Addison's Disease

Source: Wikimedia Commons

Addison disease is an uncommon, but potentially catastrophic endocrine disorder affecting the adrenal glands. In Addison disease, the adrenal glands, which sit above the kidneys, do not produce enough of the hormones cortisol and aldosterone. The disease causes muscle weakness, fatigue, weight loss, abnormal balance of salt and potassium, low blood pressure and skin changes.

Other Names

• Primary hypoadrenalism
• Primary adrenal insufficiency
• Addison's disease

Background: Hormones

In order to fully understand Addison disease, it is important to understand the normal function of the hormones that are lacking in the disease. By knowing these functions, it is easy to work out how the disease causes the problems it does. The two main hormones are called cortisol and aldosterone.

Cortisol

Chemical structure of cortisol. Source: Wikimedia Commons

Cortisol is normally produced by the adrenal glands, located just above the kidneys. This hormone is called cortisol because it is produced by the adrenal cortex, which is the zone around the outside of the adrenal gland. Cortisol is made in certain areas of the gland called the zona fasciculata and zona reticularis. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol may possibly have hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Cortisol also

• Helps maintain blood pressure and cardiovascular function,
• Helps slow the immune system's inflammatory response,
• Helps balance the effects of insulin in breaking down sugar for energy,
• Helps regulate the metabolism of proteins, carbohydrates, and fats, and
• Helps maintain proper arousal and sense of well-being.

Because cortisol is so vital to health, the amount of cortisol produced by the adrenals is precisely balanced. Like many other hormones, cortisol is regulated by the brain's hypothalamus and pituitary gland (a bean-sized organ at the base of the brain). Initially, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting hormones that regulate growth and thyroid and adrenal function, and sex hormones such as estrogen and testosterone. One of the pituitary's main functions is to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitary's signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.

Chemical structure of aldosterone. Source: Wikimedia Commons

Aldosterone

Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. Aldosterone is produced in the zona glomerulosa section of the gland. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.

Types

Cross-section of the adrenal gland (Source: Gray's Anatomy)

There are two types of Addison disease:

Primary adrenal insufficiency

Primary adrenal insufficiency happens when the adrenal glands fail to make enough cortisol. This is usually a result of an autoimmune disorder. The underlying autoimmune disorder can be a result of infectious disease, cancer, or genetics.

Secondary adrenal insufficiency

Secondary adrenal insufficiency results in a failure of the pituitary gland to produce a hormone called ACTH (adrenocorticotropin). ACTH sends a signal to the adrenal glands, telling them to produce cortisol. If the signal is interrupted, a cortisol deficiency will occur.

Causes

Like other hormones in the body, both cortisol and aldosterone are very closely regulated by many different systems. The release of each is controlled by the brain. The hypothalamus releases cortisol-releasing hormone (CRH), which acts on the pituitary gland to release adrenocorticotropic hormone (ACTH), which in turn activates the adrenal cortex to release cortisol. Damage to any part of this pathway can cause Addison disease, which is why Addison disease is divided into primary or secondary, indicating at which level this chain of control is affected.

Primary adrenal insufficiency

Autoimmune

Most cases of Addison disease not due to chronic steroid use are caused by the gradual destruction of the adrenal cortex by the body's own immune system. About 70% of reported cases of Addison disease are caused by autoimmune disorders, in which the immune system makes antibodies that attack the body's own tissues or organs, slowly destroying them. Adrenal insufficiency occurs when at least 90% of the adrenal cortex has been destroyed. As a result, often both glucocorticoid (cortisol) and mineralocorticoid (aldosterone) hormones are lacking. Sometimes only the adrenal gland is affected, as in idiopathic adrenal insufficiency. Sometimes other glands also are affected, as in the polyendocrine deficiency syndrome.

Polyendocrine deficiency syndrome

The polyendocrine deficiency syndrome is classified into two separate forms, referred to as type I and type II.

Type I occurs in children, who have not only adrenal insufficiency, but also the following signs and symptoms.

