Adrenal Insufficiency and Addisons Disease

National Endocrine and Metabolic Diseases Information Service

What is adrenal insufficiency?

U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH

slow the immune systems inflammatory response maintain levels of glucosea form of sugar used for energyin the blood regulate the metabolism of proteins, carbohydrates, and fats The amount of cortisol produced by the adrenals is precisely balanced. Like many other hormones, cortisol is regulated by the brains hypothalamus and the pituitary gland. First, the hypothalamus releases a trigger hormone called corticotropinreleasing hormone (CRH) that signals the pituitary gland. The pituitary responds by sending out ACTH, which in turn stimulates the adrenal glands. The adrenal glands respond by producing cortisol. Completing the cycle, cortisol then signals back to both the pituitary and hypothalamus to decrease these trigger hormones.

Adrenal insufficiency is an endocrineor hormonaldisorder that occurs when the adrenal glands do not produce enough of certain hormones. The adrenal glands are located just above the kidneys. Adrenal insufficiency can be primary or secondary. Primary adrenal insufficiency, also called Addisons disease, occurs when the adrenal glands are damaged and cannot produce enough of the hormone cortisol and often the hormone aldosterone. Addisons disease affects one to four of every 100,000 people, in all age groups and both sexes.1 Secondary adrenal insufficiency occurs when the pituitary glanda bean-sized organ in the brain fails to produce enough adrenocorticotropin (ACTH), a hormone that stimulates the adrenal glands to produce cortisol. If ACTH output is too low, cortisol production drops. Eventually, the adrenal glands can shrink due to lack of ACTH stimulation. Secondary adrenal insufficiency is much more common than Addisons disease.

Pituitary

Hypothalamus CRH

ACTH

What do adrenal hormones do?

Cortisol
Cortisol belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Cortisols most important job is to help the body respond to stress. Among its many vital tasks, cortisol helps maintain blood pressure and cardiovascular function
Kidneys The hypothalamus sends CRH to the pituitary, which responds by sending out ACTH. ACTH then causes the adrenals to release cortisol into the bloodstream. Adrenal glands Cortisol

1Munver

R, Volfson IA. Adrenal insufficiency: diagnosis and management. Current Urology Reports. 2006;7:8085.

Aldosterone
Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. Aldosterone helps maintain blood pressure and water and salt balance in the body by helping the kidneys retain sodium and excrete potassium. When aldosterone produc tion falls too low, the kidneys are not able to regulate water and salt balance, leading to a drop in both blood volume and blood pressure.

Hyperpigmentation, or darkening of the skin, can occur in Addisons disease but not in secondary adrenal insufficiency. This darkening is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes such as the lining of the cheek. Because the symptoms progress slowly, they are often ignored until a stressful event like an illness or accident causes them to worsen. Sud den, severe worsening of symptoms is called an Addisonian crisis, or acute adrenal insufficiency. In most cases, symptoms of adrenal insufficiency become serious enough that people seek medi cal treatment before a crisis occurs. However, sometimes symptoms first appear during an Addisonian crisis. Symptoms of an Addisonian or adrenal crisis include sudden, penetrating pain in the lower back, abdomen, or legs severe vomiting and diarrhea dehydration low blood pressure loss of consciousness If not treated, an Addisonian crisis can be fatal.

What are the symptoms of adrenal insufficiency?

The symptoms of adrenal insufficiency usually begin gradually. The most common symptoms are chronic, worsening fatigue muscle weakness loss of appetite weight loss Other symptoms can include nausea vomiting diarrhea low blood pressure that falls further when standing, causing dizziness or fainting irritability and depression a craving for salty foods due to salt loss hypoglycemia, or low blood glucose headache sweating in women, irregular or absent menstrual periods

What causes Addisons disease?

Autoimmune Disorders
The gradual destruction of the adrenal cortex, the outer layer of the adrenal glands, by the bodys immune system causes up to 80 percent of Addisons disease cases.2 In autoimmune disorders, the immune system makes antibodies that attack the bodys own tissues or organs and slowly destroy them.

2Martorell

PM, Roep BO, Smit JWA. Autoimmunity in Addisons disease. The Netherlands Journal of Medicine. 2002;60(7):269275.

