Addison's disease

Addison's disease (also known as chronic adrenal insufficiency, hypocortisolism or hypocorticism) is a rare endocrine disorder in which the adrenal gland produces insufficient amounts of steroid hormones (glucocorticoids and often mineralocorticoids). It may develop in children as well as adults, and may occur as the result of a large number of underlying causes. The condition is named after Dr Thomas Addison, the British physician who first described the condition in his 1855 On the Constitutional and Local Effects of Disease of the Suprarenal Capsules.^[1] The adjective "Addisonian" is used for features of the condition, as well as patients with Addison's disease.^[2]

The condition is generally diagnosed with blood tests, medical imaging and additional investigations.^[2] Treatment is with replacement of the hormones (oral hydrocortisone and fludrocortisone). If the disease is caused by an underlying problem, this is addressed. Regular follow-up and monitoring for other health problems is necessary.^[2]

Additional recommended knowledge

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Signs and symptoms

Symptoms

The symptoms of Addison's disease develop insidiously, and it may take some time to be recognized. The most common symptoms are fatigue, muscle weakness, weight loss, vomiting, diarrhea, headache, sweating, changes in mood and personality and joint and muscle pains. Some have marked cravings for salt or salty foods due to the urinary losses of sodium.^[2]

Clinical signs

On examination, the following may be noticed:^[2]

• Low blood pressure that falls further when standing (orthostatic hypotension)
• Darkening (hyperpigmentation) of the skin, including areas not exposed to the sun; characteristic sites are skin creases (e.g. of the hands), nipples, and the inside of the cheek (buccal mucosa), also old scars may darken.
• Signs of conditions that often occur together with Addison's: goiter and vitiligo

Addisonian crisis

An "Addisonian crisis" or "adrenal crisis" is a constellation of symptoms that indicate severe adrenal insufficiency. This may be the result of either previously undiagnosed Addison's disease, a disease process suddenly affecting adrenal function (such as adrenal hemorrhage), or an intercurrent problem (e.g. infection, trauma) in the setting of known Addison's disease. Additionally, this situation may develop in those on long-term oral glucocorticoids who have suddenly ceased taking their medication. It is also a concern in the setting of myxedema coma; thyroxine given in that setting without glucocorticoids may precipitate a crisis.

Untreated, an Addisonian crisis can be fatal. It is a medical emergency, usually requiring hospitalization. Characteristic symptoms are:^[3]

• Sudden penetrating pain in the legs, lower back or abdomen
• Severe vomiting and diarrhea, resulting in dehydration
• Low blood pressure
• Loss of consciousness/Syncope
• Hypoglycemia
• Confusion, psychosis
• Severe lethargy
• Convulsions

Diagnosis

Suggestive features

Routine investigations may show:^[2]

• Hypoglycemia, low blood sugar (worse in children)
• Hyponatraemia (low blood sodium levels)
• Hyperkalemia (raised blood potassium levels), due to loss of production of the hormone aldosterone
• Eosinophilia and lymphocytosis (increased number of eosinophils or lymphocytes, two types of white blood cells)

Testing

   In suspected cases of Addison's disease, one needs to demonstrate that adrenal hormone levels are low even after appropriate stimulation with synthetic pituitary hormone tetracosactide. Two tests are performed, the short and the long test.

The short test compares blood cortisol levels before and after 250 micrograms of tetracosactide (IM/IV) 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 failure and secondary adrenocortical failure.

The long test uses 1 mg tetracosactide (IM). Blood is taken 1, 4, 8, and 24 hours later. Normal plasma cortisol level should reach 1000 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 that may be performed to distinguish between various causes of hypoadrenalism are renin and adrenocorticotropic hormone levels, as well as medical imaging - usually in the form of ultrasound, computed tomography or magnetic resonance imaging (MRI).

Causes

Causes of adrenal insufficiency can be grouped by the way in which they cause the adrenals to produce insufficient cortisol. These are adrenal dysgenesis (the gland has not formed adequately during development), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol) or adrenal destruction (disease processes leading to the gland being damaged).^[2]

Adrenal dysgenesis

All causes in this category are genetic, and generally very rare. These include mutations to the SF1 transcription factor, congenital adrenal hypoplasia (AHC) due to DAX-1 gene mutations and mutations to the ACTH receptor gene (or related genes, such as in the Triple A or Allgrove syndrome). 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.^[2]

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 (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase), lipod CAH due to deficiency of StAR and mitochondrial DNA mutations.^[2]

Adrenal destruction

Autoimmune destruction of the adrenal cortex (often due to antibodies against the enzyme 21-Hydroxylase) is a common cause of Addison's in teenagers and adults. This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2). Adrenal destruction is also a feature of adrenoleukodystrophy (ALD), and when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body), hemorrhage (e.g. in Waterhouse-Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), deposition of abnormal protein in amyloidosis. Some medications interfere with steroid synthesis enzymes (e.g. ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g. rifampicin, phenytoin).^[2]

Treatment

Maintenance treatment

Treatment for Addison's disease involves replacing the missing cortisol (usually in the form of hydrocortisone tablets) in a dosing regimen that mimics the physiological concentrations of cortisol. Treatment must usually be continued for life. In addition, many patients require fludrocortisone as replacement for the missing aldosterone. Caution must be exercised when the person with Addison's disease becomes unwell, has surgery or becomes pregnant. Medication may need to be increased during times of stress, infection, or injury.