• Underactive parathyroid glands
• Slow sexual development
• Pernicious anemia
• Chronic Candida
• Chronic active hepatitis
• Hair loss (in very rare cases)

Type II, often called Smith-Lemli-Opitz syndrome (SMOS), is an enzyme deficiency in cholesterol metabolism. This disorder usually afflicts young adults. Features of type II may include:

• An underactive thyroid gland
• Slow sexual development
• Diabetes
• Vitiligo
• Loss of pigment on areas of the skin

Genetic causes

In Type I polyendocrine deficiency syndrome, several gene mutations have been identified. Each of these different genetic mutations causes different manifestations of Addison disease. All of these genetic causes are rare and most manifest themselves at a very young age.

Infectious causes

Tuberculosis

Tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis, is the most common infectious cause of Addison disease. It accounts for about 20 percent of cases of primary adrenal insufficiency in developed countries. When adrenal insufficiency was first identified in the mid-19th century, TB was found at autopsy in 70%–90% of cases. As the treatment for TB improved, however, the incidence of adrenal insufficiency due to TB of the adrenal glands has greatly decreased. TB is making a comeback, however, so Addison disease due to TB may become more common in future years.

Other causes

Less common causes of primary adrenal insufficiency include:

• Chronic infection (other than tuberculosis)
• Cancer cells spreading from other parts of the body to the adrenal glands
• Amyloidosis
• Surgical removal of the adrenal glands

Secondary adrenal insufficiency

Secondary adrenal insufficiency is much more common than primary adrenal insufficiency because it is often caused by the use and stoppage of chronic steroids, which many people take for various diseases. When people take an exogenous (not from the body) source of steroids, the steroids suppress the production of natural steroids from their own adrenal glands. In response, the hypothalamus and pituitary gland are tricked into behaving as if there is enough cortisol in the body, so they reduce release of ACTH. The adrenal glands' production of cortisol drops. However, aldosterone (a mineralocorticoid) is not controlled by ACTH, so it functions normally. A temporary form of secondary adrenal insufficiency may occur when a person who has been receiving a glucocorticoid (steroid) hormone such as prednisone for a long time abruptly stops or interrupts taking the medication. The body has grown accustomed to not making any cortisol, so the person experiences cortisol deficiency when the steroid medications are stopped. There may also be cortisol deficiency during periods of stress even if the person keeps taking their steroids, because the body cannot increase cortisol production to cope with the stress. In these cases, steroid doses may need to be temporarily increased.

Another cause of secondary adrenal insufficiency is the surgical removal of benign, or noncancerous, ACTH-producing tumors of the pituitary gland (Cushing disease). In this case, the source of ACTH is suddenly removed, and replacement hormone must be taken until normal ACTH and cortisol production resumes.

Less commonly, adrenal insufficiency occurs when the pituitary gland either decreases in size or stops producing ACTH. These events can result from:

• Tumors or infections of the area
• Loss of blood flow to the pituitary, which causes death of some of the tissue ("infarction")
• Radiation for the treatment of pituitary tumors
• Surgical removal of parts of the hypothalamus
• Surgical removal of the pituitary gland

One classical syndrome is acute adrenal insufficiency following bacterial meningitis from the meningococcus bacteria. This kind of adrenal insufficiency is known as the Waterhouse-Friderichsen syndrome, and it results from loss of blood supply to both adrenal glands from disseminated intravascular coagulation, or DIC; and sepsis (systemic infection) in severe meningitis.

Signs and Symptoms

The symptoms of adrenal insufficiency of any type, including Addison disease, usually begin gradually. Characteristics of the disease are:

• Chronic, worsening fatigue
• Muscle weakness
• Loss of appetite
• Weight loss

Less commonly, nausea, vomiting, and diarrhea may be present.

Other symptoms include:

• Low blood pressure that becomes even lower upon standing, causing dizziness or fainting
• Skin changes in Addison disease, with areas of hyperpigmentation, or dark tanning, covering exposed and nonexposed parts of the body. This darkening of the skin is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes.

Addison disease can cause irritability and depression. Because of salt loss, a craving for salty foods also is common. Hypoglycemia, or low blood sugar, is more severe in children than in adults. In women, menstrual periods may become irregular or stop.

Because the symptoms progress slowly, they are usually ignored until a stressful event like an illness or an accident causes them to become worse. This is called an Addisonian crisis, or acute adrenal insufficiency. In most cases, symptoms are severe enough that patients seek medical treatment before a crisis occurs. However, in about 25% of patients, symptoms first appear during an Addisonian crisis.

