Addison’s disease, or adrenal insufficiency, is usually an autoimmune disease, resulting from a faulty immune response. Other causes include infections and steroid use. Certain genetic factors can also increase the risk.

Addison’s disease disrupts the production of aldosterone and cortisol, which can lead to severe complications.

The adrenal glands are situated just above each kidney. They produce hormones that affect organs and tissues throughout the body.

The adrenal glands consist of two layers: the medulla, which is the interior layer, and the cortex, the outer layer. The medulla produces epinephrine-like hormones, while the cortex secretes corticosteroids.

Damage to the cortex can disrupt the production of hormones such as cortisol, aldosterone, and androgens.

In this article, we discuss the causes of Addison’s disease.

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Addison’s disease occurs when damage to the adrenal cortex disrupts hormone production in the adrenal glands.

This can result from:

  • a faulty autoimmune response
  • genetic factors
  • injury to or bleeding in the adrenal or pituitary glands
  • conditions such as cancer, tuberculosis (TB), and HIV
  • removal of the adrenal or pituitary glands
  • chronic steroid use

In industrialized countries, 80–90% of cases result from an autoimmune disease.

Adrenal insufficiency can lead to a range of symptoms, including:

A person may have primary or secondary adrenal insufficiency.

Primary adrenal insufficiency

This condition results from direct injury to the adrenal cortex. This is the outer layer of the adrenal glands.

Causes include:

  • an autoimmune disease
  • infections such as TB, cytomegalovirus, and HIV
  • bleeding in the adrenal glands due to trauma, blood clotting, or other factors
  • conditions such as hemochromatosis, cancer, and amyloidosis
  • conditions a person has from birth, such as congenital adrenal hyperplasia
  • the use of drugs that prevent the production of cortisol, including ketoconazole and etomidate

Secondary adrenal insufficiency

Indirectly, issues with the pituitary gland can cause Addison’s disease. The pituitary gland produces adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce other hormones.

Issues with the pituitary glands can cause them to produce less ACTH. Consequently, the adrenal glands will also produce lower levels of hormones.

Other causes of secondary adrenal insufficiency include:

  • pituitary tumors or infection
  • surgery to remove the pituitary gland
  • bleeding in the pituitary gland
  • genetic conditions that affect the pituitary gland

Secondary adrenal deficiency can also develop when a person uses steroid drugs that affect the hypothalamus and the pituitary gland and prevent the body from producing ACTH. This leads to a reduction in a type of steroid known as glucocorticoid. Symptoms usually appear after a person stops using the drugs, especially if they do so abruptly.

The immune system defends the body from disease, toxins, and infection. In a person with an autoimmune condition, the immune system attacks and damages healthy tissues and organs.

In Addison’s disease, the immune system attacks cells of the adrenal glands, and they gradually stop working.

People are more likely to develop autoimmune Addison’s disease if they already have one of the following autoimmune conditions:

  • type 1 diabetes
  • problems with the thyroid or pituitary gland, including Grave’s disease
  • pernicious anemia
  • dermatitis herpetiformis
  • vitiligo
  • myasthenia gravis

People with certain genetic features and conditions have a higher risk of adrenal insufficiency.

These include:

  • congenital adrenal hyperplasia, a group of disorders that affect cortisol production
  • adrenal leukodystrophy, which affects the adrenal glands, the brain, and the myelin sheath, which protects the nerves
  • Wolman disease, which causes calcification of the adrenal glands
  • antiphospholipid syndrome (APS)

The genes most likely linked with autoimmune Addison’s disease belong to the human leukocyte antigen complex. This genetic complex helps the immune system distinguish between the body’s own proteins and those made by viruses and bacteria.

Many people with autoimmune Addison’s disease have another autoimmune condition, such as hypothyroidism, type 1 diabetes, or vitiligo.

Bleeding into the adrenal glands, which health experts also call adrenal hemorrhage, can result from:

It is also more common during pregnancy.

Cancer can cause symptoms of Addison’s disease in the following ways:

  • tumors developing in the adrenal glands
  • metastasis, when cancer spreads to the adrenal glands from another area
  • lymphoma developing

Researchers are also investigating whether some drugs used in cancer treatment, such as steroids with chemotherapy, may increase the risk of fatigue due to adrenal insufficiency.

Other conditions that may lead to Addison’s disease include:

  • amyloidosis, which occurs when too much amyloid protein builds up in the body
  • sarcoidosis, when small patches of inflamed tissue, or granulomas, develop in the body’s organs
  • hemochromatosis, when too much iron builds up in the body

Hemochromatosis is an infiltrative condition. It infiltrates the adrenal glands substances that are harmful to the glands, namely iron.

Infections that can increase the risk of Addison’s disease include:

These infections can damage the adrenal glands and affect the production of hormones.

Some people have surgery to remove the adrenal glands, called adrenalectomy.

A doctor may recommend this if:

  • there is cancer in the adrenal glands
  • cancer has spread, for example, from the kidneys
  • the glands are overproducing hormones, as in Conn’s syndrome or Cushing’s syndrome
  • there is a change in size in the glands

If the surgeon removes both adrenal glands, the person may need medication for the rest of their life to make up for the loss of hormone production.

Surgery to remove the pituitary gland can also impact hormone production in the adrenal glands.

People take steroids for various conditions, as they help manage inflammation. However, long-term use can disrupt hormone production in the adrenal glands and increase the risk of Addison’s disease.

Glucocorticoids — such as cortisone, hydrocortisone, prednisone, and dexamethasone — act like cortisol. When a person takes them, the body perceives an increase in cortisol and produces less ACTH. As a result, the adrenal glands produce lower levels of hormones.

Stopping oral corticosteroids suddenly can lead to adrenal insufficiency. A doctor will gradually reduce the dose over several weeks or months to allow the adrenal glands to work properly again.

Adrenal insufficiency can also occur after effective treatment for Cushing’s syndrome. In this condition, a person’s body produces too much cortisol. Treatment reduces cortisol levels but can disrupt the function of the adrenal glands for a while.

Changes in hormone levels usually happen over time, and a person may not notice any difference.

However, when damage affects 90% of the adrenal cortex, the body will no longer be able to produce aldosterone or cortisol, and symptoms will start to appear.

As symptoms progress, a crisis may develop, which health experts call an Addisonian or acute adrenal crisis.

It can happen suddenly and can be life threatening. It is a medical emergency.

Symptoms include:

Tests may show:

Factors that can trigger a crisis include:

  • high stress levels
  • infection
  • trauma or injury
  • surgery
  • diarrhea and vomiting

For this reason, it is essential to seek prompt advice if anyone experiences symptoms that could indicate adrenal insufficiency.

Anyone who believes they have symptoms of Addison’s disease — such as weakness, fatigue, and unintentional weight loss — should seek medical help.

Seeking treatment when symptoms first appear may help reduce the risk of an Addisonian crisis.

Here, learn about how doctors diagnose Addison’s disease.

Addison’s disease, or adrenal insufficiency, occurs when the adrenal glands no longer produce hormones effectively.

The main cause of Addison’s disease is a faulty autoimmune response. Other causes include injury, steroid use, and conditions such as cancer, HIV, and TB.

Symptoms include fatigue and weight loss, but they may not appear until a later stage, as the progression is gradual.

In time, however, an Addisonian crisis can develop, where symptoms suddenly become severe. This is potentially life threatening.