Adrenal Insufficiency and Addisons Disease

Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed. As a result, often both cortisol and aldosterone are lacking. Sometimes only the adrenal glands are affected. Sometimes other endocrine glands are affected as well, as in polyendocrine deficiency syndrome. Polyendocrine deficiency syndrome is classified into two separate forms, type 1 and type 2. Type 1 is inherited and occurs in children. In addition to adrenal insufficiency, these children may have underactive parathyroid glands, which pro duce a hormone that regulates calcium and phosphorus balance in the body slow sexual development pernicious anemia, a severe type of anemia chronic candida infections, a type of fungal infection chronic active hepatitis, a liver disease Type 2, sometimes called Schmidts syndrome, usually affects young adults and may include an underactive thyroid gland, which pro duces hormones that regulate metabolism slow sexual development diabetes vitiligo, a loss of pigment on areas of the skin Scientists think type 2 polyendocrine deficiency syndrome is also inherited because often more than one family member has one or more endo crine deficiencies.

Other Causes
Less common causes of Addisons disease are chronic infection, mainly fungal infections cancer cells spreading from other parts of the body to the adrenal glands amyloidosis, a disease that causes abnormal protein buildup in, and damage to, various organs surgical removal of the adrenal glands AIDS-associated infections bleeding into the adrenal glands genetic defects including abnormal adrenal gland development, an inability of the adre nal gland to respond to ACTH, or a defect in adrenal hormone production

What causes secondary adrenal insufficiency?

Secondary adrenal insufficiency can be traced to a lack of ACTH. Without ACTH to stimulate the adrenal glands, the adrenals production of cortisol drops. Aldosterone production is not usually affected. A temporary form of secondary adrenal insuf ficiency may occur when a person who has been taking a synthetic glucocorticoid hormone such as prednisone for a long time stops taking the medication, either abruptly or gradually. Glu cocorticoid hormones, which are often used to treat inflammatory illnesses such as rheumatoid arthritis, asthma, and ulcerative colitis, block the release of both CRH and ACTH. As a result, the adrenals may begin to atrophyor shrink from lack of ACTH stimulation and then fail to secrete sufficient levels of cortisol. A person who stops taking a synthetic gluco corticoid hormone may have enough ACTH to function when healthy. However, when a person is under the stress of an illness, accident, or surgery, the persons body may not have enough ACTH to stimulate the adrenal glands to pro duce cortisol. Another cause of secondary adrenal insuffi ciency is surgical removal of the noncancerous, ACTH-producing tumors of the pituitary gland

Tuberculosis
Tuberculosis (TB), an infection that can destroy the adrenal glands, accounts for less than 20 per cent of cases of Addisons disease in developed countries.3 When adrenal insufficiency was first identified by Dr. Thomas Addison in 1849, TB was the most common cause of the disease. As TB treatment improved, the incidence of adrenal insufficiency due to TB of the adrenal glands greatly decreased.
3Munver

R, Volfson IA. Adrenal insufficiency: diagnosis and management. Current Urology Reports. 2006;7:8085.

Adrenal Insufficiency and Addisons Disease

that cause Cushings disease. Cushings disease is another disorder that leads to excess cortisol in the body. 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 radiation for the treatment of pituitary tumors surgical removal of parts of the hypothalamus surgical removal of the pituitary gland

Both low- and high-dose ACTH stimulation tests may be used depending on the suspected cause of adrenal insufficiency. For example, if secondary adrenal insufficiency is mild or of recent onset, the adrenal glands may still respond to ACTH because they have not yet atrophied. Some stud ies suggest a low dose1 microgrammay be more effective in detecting secondary adrenal insufficiency because the low dose is still enough to raise cortisol levels in healthy people but not in people with mild or recent secondary adrenal insufficiency.

CRH Stimulation Test

When the response to the ACTH test is abnor mal, a CRH stimulation test can help 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 Addisons disease respond by producing high lev els of ACTH but no cortisol. People with second ary adrenal insufficiency have absent or delayed ACTH responses. CRH will not stimulate ACTH secretion if the pituitary is damaged, so an absent ACTH response points to the pituitary as the cause. A delayed ACTH response points to the hypothalamus as the cause.

How is adrenal insufficiency diagnosed?