Symptoms of an Addisonian crisis include:

• Sudden penetrating pain in the lower back, abdomen, or legs
• Severe vomiting and diarrhea
• Dehydration
• Low blood pressure
• Loss of consciousness

Left untreated, an Addisonian crisis can be fatal.

Diagnosis

In its early stages, adrenal insufficiency can be difficult to diagnose. A review of a patient's medical history based on the symptoms, especially the dark discoloration of the skin, will lead a doctor to suspect Addison disease.

A diagnosis of Addison disease is made by laboratory tests.^[1] The aim of these tests is first to determine whether levels of cortisol are insufficient and then to establish the cause. X-ray exams of the adrenal and pituitary glands also are useful in helping to establish the cause.

Laboratory tests

Often, patients with Addison disease will have a set of blood tests called a metabolic panel taken as part of a routine workup of the reason behind their fatigue. Abnormally low aldosterone can lead to very low levels of sodium and high levels of potassium, calcium and BUN (blood urea nitrogen). This is because usually aldosterone conserves sodium by exchanging it in the kidneys for potassium, which then leaves the body in the urine. When there is no aldosterone, sodium is lost and potassium is retained. This leads to dehydration, which causes the calcium and BUN to rise. This finding is not specific for Addison disease, and may be found in other diseases.

Cortisol level

If acute Addisonian crisis is suspected, doctors often check a cortisol level, which is a blood test. This is known as a random cortisol level. The concentration of cortisol varies with the time of day. Taking a random cortisol level is rather like measuring the temperature in the air when you do not know what time of day it is. If you measure the air temperature and it is 50 degrees, you would say it was roughly normal no matter what the time of day, whereas if it was -20 degrees you would know it was abnormally cold. Similarly, if the random cortisol level is low, particularly in patients who are ill (and therefore stressed and usually needing high levels of cortisol), it strongly suggests adrenal insufficiency.

ACTH stimulation test

The ACTH, or co-syntropin, stimulation test is the most specific test for diagnosing Addison disease. In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection. In the so-called short, or rapid, ACTH test, measurement of cortisol in blood is repeated 30 to 60 minutes after an intravenous ACTH injection. The normal response after an injection of ACTH is an increase in blood and urine cortisol levels. Patients with either form of adrenal insufficiency respond poorly or do not respond at all.

CRH stimulation test

When the response to the short ACTH test is abnormal, a "long" CRH stimulation test is required to determine the cause of adrenal insufficiency. In this test, synthetic CRH is injected intravenously and blood cortisol is measured before and 30, 60, 90, and 120 minutes after the injection. People with primary adrenal insufficiency have high ACTHs but do not produce cortisol because the adrenal glands cannot make it. People with secondary adrenal insufficiency absent or delayed ACTH responses, which leads to low levels of cortisol. Absent ACTH response points to the pituitary as the cause; a delayed ACTH response points to the hypothalamus as the cause.

In patients suspected of having an Addisonian crisis, the doctor must begin treatment with injections of salt, fluids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible while the patient is being treated for the crisis, measurement of blood ACTH and cortisol during the crisis and before glucocorticoids are given is enough to make the diagnosis. Once the crisis is controlled and medication has been stopped, the doctor will delay further testing for up to one month to obtain an accurate diagnosis.

Other Tests

Once a diagnosis of primary adrenal insufficiency has been made, x-ray exams of the abdomen may be taken to see if the adrenals have any signs of calcium deposits. Calcium deposits may indicate TB. A tuberculin skin test also may be used to test for tuberculosis.

If secondary adrenal insufficiency is the cause, doctors may use different imaging tools to reveal the size and shape of the pituitary gland. The most common is the CT scan, which produces a series of x-ray pictures giving a cross-sectional image of a body part. The function of the pituitary and its ability to produce other hormones also are tested.

Treatment

Treatment of Addison disease involves replacing the hormones not being produced by the adrenal glands. Cortisol is replaced orally with hydrocortisone, a synthetic glucocorticoid, taken once or twice a day. If aldosterone is also deficient, it is replaced with oral doses of a mineralocorticoid called fludrocortisone acetate (Florinef), which is taken once a day. Patients receiving aldosterone replacement therapy are usually advised by a doctor to increase their salt intake. Because patients with secondary adrenal insufficiency normally maintain aldosterone production, they do not require aldosterone replacement therapy. The doses of each of these medications are adjusted to meet the needs of individual patients.

