Eponymous diseases:(3) Addison's disease

Addison’s disease (also chronic adrenal insufficiency, hypocortisolism, and hypocorticism) is a rare endocrine disorder wherein the adrenal glands produce insufficient steroid hormones (glucocorticoids and often mineralocorticoids). It is generally diagnosed via blood tests and medical imaging. Treatment involves replacing the absent hormones (oral hydrocortisone and fludrocortisone). Regular follow-up treatment and monitoring for other health problems is necessary.

Addison’s disease is named after Dr. Thomas Addison, the British physician who first described the condition in On the Constitutional and Local Effects of Disease of the Suprarenal Capsules (1849).The adjective "Addisonian" describes features of the condition, and patients suffering Addison’s disease. While Addison's six patients in 1855 all had adrenal tuberculosis, the term "Addison's disease" does not imply an underlying disease process.

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, dizziness, muscle weakness, weight loss, difficulty in standing up, anxiety, diarrhea, headache, sweating, changes in mood and personality, sudden drops in blood pressure especially when going from a seated position to standing (orthostatic hypotension), and joint and muscle pains. Some have marked cravings for salt or salty foods due to the urinary losses of sodium. Adrenal insufficiency is manifested in the skin primarily by hyperpigmentation.

Clinical signs

On examination, the following may be noticed:

• Low blood pressure that falls further when standing (orthostatic hypotension)
• Most people with primary Addison's have darkening (hyperpigmentation) of the skin, including areas not exposed to the sun; characteristic sites are skin creases (e.g. of the hands), nipple, and the inside of the cheek (buccal mucosa), also old scars may darken. This occurs because melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) share the same precursor molecule, Pro-opiomelanocortin (POMC). After production in 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 Addison's, skin darkening does not occur.
• Medical conditions such as goiter and vitiligo often occur together with Addison's

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. In these people, long term use of synthetic glucocorticoids will have caused further atrophy of the adrenal glands by negative feedback. 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

• Sudden penetrating pain in the legs, lower back or abdomen
• Severe vomiting and diarrhea, resulting in dehydration
• Low blood pressure
• Syncope (loss of consciousness)
• Hypoglycemia
• Confusion, psychosis, slurred speech
• Severe lethargy
• Hypercalcaemia
• Convulsions
• Fever

Causes

Causes of adrenal insufficiency can be grouped by the way 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).

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.

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), lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations. 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).

Adrenal destruction

Autoimmune adrenalitis can be a cause of Addison's disease. 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, especially lung), hemorrhage (e.g. in Waterhouse-Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), deposition of abnormal protein in amyloidosis.

Diagnosis

Suggestive features

Routine investigations may show:

• Hypercalcemia
• Hypoglycemia, low blood sugar (worse in children due to loss of glucocorticoid's glucogenic effects)
• Hyponatraemia (low blood sodium levels), due to loss of production of the hormone aldosterone
• Hyperkalemia (raised blood potassium levels), also due to loss of production of the hormone aldosterone
• Eosinophilia and lymphocytosis (increased number of eosinophils or lymphocytes, two types of white blood cells)
• Metabolic acidosis (increased blood acidity), also due to loss of the hormone aldosterone because sodium reabsorption in the distal tubule is linked with acid/hydrogen ion (H+) secretion. Low levels of aldosterone stimulation of the renal distal tubule leads to sodium wasting in the urine and H+ retention in the serum.

Testing

In suspected cases of Addison's disease, one needs to demonstrate that adrenal hormone levels are low even after appropriate stimulation (called the ACTH stimulation test) with synthetic pituitary ACTH hormone tetracosactide . Two tests are performed, the short and the long test. The testing of salivary cortisol levels is growing in popularity as a non-invasive alternative to taking blood for cortisol testing of any kind. 

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).

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 approximately 35% of male patients 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 (VLCFA).

Treatment

Maintenance

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. Alternatively one quarter as much prednisolone may be used for equal glucocorticoid effect as hydrocortisone. 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.

Epidemiology

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

Prognosis

With proper medication, patients can expect to live a healthy and normal life.

A person with adrenal insufficiency should always carry identification stating their 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'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, vomiting, or diarrhea occur, as these conditions can precipitate an Addisonian crisis. A patient who is vomiting may require injections of hydrocortisone, since oral hydrocortisone supplements cannot be adequately metabolised.