In its early stages, adrenal insufficiency can be difficult to diagnose. A review of a patients medical history and symptoms may lead a doctor to suspect Addisons disease. A diagnosis of adrenal insufficiency is confirmed through laboratory tests. The aim of these tests is first to determine whether levels of cortisol are insufficient and then to establish the cause. Radiologic exams of the adrenal and pituitary glands also are useful in helping to establish the cause.

Diagnosis during an Emergency

In patients suspected of having an Addisonian crisis, health professionals must begin treatment with injections of salt, glucose-containing flu ids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible during crisis treatment, measurement of blood ACTH and cortisol during the crisisbefore glucocorticoids are givenis enough to make a preliminary diagnosis. Low blood sodium, low blood glucose, and high blood potassium are also usually present at the time of an adrenal crisis. Once the crisis is controlled, an ACTH stimula tion test can be performed to obtain the specific diagnosis. More complex laboratory tests are sometimes used if the diagnosis remains unclear.

ACTH Stimulation Test

The ACTH stimulation test is the most com monly used test for diagnosing adrenal insuffi ciency. In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection. The nor mal response after an ACTH injection is a rise in blood and urine cortisol levels. People with Addisons disease or long-standing secondary adrenal insufficiency have little or no increase in cortisol levels.

Adrenal Insufficiency and Addisons Disease

Other Tests
Once a diagnosis of Addisons disease is made, radiologic studies such as an x ray or an ultra sound of the abdomen may be taken to see if the adrenals have any signs of calcium deposits. Calcium deposits may indicate bleeding in the adrenal gland or TB, for which a tuberculin skin test also may be used. Blood tests can detect antibodies associated with autoimmune Addi sons disease. If secondary adrenal insufficiency is diagnosed, doctors may use different imaging tools to reveal the size and shape of the pituitary gland. The most common is the computerized tomography (CT) scan, which produces a series of x-ray pic tures giving cross-sectional images. A magnetic resonance imaging (MRI) scan may also be used to produce a three-dimensional image of this region. The function of the pituitary and its abil ity to produce other hormones also are assessed with blood tests.

solution with dextrose, a type of sugar. This treatment usually brings rapid improvement. When the patient can take fluids and medica tions by mouth, the amount of glucocorticoids is decreased until a maintenance dose is reached. If aldosterone is deficient, maintenance therapy also includes oral doses of fludrocortisone acetate.

What special problems can occur with adrenal insufficiency?

Surgery
Because cortisol is a stress hormone, people with chronic adrenal insufficiency who need any type of surgery requiring general anesthesia must be treated with intravenous glucocorticoids and saline. Intravenous treatment begins before surgery and continues until the patient is fully awake after surgery and able to take medication by mouth. The stress dosage is adjusted as the patient recovers until the presurgery mainte nance dose is reached. In addition, people who are not currently taking glucocorticoids but who have taken long-term glucocorticoids in the past year should tell their doctor before surgery. These people may have sufficient ACTH for normal events, but they may need intravenous treatment for the stress of surgery.

How is adrenal insufficiency treated?

Treatment of adrenal insufficiency involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced with a synthetic glucocorticoid such as hydrocortisone, prednisone, or dexametha sone, taken orally once to three times each day, depending on which medication is chosen. If aldosterone is also deficient, it is replaced with oral doses of a mineralocorticoid, called fludro cortisone acetate (Florinef), taken once or twice a day. Doctors usually advise patients receiving aldosterone replacement therapy to increase their salt intake. Because people with secondary adrenal insufficiency normally maintain aldos terone production, they do not require aldos terone replacement therapy. The doses of each medication are adjusted to meet the needs of the individual. During an Addisonian crisis, low blood pressure, low blood glucose, and high levels of potas sium can be life threatening. Standard therapy involves intravenous injections of glucocorti coids and large volumes of intravenous saline

Illness
During illness, oral dosing of glucocorticoid may be adjusted to mimic the normal response of the adrenal glands to this stress on the body. Significant fever or injury may require triple oral dosing. Once recovery from the stress event is achieved, dosing is then returned to maintenance levels. People with adrenal insufficiency should know how to increase medication during such periods of stress. Immediate medical attention is needed if severe infections, vomiting, or diar rhea occur. These conditions can precipitate an Addisonian crisis.

