responds by pushing cortisol above 18 micrograms per deciliter. If your cortisol stays below that threshold, it confirms the glands aren’t working properly.
Once adrenal insufficiency is confirmed, additional tests help pinpoint the cause. Antibodies against 21-hydroxylase point to autoimmune destruction. Imaging of the adrenal glands can reveal enlargement from TB or fungal infection, shrinkage from long-standing autoimmune damage, or masses from metastatic cancer. In areas where TB is common, screening for active or past tuberculosis infection is a routine part of the workup.
Medications That Suppress Adrenal Function
Certain medications can interfere with cortisol production by blocking the enzymes involved in its synthesis. Antifungal drugs like ketoconazole are well-known inhibitors of adrenal steroidogenesis, which is why they’re sometimes repurposed to treat conditions involving excess cortisol. The anesthetic agent etomidate also suppresses cortisol production, a concern when it’s used in critically ill patients. These drugs don’t destroy the adrenal glands permanently. Once the medication is stopped, hormone production typically recovers.
A more common medication-related cause of adrenal insufficiency involves long-term use of corticosteroid drugs like prednisone. When you take synthetic cortisol for weeks or months, your brain’s signaling system dials down its instructions to the adrenal glands. The glands shrink from disuse. If you then stop the medication abruptly, your adrenals can’t ramp up production fast enough to meet your body’s needs. This is technically secondary adrenal insufficiency rather than true Addison’s disease, since the glands themselves are intact, but the symptoms overlap considerably.