Primary adrenal insufficiency

What is Primary Adrenal Insufficiency?

Primary adrenal insufficiency is a disorder that occurs when the adrenal glands themselves are damaged and cannot make enough of certain hormones that are essential for life1. The adrenal glands are two small, triangle-shaped organs located just above your kidneys2. When these glands are damaged by disease, they lose their ability to produce the hormones your body needs to function properly.

This condition is different from secondary or tertiary adrenal insufficiency, which occur when problems in the pituitary gland or hypothalamus (areas of the brain) prevent proper signaling to the adrenal glands1. In primary adrenal insufficiency, the problem is directly in the adrenal glands themselves.

Addison's disease, primary adrenal insufficiency

Understanding the Adrenal Glands and Their Hormones

The adrenal glands produce two main types of hormones that are critical for survival. The outer layer of the gland, called the cortex, makes steroid hormones that control many body functions3.

Cortisol is sometimes called the "stress hormone" because it helps your body respond to physical and emotional stress, including illness, injury, or surgery1. This hormone also helps control your blood pressure, supports heart function, strengthens your immune system, and regulates blood sugar levels. Cortisol belongs to a class of hormones called glucocorticoids1.

Aldosterone is a hormone that helps maintain the balance of sodium (salt) and potassium in your blood1. This balance controls how much fluid your kidneys remove as urine, which in turn affects your blood volume and blood pressure2. Aldosterone is a type of mineralocorticoid hormone4.

The adrenal cortex also produces a weak hormone called DHEA (dehydroepiandrosterone), though this is not critical for life5.

• Adrenal glands
• Kidneys

What Causes Primary Adrenal Insufficiency?

The most common cause of primary adrenal insufficiency is an autoimmune reaction, in which the body's defense system mistakenly attacks and destroys the cells of the adrenal cortex35. In autoimmune adrenalitis, the immune system creates antibodies against the adrenal glands and slowly destroys them over months to years5. This autoimmune form accounts for the majority of cases in developed countries.

Other causes of primary adrenal insufficiency include56:

• Tuberculosis (which was the leading cause until the mid-20th century)
• Other infections, including fungal infections
• CMV virus, particularly in people with AIDS
• Cancer cells that have spread to the adrenal glands from other parts of the body, especially breast cancer
• Bleeding into the adrenal glands during severe illness or shock
• Genetic or inherited diseases
• Surgical removal of both adrenal glands

The process of adrenal destruction typically happens gradually. Primary adrenal insufficiency is usually diagnosed when about 90 percent of the adrenal cortex has been destroyed3.

Who is Most Likely to Develop This Condition?

Primary adrenal insufficiency is rare, affecting approximately 1 in 100,000 people in the United States2. The condition can affect people of all age groups, but it is most common in people between 30 and 50 years old27.

Certain groups of people have a higher risk of developing the autoimmune form of primary adrenal insufficiency. People who have autoimmune polyendocrine syndrome—a rare, inherited condition in which the immune system attacks multiple organs and tissues—are much more likely to develop Addison's disease2.

Additionally, people with certain other autoimmune diseases have an increased risk, including those with2:

• Type 1 diabetes
• Pernicious anemia
• Graves' disease
• Chronic thyroiditis
• Dermatitis herpetiformis
• Vitiligo
• Myasthenia gravis

Up to 50 percent of patients with primary adrenal insufficiency develop another autoimmune disorder during their lifetime8.

Signs and Symptoms

With primary adrenal insufficiency, the damage to your adrenal glands usually happens slowly over time, so symptoms typically appear gradually27. The disease may progress so slowly that people might ignore the symptoms at first7. Symptoms vary from person to person.

Common symptoms of primary adrenal insufficiency include275:

• Chronic, steadily worsening fatigue (the most common symptom)
• Patches of darkened skin, especially around scars, skin creases, and on the gums—a condition called hyperpigmentation
• Loss of appetite and unintentional weight loss
• Nausea, sometimes with vomiting
• Diarrhea
• Abdominal pain or pain in the stomach area
• Muscle weakness, muscle pain, or muscle spasms
• Joint pain
• Low blood pressure, which can cause dizziness or lightheadedness when standing up
• Dehydration
• Craving for salty foods
• Low blood sugar (hypoglycemia)
• Changes in mood and behavior, such as irritability, depression, and poor concentration

Women with primary adrenal insufficiency may also experience abnormal or missed menstrual periods, loss of body hair, and decreased sexual desire2.

The darkening of the skin is a particularly distinctive feature of primary adrenal insufficiency. This occurs because when cortisol levels are low, the body produces more ACTH (adrenocorticotropic hormone) in an attempt to stimulate the adrenal glands. High levels of ACTH cause increased production of skin pigment4. These changes may be harder to see on people with darker skin tones79.

Adrenal Crisis: A Medical Emergency

In some cases—especially after an injury, severe illness, or time of intense stress—symptoms can come on quickly and cause a life-threatening event called an adrenal crisis or acute adrenal failure29. This is a medical emergency that requires immediate treatment. Without treatment, an adrenal crisis can lead to shock and death2.

Symptoms of an adrenal crisis include29:

• Extreme weakness
• Sudden, severe pain in the lower back, abdomen, or legs
• Severe vomiting and diarrhea, leading to dehydration
• Very low blood pressure (hypotension)
• Fast heart rate
• Severe drowsiness, confusion, or loss of consciousness
• Seizures (fits)
• High fever

An adrenal crisis can be triggered by infections, injuries, surgery, or other stressful situations. It can also occur if a person with adrenal insufficiency suddenly stops taking their steroid medication9. If you or someone you know with primary adrenal insufficiency experiences these symptoms, call emergency services immediately. Even if an emergency steroid injection has been given, it's important to seek medical care right away9.