Adrenal Insufficiency and Addisons Disease

Pregnancy
Women with adrenal insufficiency who become pregnant are treated with standard replacement therapy. If nausea and vomiting in early preg nancy interfere with taking medication by mouth, injections of the hormone may be necessary. During delivery, treatment is similar to that of people needing surgery. Following delivery, the dose is gradually tapered and the usual mainte nance doses of oral hydrocortisone and fludro cortisone acetate are reached about 10 days after childbirth.

Points to Remember
Adrenal insufficiency is a disorder that occurs when the adrenal glands do not produce enough of certain hormones. Primary adrenal insufficiency, also called Addisons disease, occurs when the adrenal glands are damaged and cannot produce enough of the hor mone cortisol and often the hormone aldosterone. Secondary adrenal insufficiency occurs when the pituitary gland fails to produce enough adrenocorticotropin (ACTH), a hormone that stimulates the adrenals to produce cortisol. If ACTH output is too low, cortisol pro duction drops. The most common symptoms of adre nal insufficiency are chronic, worsen ing fatigue; muscle weakness; loss of appetite; and weight loss. Adrenal insufficiency is most often diagnosed through blood or urine tests. Imaging studies such as x rays, ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI) may also be used. Treatment of adrenal insufficiency involves replacing, or substituting, the hormones that the adrenal glands are not making. People with adrenal insufficiency should always carry identification stating their condition in case of an emergency.

How can someone with adrenal insufficiency prepare for an emergency?

People with adrenal insufficiency should always carry identification stating their condition in case of an emergency. A card or medical alert tag should notify emergency health care providers of the need to inject cortisol if the person is found severely injured or unable to answer questions. The card or tag should also include the name and telephone number of the persons doctor and the name and telephone number of a family mem ber to be notified. The dose of hydrocortisone needed may vary with a persons age or size. For example, a child younger than 2 years of age can receive 25 milligrams (mg), a child between 2 and 8 years of age can receive 50 mg, and a child older than 8 years should receive the adult dose of 100 mg. When traveling, people with adrenal insufficiency should carry a needle, syringe, and an injectable form of cortisol for emergencies.

Adrenal Insufficiency and Addisons Disease

Hope through Research

Researchers are evaluating the use of another adrenal hormone, dehydroepiandrosterone, in improving the health-related quality of life in people with adrenal insufficiency. Scientists are also studying the occurrence of relative adrenal insufficiencybelow normal production of adre nal hormones during critical illnessto further define this type of adrenal insufficiency, develop diagnostic tests, and identify the best treatment options. Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research. For information about cur rent studies, visit www.ClinicalTrials.gov.

The following organizations might also be able to assist with certain types of information: American Autoimmune Related Diseases Association National Office 22100 Gratiot Avenue East Detroit, MI 48021 Phone: 5867763900 Email: aarda@aol.com Internet: www.aarda.org National Adrenal Diseases Foundation 505 Northern Boulevard, Suite 200 Great Neck, NY 11021 Phone: 5164874992 Email: NADFmail@aol.com Internet: www.nadf.us

For More Information

The following articles about Addisons disease can be found in medical libraries, some college and university libraries, and through interlibrary loan in most public libraries. Chrousos GP. Glucocorticoid therapy. In: Felig P, Frohman L, eds. Endocrinology and Metabolism. 4th ed. New York: McGraw-Hill; 2001:609632. Munver R, Volfson IA. Adrenal insufficiency: diagnosis and management. Current Urology Reports. 2006;7:8085. Nieman LK, Chanco Turner ML. Addisons disease. Clinics in Dermatology. 2006;24(4):276280. Stewart PM. The adrenal cortex. In: Larsen P, ed. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders; 2003:491551. Ten S, New M, Maclaren N. Clinical Review 130: Addisons disease 2001. Journal of Clinical Endocrinology & Metabolism. 2001;86(7):29092922. Williams GH, Dluhy RC. Disorders of the adrenal cortex. In: Braunwald E, ed. Harrisons Principles of Internal Medicine. 17th ed. New York: McGraw-Hill Professional; 2008:22472268. 7 Adrenal Insufficiency and Addisons Disease

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NIH Publication No. 093054 May 2009