ADDISON'S DISEASE AND HYPOCORTISOLISM

Addison's disease is a rare endocrine, or hormonal disorder that affects about 1 in 100,000 people. It occurs in all age groups and afflicts men and women equally. The disease is characterized by weight loss, muscle weakness, fatigue, low blood pressure, and sometimes darkening of the skin in both exposed and nonexposed parts of the body.

Addison's disease occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.

Cortisol is normally produced by the adrenal glands, located just above the kidneys. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol has possibly hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Among its other vital tasks, cortisol:

·         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; and

·         helps regulate the metabolism of proteins, carbohydrates, and fats.

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 the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting other hormones that regulate growth, 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.

Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. 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.

Causes

Failure to produce adequate levels of cortisol, or adrenal insufficiency, can occur for different reasons. The problem may be due to a disorder of the adrenal glands themselves (primary adrenal insufficiency) or to inadequate secretion of ACTH by the pituitary gland (secondary adrenal insufficiency).

Primary Adrenal Insufficiency

Most cases of Addison's disease are caused by the gradual destruction of the adrenal cortex, the outer layer of the adrenal glands, by the body's own immune system. About 70 percent of reported cases of Addison's disease are due to autoimmune disorders, in which the immune system makes antibodies that attack the body's own tissues or organs and slowly destroy them. Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed. As a result, often both glucocorticoid and mineralocorticoid 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.

Tuberculosis (TB) accounts for about 20 percent of cases of primary adrenal insufficiency in developed countries. Less common causes of primary adrenal insufficiency are chronic infections, mainly fungal infections; cancer cells spreading from other parts of the body to the adrenal glands; amyloidosis; and surgical removal of the adrenal glands.

Secondary Adrenal Insufficiency

This form of Addison's disease can be traced to a lack of ACTH, which causes a drop in the adrenal glands' production of cortisol but not aldosterone. A temporary form of secondary adrenal insufficiency may occur when a person who has been receiving a glucocorticoid hormone such as prednisone for a long time abruptly stops or interrupts taking the medication. Glucocorticoid hormones, which are often used to treat inflammatory illnesses like rheumatoid arthritis, asthma, or ulcerative colitis, block the release of both corticotropin-releasing hormone (CRH) and ACTH. Normally, CRH instructs the pituitary gland to release ACTH. If CRH levels drop, the pituitary is not stimulated to release ACTH, and the adrenals then fail to secrete sufficient levels of cortisol.

Another cause of secondary adrenal insufficiency is the surgical removal of pituitary gland tumors. Cortisol production also falls if the pituitary gland either decreases in size or stops producing ACTH. This can result from infections of the area, loss of blood flow to the pituitary, radiation for the treatment of pituitary tumors or nasopharyngeal carcinoma.

Symptoms

The symptoms of adrenal insufficiency usually begin gradually. Chronic, worsening fatigue and muscle weakness, loss of appetite, and weight loss are characteristic of the disease. Nausea, vomiting, and diarrhea occur in about 50 percent of cases. Blood pressure is low and falls further when standing, causing dizziness or fainting. Skin changes also are common in Addison's 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's disease can cause irritability and depression. Because of salt loss, craving of 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 patients, symptoms are severe enough to seek medical treatment before a crisis occurs. However, in about 25 percent 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, followed by dehydration; low blood pressure; and 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 tanning of the skin, will lead a doctor to suspect Addison's disease. A diagnosis of Addison's disease is made by biochemical laboratory tests. The aim of these tests is first to determine whether there are insufficient levels of cortisol and then to establish the cause. X-ray exams of the adrenal and pituitary glands also are useful in helping to establish the cause.

Treatment

Treatment of Addison's disease involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced orally with hydrocortisone tablets, 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 the patient 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.

Special Problems

Surgery. Patients 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 dosage 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 patients needing surgery; following delivery, the dose is gradually tapered and the usual maintenance doses of hydrocortisone and fludrocortisone acetate by mouth are not reached until about 10 days after childbirth.

Patient Education

A person who has adrenal insufficiency should 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. A person with Addison's 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 or vomiting or diarrhea occur. These conditions can precipitate an addisonian crisis. A patient who is vomiting may require injections of hydrocortisone.