Addisonian crisis

Treatment for an acute attack, an Addisonian crisis, usually involves intravenous (into blood veins) injections of:

• Cortisone (cortisol)
• Saline solution (basically a salt water, same clear IV bag as used to treat dehydration)
• Glucose

Surgery

Surgeries may require significant adjustments to medication regimens prior to, during, and following any surgical procedure. The best preparation for any surgery, regardless of how minor or routine it may normally be, is to speak to one's primary physician about the procedure and medication implications well in advance of the surgery.

Pregnancy

Many women with Addison's have given birth successfully and without complication, both through natural labor and through cesarean delivery. Both of these methods will require different preventative measures relating to Addison's medications and dosages. As is always the case, thorough communication with one's primary physician is the best course of action. Occasionally, oral intake of medications will cause debilitating nausea and vomiting, and thus the woman may be switched to injected medications until delivery. ^[4] Addison's treatment courses by the mother are generally considered safe for baby during pregnancy.

Epidemiology

The frequency rate of Addison's disease in the human population is sometimes estimated at roughly 1 in 100,000.^[5] Some research and information sites put the number closer to 40-60 cases per 1 million population. (1/25,000-1/16,600)^[6] (Determining accurate numbers for Addison's is problematic at best and some incidence figures are thought to be underestimates.^[7]) Addison's can afflict persons of any age, gender, or ethnicity, but it typically presents in adults between 30 and 50 years of age. Young women are most affected, outnumbering men by a factor of four.^[8] Research has shown no significant predispositions based on ethnicity.^[6]

Prognosis

While treatment solutions for Addison's disease are far from precise, overall long-term prognosis is typically good. Because of individual physiological differences, each person with Addison's must work closely with their physician to adjust their medication dosage and schedule to find the most effective routine. Once this is accomplished (and occasional adjustments must be made from time to time, especially during periods of travel, stress, or other medical conditions), symptomology is usually greatly reduced or occasionally eliminated so long as the person continues their dosage schedule.

Canine hypoadrenocorticism

The condition is relatively rare, but has been diagnosed in all breeds of dogs. In general, it is underdiagnosed, and one has to have a clinical suspicion of it as an underlying disorder for many presenting complaints. Females are overrepresented, and the disease often appears in middle age (4-7 years), although any age or gender may be affected.

Hypoadrenocorticism is treated with prednisolone and/or fludrocortisone (Florinef (r)) or a monthly injection called Percorten V (desoxycorticosterone pivlate (DOCP)). Routine blood work is necessary periodically to assess therapy.

Most of the medications used in the therapy of hypoadrenocorticism cause excessive thirst and urination. It is absolutely vital to provide fresh drinking water for the canine sufferer.

If the owner knows about an upcoming stressful situation (shows, traveling etc.), patients generally need an increased dose of prednisone to help deal with the added stress. Avoidance of stress is important for dogs with hypoadrenocorticism.

Famous Addisonians

• President John F. Kennedy was one of the best-known Addison's disease sufferers.
• Popular singer Helen Reddy.^[9]
• Scientist Eugene Merle Shoemaker Co-discoverer of the Comet Shoemaker-Levy 9.^[10]
• French Carmelite nun and religious writer Blessed Elizabeth of the Trinity ^[11]
• Some have suggested that Jane Austen was an avant la lettre case, but others have disputed this.^[12]
• According to Dr. Carl Abbott, a Canadian medical researcher, Charles Dickens may also have been afflicted.^[13]
• Osama bin-Laden - may be an Addisonian: Lawrence Wright (The Looming Tower, 2006, p. 139) notes that bin-Laden manifests all the key symptoms: "low blood pressure, weight loss, muscle fatigue, stomach irritability, sharp back pains, dehydration, and an abnormal craving for salt". Bin-Laden is known to have been consuming large amounts of the drug Arcalion to treat his symptoms.

See also

• Cushing's syndrome

References

Support groups

• Addison's Disease Self Help Group (ADSHG) - UK support group
• Australian Addison's Disease Association - Australian support and information group
• Nederlandse Vereniging voor Addison en Cushing Patiënten - Dutch support and information group with information and documentation in English
• Addresses of patient organisations and support groups around the world