Addison's Disease: An Overview

Addison’s disease, also known as primary adrenal insufficiency and hypocortisolism, is a rare disorder in which the adrenal glands (which sit atop the kidneys) don’t produce enough of the hormones cortisol and sometimes aldosterone.

Symptoms tend to come and go and may include abdominal pain, dizziness, fatigue, weight loss, salt cravings, and darkening of the skin. During periods of extreme stress or poor health, Addison’s disease can trigger a rapid drop in cortisol levels and a potentially life-threatening event known as an adrenal crisis.

While Addison’s disease can be diagnosed with blood and imaging tests, it is so rare—affecting only 1 of every 100,000 people—that diagnoses are typically delayed until more serious manifestations of the disease develop. 

Addison’s disease cannot be cured but can be significantly improved with hormone replacement therapy and the avoidance of common triggers. If treated properly, Addison’s disease can be brought under control and you can be better assured of living a long and healthy life.

This article discusses the causes, symptoms, and diagnosis of Addison's disease, with some added tips for living with this chronic condition.

What Are the Symptoms of Addison's Disease?

The primary symptoms of Addison’s disease tend to be episodic and non-specific. Common symptoms include:

• Extreme fatigue
• Abdominal pain
• Decreased appetite
• Salt craving
• Lightheadedness
• Dizziness when rising (postural hypotension)
• Blurry vision
• Shakiness or tremors
• Heart palpitations
• Nausea or vomiting
• Anxiety or irritability
• Depression
• Pins-and-needles sensations (peripheral neuropathy)
• Reduced sex drive (low libido)
• Hair loss
• Muscle or joint pain
• Weight loss
• Auditory and visual hallucinations
• Darkening of the skin (hyperpigmentation), particularly in areas where there are skin creases or scars, as well as on the palms, nipples, and inside the cheek
  

The symptoms of Addison’s disease are directly associated with the degree of adrenal impairment. As a progressive disease, the symptoms tend to worsen over time if left untreated.

They can start incidentally, with odd moments of stomach pain and weakness, but become increasingly more apparent as the attacks recur, particularly during moments of stress.

Depending on the cause of the underlying impairment, the symptoms of Addison’s disease can either develop slowly and steadily or fast and furiously.

The majority of symptoms are caused when a drop in cortisol levels (hypocortisolism) triggers an associative drop in blood pressure (hypotension) and blood sugar (hypoglycemia). Other symptoms are related to a drop in aldosterone, the hormone responsible for sodium retention. 

Adrenal Crisis

Adrenal crisis, also known as an Addisonian crisis, occurs when cortisol levels have dropped so rapidly that it causes serious and potentially life-threatening symptoms, including:

• Severe vomiting and/or diarrhea leading to dehydration
• Pain in the lower back, legs, or abdomen
• Fainting (syncope)
• Muscle spasms
• Confusion and disorientation
• Extreme thirst and the inability to urinate
• Abnormal heartbeats (arrhythmia)
• Intermittent muscle paralysis

If not treated aggressively with intravenous fluids and steroids, death may ensue, most often as a result of hypotensive shock or respiratory failure. According to research, an adrenal crisis results in death in one of every 16 cases, most often due to delayed or inadequate treatment.

What Are the Causes of Addison's Disease?

Addison’s disease is caused by a failure of the adrenal glands. The adrenal glands are one of several organs that comprise the endocrine system. The glands are situated atop each kidney and are responsible for producing a variety of hormones, including cortisol, aldosterone, and adrenaline. 

Cortisol, often referred to as the “stress hormone,” rises when the "fight or flight" instinct is triggered during a crisis. It also plays a central role in the regulation of blood pressure, blood sugar, protein, fat, and carbohydrate metabolism, bone mineralization and density, inflammation, sleep, and energy levels. It is produced in a part of the adrenal glands known as the zona fasciculata.

Aldosterone helps regulate the balance of sodium and potassium in the body and, by doing so, influences blood pressure, blood volume, and the retention of water in cells. It is produced in a different part of the gland known as the zona glomerulosa.

Risk Factors for Addison's Disease

Risk factors for the most common type of Addison's disease (autoimmune) include other autoimmune diseases:

• Type I diabetes
• Hypoparathyroidism
• Hypopituitarism
• Pernicious anemia
• Graves' disease
• Chronic thyroiditis
• Dermatis herpetiformis
• Vitiligo
• Myasthenia gravis

Adrenal Impairment

There are a number of reasons why the adrenal glands will no longer function as they should. With Addison’s disease, primary adrenal insufficiency is most often caused by a disease or disorder that directly impairs the organ itself.