During an Addisonian crisis, low blood pressure, low blood sugar, and high levels of potassium can be life-threatening. Standard therapy involves intravenous injections of hydrocortisone, saline (salt water), and dextrose (sugar). This treatment usually brings rapid improvement. When a person can take fluids and medications by mouth, the amount of hydrocortisone is decreased until a maintenance dose is achieved. If aldosterone is deficient, maintenance therapy also includes oral doses of fludrocortisone acetate.

Prevention of Addison Disease

Prevention of Addison disease involves the prevention of damage to the pituitary and adrenal glands. Most notably, the massive decline in the number of TB cases over the 20th century led to a large decrease in the numbers of people with Addison disease. Prevention of TB is important for maintaining this low disease prevalence. Preventing an Addisonian crisis in people who are critically ill is now a common early goal during intensive care treatment. The widespread practices of measuring cortisol and replacing glucocorticoids in people found to be deficient is very likely to save lives. So far, however, there are no known methods of preventing autoimmune Addison, or PGA syndromes.

Living with Addison Disease

Aside from the need to take medications (often lifelong), there are several other considerations for people with Addison. The most notable is that, since cortisol and all glucocorticoids are stress hormones, their requirements increase in times of stress. This means that patients must self-alter their treatments in times of stress and illness to prevent an Addisonian crisis.

Patient Education

A person who has adrenal insufficiency needs to always carry identification stating his or her condition in case of an emergency. The card should alert emergency personnel about the need to inject 100 mg of cortisol if its bearer is found severely injured or unable to answer questions. The card should also include the doctor's name and telephone number, and the name and telephone number of the nearest relative to be notified. When traveling, a needle, syringe, and an injectable form of cortisol should be carried for emergencies. A person with Addison disease also should know how to increase medication during periods of stress or mild upper respiratory infections. Immediate medical attention is needed when severe infections, vomiting, or diarrhea occur. These conditions can precipitate an Addisonian crisis. A person who is vomiting may require injections of hydrocortisone.

People with medical problems may wish to wear a descriptive warning bracelet or neck chain to alert emergency personnel. A number of companies manufacture medical identification products.

Surgery

People with chronic adrenal insufficiency who need surgery with general anesthesia are treated with injections of hydrocortisone and saline. Injections begin on the evening before surgery and continue until the patient is fully awake and able to take medication by mouth. The dosage is adjusted until the maintenance dose given before surgery is reached.

Pregnancy

Women with primary adrenal insufficiency who become pregnant are treated with standard replacement therapy. If nausea and vomiting in early pregnancy interfere with oral medication, injections of the hormone may be necessary. During delivery, treatment is similar to that of people undergoing surgery. Following delivery, the dose is gradually tapered. The usual maintenance oral doses of hydrocortisone and fludrocortisone acetate are normally reached by about 10 days after childbirth.

Chances of Developing Addison's Disease

Addison disease occurs in about 120 per million people in Western countries.^[2]

History

Addison disease was described in 1855 by the British physician T. Addison.^[2]

Interesting Facts

Addison disease also occurs in dogs.

Famous people

• President John F. Kennedy is probably the best-known Addison disease sufferer.^[3]
• Popular singer Helen Reddy has Addison disease. ^[4]

Other Resources

Offline reading about Addison disease can be found in textbooks of endocrinology or internal medicine.

References

1. ↑ Lab Tests Online: Adrenal Insufficiency and Addison's Disease.
2. ↑ ^{2.0 2.1} Ten S, New M, Maclaren N. Clinical review 130: Addison's disease 2001. J Clin Endocrinol Metab. 2001 Jul;86(7):2909-22. Abstract | Full Text
3. ↑ Loughlin KR. John F. Kennedy and his adrenal disease. Urology. 59(1):165-9, 2002 Jan. Abstract
4. ↑ Transcript of "Catching Up With...Helen Reddy." Washington Post. Tuesday, May 9, 2006.

External Links

National Institutes of Health: Managing Adrenal Insufficiency

Addison's Disease Support And Information

National Adrenal Diseases Foundation