How Doctors Diagnose the Condition

If your doctor suspects you might have primary adrenal insufficiency after reviewing your symptoms and medical history, they will refer you to a specialist—usually an endocrinologist, a doctor who specializes in hormones and hormone-related conditions9.

The diagnosis of adrenal insufficiency is made by demonstrating low levels of cortisol in the blood4. The first step is often to measure your early-morning cortisol level, as cortisol levels are naturally highest in the morning10.

The main diagnostic test is called the cosyntropin stimulation test (also known as the ACTH stimulation test). This test measures how well your adrenal glands respond to ACTH14. During the test, a blood sample is taken to measure your baseline cortisol level. Then you receive an injection of synthetic ACTH (cosyntropin), and blood samples are taken again after 30 and 60 minutes to see if your cortisol levels rise. In primary adrenal insufficiency, the cortisol levels remain low because the damaged adrenal glands cannot respond to the ACTH signal11.

To confirm that the problem is in the adrenal glands themselves (primary insufficiency) rather than in the pituitary or brain, doctors will also measure your ACTH level. In primary adrenal insufficiency, ACTH levels are high because the pituitary gland is trying to stimulate the failing adrenal glands410. This is in contrast to secondary adrenal insufficiency, where ACTH levels are low.

Additional tests may be done to determine the cause of the adrenal damage, such as testing for antibodies against adrenal tissue or imaging studies9. Blood tests to check how well your thyroid gland is working may also be performed9.

Treatment and Management

There is currently no cure for primary adrenal insufficiency, but the condition can be effectively managed with hormone replacement medication taken every day for the rest of your life79. With proper treatment, most people with adrenal insufficiency can have a normal, active life and a normal life expectancy19.

Since your adrenal glands are not producing enough hormones, the main treatment is taking steroid medicines to replace the missing hormones9. Treatment for primary adrenal insufficiency requires replacement of both glucocorticoids and mineralocorticoids410.

Glucocorticoid replacement: Cortisol is replaced with a corticosteroid medicine. The most commonly prescribed medication is hydrocortisone, which you typically take two or three times a day by mouth12. Less often, doctors may prescribe prednisone or dexamethasone912. Your doctor will adjust the dose of medicine to meet your body's needs and will work to find the lowest dose that relieves your symptoms8.

Mineralocorticoid replacement: If your adrenal glands aren't making aldosterone, you will take a medicine called fludrocortisone, which helps balance the amount of sodium and fluids in your body12. This medication is typically taken once daily. Your doctor will adjust the dose to keep your blood pressure and electrolyte levels in a healthy range4.

Stress dosing: During times of physical stress—such as illness, surgery, or injury—your body needs more cortisol than usual. You will need to temporarily increase your dose of corticosteroids during these times128. Your specialist will provide guidance on when and how to adjust your medication.

If you're having surgery that uses general anesthesia, you'll need treatment with intravenous (IV) corticosteroids and saline solution starting before surgery and continuing until you can take medicine by mouth again12.

If you become severely ill with a high fever, have severe infection, or experience vomiting and cannot keep your medication down, you will need immediate medical attention, as these situations can lead to an adrenal crisis12.

Living with Primary Adrenal Insufficiency

Living with primary adrenal insufficiency requires daily medication and careful attention to your health. However, with proper treatment and education, you can live a full and active life with minimal disability13.

It is essential that you always have enough medication and never run out9. You should carry a steroid emergency card with you at all times. This card tells healthcare professionals that you have adrenal insufficiency and take steroid medicine that should not be stopped suddenly9. You can also get medical alert jewelry, such as bracelets or necklaces, with details of your condition and medication engraved on them9.

You should be given an emergency injection kit containing a dose of hydrocortisone so that you or a caregiver can give yourself an injection if needed during an adrenal crisis9. Your specialist will provide training on when and how to use this kit.

Patient education is a key feature of managing this condition13. You need to understand:

• When to increase your medication dose (during illness, stress, or injury)
• Signs and symptoms of adrenal crisis
• When to seek emergency medical care
• How to give yourself an emergency injection if needed
• The importance of never stopping your medication suddenly

Talk with your doctor about how to adjust your dose of corticosteroids during illness. You will generally need to increase your dose if you have a high fever. Once you recover, your doctor will adjust your dose back to your regular level12.

If you become pregnant, you'll need to continue your medication throughout pregnancy and may need dose adjustments12. Be sure to work closely with your healthcare team during this time.

Complications and Monitoring

The most serious complication of primary adrenal insufficiency is adrenal crisis, a life-threatening medical emergency that can cause severe dehydration, very low blood pressure, seizures, loss of consciousness, or cardiac arrest9. With proper education, emergency preparedness, and prompt treatment, adrenal crises can usually be prevented or successfully treated.

Treatment complications can arise from taking too much or too little hormone replacement medication4. Taking too much glucocorticoid over time can lead to weight gain, osteoporosis (weak bones), high blood pressure, diabetes, and mood changes. Taking too little can result in persistent symptoms of adrenal insufficiency and increased risk of adrenal crisis. This is why regular monitoring is essential.

You will have regular appointments with your specialist to monitor for signs of under-replacement or over-replacement of your medications13. During these visits, your doctor will check your blood pressure, electrolyte levels, and overall health. They will also screen for other autoimmune conditions, as people with autoimmune adrenal insufficiency are at higher risk for developing additional autoimmune diseases.

With careful management, ongoing education, and regular medical follow-up, people with primary adrenal insufficiency can maintain a good quality of life and normal life expectancy9.