An Overview of Addison's Disease

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Fatigued after exercise.
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Addison’s disease, also known as primary adrenal insufficiency and hypocortisolism, is a rare disorder in which the adrenal glands 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 craving, and the 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.

The most common cause of Addison’s disease is autoimmune adrenalitis, a disorder in which the body’s immune system inadvertently attacks and damages cells of the adrenal glands.

While Addison’s disease can be diagnosed with blood and imaging tests, it is so rare—affecting only one 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.

Symptoms

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 or 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. 

The primary symptoms of Addison’s disease tend to be episodic and non-specific and may 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

Darkening of the skin (hyperpigmentation) can also occur, particularly in areas where there are skin creases or scars, as well as on the palms, nipples, and inside the cheek

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 prospective research published in the Journal of Clinical Endocrinology and Metabolism, an adrenal crisis results in death in one of every 16 cases, most often due to delayed or inadequate treatment.

Causes

Addison’s disease is caused by the 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," triggers the "fight-or-flight" instinct during a crisis but also plays a central role in the regulation of blood pressure, blood sugar, 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.

Addison’s disease develops when the adrenal glands can no longer adequately supply the body with cortisol and aldosterone. It affects men and women equally and occurs in all age groups, but is most common between the ages of 30 and 50.

Adrenal Impairment

There is any number of reasons why the adrenal glands will no longer function as it 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.

In addition to autoimmune adrenalitis, there are other conditions that can directly impair the adrenal glands:

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-Lemeli-Optiz 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 so rapid and severe that sodium and potassium levels plummet, leading to hyponatremia (low blood sodium) and hypokalemia (low blood potassium). Both conditions are potentially life-threatening if the drops are sustained and severe.

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 a study published in the European Journal of Endocrinology, the most common precipitating factors for an adrenal crisis include:

  • Gastrointestinal illness at 29 percent
  • Other infections at 22 percent
  • Surgery at 10 percent
  • Unknown at 9 percent
  • Physical stress/pain at 7 percent
  • Psychological stress at 3 percent
  • Accidents (falls, cuts, etc.) at 3 percent

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-distant flights. Other 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 (HPA) axis. Its role it is to "instruct" the adrenal gland when to produce more cortisol and how much. It does so with a hormone called adrenocorticotropic hormone (ACTH).

If a crisis occurs as a result of pituitary gland failure (perhaps caused by cancer or pituitary gland surgery), it would be referred to as a secondary adrenal insufficiency.

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.

Diagnosis

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 tell-tale 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 percent of cases, according to a review published in the American Journal of Medicine.

If suspected, Addison’s disease can be confirmed with a series of tests:

  • Serum cortisol tests can be used to measure the levels of cortisol in your blood. A cortisol value of 25 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 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 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.

Treatment

As a disorder characterized by the depletion of key hormones, Addison’s disease is primarily treated and managed with life-long hormone replacement therapy. In most cases, this would involve oral steroid medications taken two to three time 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 alleviated 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, another commonly used corticosteroid, can stimulate the production of cortisol and may be used if you are unable to tolerate Cortef. Prednisone can be taken as a daily dose of 3 to 5 milligrams.
  • Dexamethasone is an injectable corticosteroid which may be used if Cortef is intolerable. It is injected intramuscularly in a daily 0.5 milligram dose.

    Side effects include headaches, dizziness, nausea, stomach upset, acne, dry skin, easy bruising, insomnia, muscle weakness, slowed wound healing, and changes in menstrual periods. Long-term use may cause lipodystrophy (the redistribution of body fat), osteoporosis (bone thinning), and glaucoma (a type of optic nerve damage), although these are more likely due to overmedication then the duration of treatment.

    Grapefruit and licorice can also amplify side effects and should be consumed sparingly. Speak to your doctor 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 would also be advised to wear a medical ID bracelet in the event of an adrenal crisis. Moreover, you would be advised to carry an emergency kit containing a needle, syringe, and a 100 milligram ampule of injectable hydrocortisone.

    In the event of vomiting, persistent diarrhea, or other symptoms of an adrenal crisis, emergency care should be sought without delay. As an adrenal crisis can progress rapidly, you would need to provide yourself an emergency intramuscular injection of hydrocortisone until helps arrives. This requires you or a family member to learn the proper injection techniques and to 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 comprised of 0.9 percent sodium chloride.

    Coping

    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.

    The management of stress, however, is key. Particularly at times 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 such techniques as mindfulness meditation, guided imagery, progressive muscle relaxation (PMR), biofeedback, Tai chi, and gentle yoga.

    While exercise remains vital to good health, you need to do so without causing undue physical stress. If you plan to engage in athletics, tell your doctor so that your medication doses can be increased to compensate for the increased activity. The same applies if you are ill, have a fever over 100 F, or are undergoing a medical procedure.

    While there is no special diet for Addison’s disease, you should avoid low-sodium diets and even increase salt intake if you plan to be in hot weather or engage in strenuous activity. If fatigued, don’t push it—allow your body time to recover.

    With the right medical support, women 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.

    A Word From Verywell

    Thanks to advances in therapy, people with Addison’s disease can enjoy better health and near-normal life expectancies. In fact, according to research published in Clinical Endocrinology, the average life expectancy for people with Addison's disease has leaped to 64.8 years in men and 75.7 years in women.

    Early diagnosis and treatment may further increase these rates. To this end, it is important to see a doctor 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 doctor doesn’t know what Addison’s disease is, do not hesitate to ask for a referral to an endocrinologist who can run tests to either confirm or rule out the disease.

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