Addison's disease


Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrenal glands, causing adrenal insufficiency. Symptoms generally develop slowly and insidiously and may include abdominal pain and gastrointestinal abnormalities, weakness, and weight loss. Darkening of the skin in certain areas may also occur. Under certain circumstances, an adrenal crisis may occur with low blood pressure, vomiting, lower back pain, and loss of consciousness. Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency. An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection.
Addison's disease arises when the adrenal gland does not produce sufficient amounts of the steroid hormones cortisol and aldosterone. It is an autoimmune disease which affects some genetically predisposed people in whom the body's own immune system has started to target the adrenal glands. In many adult cases it is unclear what has triggered the onset of this disease, though it sometimes follows tuberculosis. Causes can include certain medications, sepsis, and bleeding into both adrenal glands. Addison's disease is generally diagnosed by blood tests, urine tests, and medical imaging.
Treatment involves replacing the absent or low hormones. This involves taking a synthetic corticosteroid, such as hydrocortisone or fludrocortisone. These medications are typically taken orally. Lifelong, continuous steroid replacement therapy is required, with regular follow-up treatment and monitoring for other health problems which may occur. A high-salt diet may also be useful in some people. If symptoms worsen, an injection of corticosteroid is recommended. Often, large amounts of intravenous fluids with the sugar dextrose are also required. With appropriate treatment, the overall outcome is generally favorable, and most people are able to lead a reasonably normal life. Without treatment, an adrenal crisis can result in death.
Addison's disease affects about 9 to 14 per 100,000 people in the developed world. It occurs most frequently in middle-aged females. The disease is named after Thomas Addison, a graduate of the University of Edinburgh Medical School, who first described the condition in 1855.

Signs and symptoms

The symptoms of Addison's disease can develop over several months and resemble other medical conditions. Most common symptoms are caused by low levels of hormones that would normally be produced by the adrenal glands. Low blood cortisol can cause a variety of symptoms, including fatigue, malaise, muscle and joint pain, reduced appetite, weight loss, and increased sensitivity to cold. Gastrointestinal symptoms such as nausea, abdominal pain, and vomiting are particularly common. Low aldosterone can cause affected people to crave salty foods, as well as develop low blood pressure that leads to dizziness upon standing. In women, low dehydroepiandrosterone can result in dry and itchy skin, loss of armpit and pubic hair, and reduced sexual drive. Young children with Addison's disease may have insufficient weight gain and recurrent infections. Low cortisol also interferes with adrenocorticotropic hormone regulation, sometimes resulting in the darkening of the skin and mucous membranes, particularly in areas exposed to sun or regular friction.
Blood tests in people with Addison's disease often reveal low blood sodium. Many also have high blood potassium and/or high thyroid-stimulating hormone.
Most people with Addison's disease develop or have a preexisting autoimmune disease. Particularly common comorbid conditions are autoimmune thyroid disease, premature ovarian failure, type 1 diabetes, pernicious anemia, vitiligo and celiac disease. The combination of Addison's disease in addition to mucocutaneous candidiasis, hypoparathyroidism, or both, is called autoimmune polyendocrine syndrome type 1. The presence of Addison's in addition to autoimmune thyroid disease, type 1 diabetes, or both, is called autoimmune polyendocrine syndrome type 2.

Adrenal crisis

An "adrenal crisis" or "Addisonian crisis" is a constellation of symptoms that indicates severe adrenal insufficiency. This may be the result of either previously undiagnosed Addison's disease, a disease process suddenly affecting adrenal function, or an intercurrent problem in someone known to have Addison's disease. It is a medical emergency and potentially life-threatening situation requiring immediate emergency treatment.
Characteristic symptoms are:
Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol. This can be due to damage or destruction of the adrenal cortex. These deficiencies include glucocorticoid and mineralocorticoid hormones as well. These are adrenal dysgenesis, impaired steroidogenesis, or adrenal destruction.
Darkening of the skin, including areas not exposed to the sun – characteristic sites of darkening are skin creases, nipple, and the inside of the cheek ; also, old scars may darken. This occurs because melanocyte-stimulating hormone and ACTH share the same precursor molecule, pro-opiomelanocortin. After production in the anterior pituitary gland, POMC gets cleaved into gamma-MSH, ACTH, and beta-lipotropin. The subunit ACTH undergoes further cleavage to produce alpha-MSH, the most important MSH for skin pigmentation. In secondary and tertiary forms of adrenal insufficiency, skin darkening does not occur, as ACTH is not overproduced.

Adrenal destruction

Autoimmune adrenalitis is the most common cause of Addison's disease in the industrialized world as it represents between 68% and 94% of cases. Autoimmune destruction of the adrenal cortex is caused by an immune reaction against the enzyme 21-hydroxylase. This may be isolated or in the context of autoimmune polyendocrine syndrome, in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected.
Adrenal destruction is also a feature of adrenoleukodystrophy, and when the adrenal glands are involved in metastasis, hemorrhage, particular infections, or the deposition of abnormal protein in amyloidosis.

Adrenal dysgenesis

All causes in this category are genetic, and generally very rare. These include mutations to the SF1 transcription factor, congenital adrenal hypoplasia due to DAX-1 gene mutations and mutations to the ACTH receptor gene. DAX-1 mutations may cluster in a syndrome with glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes.

Impaired steroidogenesis

To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include Smith–Lemli–Opitz syndrome and abetalipoproteinemia. Of the synthesis problems, congenital adrenal hyperplasia is the most common, lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations. Some medications interfere with steroid synthesis enzymes, while others accelerate the normal breakdown of hormones by the liver.

Diagnosis

Suggestive features

Routine laboratory investigations may show:
In suspected cases of Addison's disease, demonstration of low adrenal hormone levels even after appropriate stimulation with synthetic pituitary ACTH hormone tetracosactide is needed for the diagnosis. Two tests are performed, the short and the long test. Dexamethasone does not cross-react with the assay and can be administered concomitantly during testing.
The short test compares blood cortisol levels before and after 250 micrograms of tetracosactide is given. If one hour later, plasma cortisol exceeds 170 nmol/L and has risen by at least 330 nmol/L to at least 690 nmol/L, adrenal failure is excluded. If the short test is abnormal, the long test is used to differentiate between primary adrenal insufficiency and secondary adrenocortical insufficiency.
The long test uses 1 mg tetracosactide. Blood is taken 1, 4, 8, and 24 hours later. Normal plasma cortisol level should reach 1,000 nmol/L by 4 hours. In primary Addison's disease, the cortisol level is reduced at all stages, whereas in secondary corticoadrenal insufficiency, a delayed but normal response is seen. Other tests may be performed to distinguish between various causes of hypoadrenalism, including renin and adrenocorticotropic hormone levels, as well as medical imaging – usually in the form of ultrasound, computed tomography or magnetic resonance imaging.
Adrenoleukodystrophy, and the milder form, adrenomyeloneuropathy, cause adrenal insufficiency combined with neurological symptoms. These diseases are estimated to be the cause of adrenal insufficiency in about 35% of diagnosed males with idiopathic Addison's disease and should be considered in the differential diagnosis of any male with adrenal insufficiency. Diagnosis is made by a blood test to detect very long-chain fatty acids.