By far the most common cause of this is autoimmune adrenalitis, an autoimmune disease in which the body turns its defenses on itself and attacks the cells in the adrenal glands that produce steroids. No one is exactly sure why this happens, although genetics are believed to play a central role.

Generally speaking, the zona fasciculata (where cortisol is produced) is the site of the major autoimmune assault, followed by the zona glomerulosa (where aldosterone is produced). In some cases, the third and final zone, known as the zona reticularis, may sustain collateral damage, resulting in the impairment of certain sex hormones.

Antibodies to all three zones of the adrenal cortex are present in the serum of 60% to 75% of patients with primary adrenal insufficiency caused by autoimmune adrenalitis.

In addition to autoimmune adrenalitis, other conditions can directly impact the adrenal glands, including:

• Tuberculosis
• Advanced HIV infection
• Systemic fungal infections
• Secondary (metastatic) cancers
• Adrenal hemorrhage
• Adrenomyeloneuropathy, an inherited neurological disorder that can cause the adrenal glands to fail (usually in adulthood)

Less commonly, a genetic disorder can indirectly impair adrenal function by robbing the body of the compounds it needs to make steroids. One such compound is cholesterol, which the adrenal glands convert into cortisol and aldosterone.

Rare genetic disorders like Smith-Lemli-Opitz syndrome (an inborn error affecting cholesterol synthesis) and abetalipoproteinemia (which interferes with the absorption of fat) are among some of the inherited disorders that can indirectly lead to Addison’s disease.

Adrenal Crisis

An adrenal crisis can occur as either an extension of Addison’s disease or independent of it. More specifically, an adrenal crisis develops when the drop in cortisol is rapid and severe, leading to low blood pressure, low blood sugar, and high blood levels of potassium. The condition is potentially life-threatening and requires immediate medical care.

An adrenal crisis may be caused by any event in which the body cannot adequately respond to extreme stress, whether psychological or physical. According to one study, the following are the most common precipitating factors for an adrenal crisis.

Other studies have also supported gastrointestinal illness as the predominant trigger for an acute adrenal crisis. Other causes include seizures, severe migraine, hot weather, atrial fibrillation (irregular heartbeat), and even long-distance flights. Additional risk factors include pregnancy and diabetes.

Secondary Adrenal Insufficiency

An adrenal crisis can also occur if the pituitary gland is damaged or diseased. The pituitary gland is part of the hypothalamic-pituitary-adrenal axis. Its role is to “instruct” the adrenal gland when to produce more cortisol and how much. It does so with a hormone called adrenocorticotropic hormone (ACTH).

Another common cause of secondary adrenal insufficiency is the sudden termination of corticosteroid drugs used to treat arthritis, asthma, and other inflammatory diseases. By stopping the drugs abruptly, undiagnosed Addison’s disease may be inadvertently “unmasked” in the form of an adrenal crisis.

How Is Addison's Disease Diagnosed?

Addison’s disease is diagnosed with a variety of blood and imaging tests used to confirm adrenal insufficiency. A diagnosis is typically initiated based on the appearance of telltale symptoms, such as hyperpigmentation, fatigue, and salt cravings (a classic triad of adrenal symptoms).

In others, a routine blood test may reveal abnormalities suggestive of the disease, such as the unexplained recurrent episodes of hypoglycemia, hyponatremia, and hypokalemia.

More commonly, an adrenal crisis will be the first symptom of Addison’s disease in around 50% of cases.

• Serum cortisol tests can be used to measure the levels of cortisol in your blood. A cortisol value of 25 micrograms per decilitre (mcg/dL) or more excludes adrenal insufficiency of any kind.
• ACTH stimulation test involves the use of a synthetic ACTH called Cosyntropin (tetracosactide). The test compares cortisol levels before and after an ACTH injection. A cortisol value of 7 mcg/dL or more at baseline increasing to 20 micrograms per decilitre (mcg/dL) or more in 30 to 60 minutes excludes adrenal insufficiency as the cause.
• Autoantibody studies can be used to detect proteins, called 21-hydroxylase antibodies, associated with autoimmune adrenalitis.
• Insulin-induced hypoglycemia test is used to diagnose secondary adrenal insufficiency. The test compares cortisol and blood glucose levels before and after an insulin shot to see if the pituitary gland responds as it should.
• Imaging tests, such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), would be ordered to check for any abnormalities in the adrenal glands themselves.

Additional investigations may be needed to exclude all other causes of adrenal insufficiency—a process known as the differential diagnosis. Other possible causes include hyperthyroidism (overactive thyroid), lymphoma, anorexia nervosa, hemochromatosis (iron overload), and adrenal suppression due to corticosteroid therapy.

How Is Addison's Disease Treated?

As a disorder characterized by the depletion of key hormones, Addison’s disease is primarily treated and managed with lifelong hormone replacement therapy. In most cases, this would involve oral steroid medications taken two to three times daily.

Among those most commonly prescribed:

• Cortef (hydrocortisone) is used to replace cortisol. Prescribed in a daily dose of 15 to 25 milligrams, the medication is taken in two to three divided doses with food and a full glass of water to prevent stomach upset.
• Florinef (fludrocortisone) is used to replace aldosterone. It is prescribed in a daily dose of 50 to 200 micrograms, taken in one or two doses with or without food.
• Dehydroepiandrosterone (DHEA) is an oral steroid supplement sometimes prescribed to alleviate chronic fatigue associated with Addison’s disease, particularly in women. It is prescribed in a daily dose of 25 to 50 milligrams, taken either when waking or at bedtime.
• Prednisone is a glucocorticoid that suppresses the production of cortisol via its effect on the HPA axis. It can be taken as a daily dose of 3 to 5 milligrams.
• Dexamethasone is a corticosteroid that may be used if Cortef is intolerable. It is injected intramuscularly in a daily 0.5-milligram dose. There is also an oral version.

As with many medications, there are several common side effects of those commonly prescribed to treat Addison’s disease including:

• Headache
• Dizziness
• Nausea
• Upset stomach
• Acne
• Dry skin
• Easy bruising
• Insomnia
• Muscle weakness
• Slowed wound healing
• Changes in menstrual periods

Long-term use may cause lipodystrophy (the redistribution of body fat) and osteoporosis (bone thinning), although these are more likely due to overmedication than the duration of treatment.

Grapefruit and licorice can also amplify side effects and should be consumed sparingly. Speak to your healthcare provider if the side effects are intolerable or causing you distress. In some cases, treatment can be changed or the dosages reduced.

Adrenal Crisis

If you have Addison’s disease, you will likely be advised to wear a medical ID bracelet in the event of an adrenal crisis. Moreover, you will likely be advised to carry an emergency kit containing a needle, syringe, and a 100-milligram ampule of injectable hydrocortisone.

As an adrenal crisis can progress rapidly, you would need to give yourself an emergency intramuscular injection of hydrocortisone until help arrives. This requires that you or a family member learn proper injection techniques and recognize the signs and symptoms of an adrenal crisis.

Giving too much hydrocortisone in an emergency situation will do no harm. By contrast, under-dosing will do little to prevent the rapid deterioration of your condition. An adrenal crisis requires hospitalization with intravenous hydrocortisone and intravenous fluids composed of 0.9% sodium chloride.

How to Cope With Addison's Disease

Living with any chronic disease can be challenging. With Addison’s disease, the greatest challenge may be the avoidance of any illness or event that can trigger an adrenal crisis.

Important strategies include:

• Managing stress: When you are worn out and riddled with anxiety, stress-reduction techniques may reduce the risk of a crisis or, at the very least, lessen the severity or frequency of a chronic episode. These include mindfulness meditation, guided imagery, progressive muscle relaxation, biofeedback, tai chi, and gentle yoga.
• Exercising without undue physical stress: While exercise remains vital to good health, you need to do so without causing added stress to your body. If you plan to engage in athletics, tell your healthcare provider so that your medication doses can be increased to compensate for the increased activity.
• Consulting your healthcare provider when you are ill: If you are ill, have a fever over 100 degrees F, or are undergoing a medical procedure, let your healthcare provider know.
• Taking proper precautions while pregnant: With the right medical support, people with Addison’s disease can fully expect to have a healthy pregnancy and a normal birth. However, endocrine levels should be monitored during the first trimester, and medications should be increased as you approach childbirth. If your fertility is impaired, you can explore assisted reproductive options with a fertility specialist in tandem with your endocrinologist.

Summary

Thanks to advances in therapy, people with Addison’s disease can enjoy better health and near-normal life expectancies. Early diagnosis and treatment may further increase these rates. To this end, it is important to see a healthcare provider if you experience recurrent episodes of fatigue, low blood pressure, weight loss, salt craving, or skin color changes that you simply can’t explain. An adrenal crisis doesn’t need to be your first symptom.

If your healthcare provider isn't familiar with Addison’s disease, ask for a referral to an endocrinologist who can run tests to either confirm or rule out the disease.

A Word From Verywell

While not very common, Addison's disease can be serious when it occurs. Hence, prompt identification and management are key to ensuring a good outcome. To manage Addison's disease and avoid potentially severe complications, regular electrolyte monitoring and timely imbalance corrections are essential.

— KASHIF J. PIRACHA, MD, MEDICAL EXPERT BOARD