Addison's Disease

Addison's Disease

Dr. KennedyAddison’s disease is named after Dr Thomas Addison, a British physician who described the condition in 1855 Addison’s

disease (aka chronic adrenal insufficiency, hypocortisolism or hypocorticism) is a rare endocrine disorder in which

the adrenal gland produces insufficient amounts of steroid hormones glucocorticoids and sometimes also mineralocorticoids. It

may develop in children or adults as the result of a large number of underlying causes. The term “Addisonian” is used

for features of the condition, as well as for patients with Addison’s disease. Addison’s is generally diagnosed with hormone

testing and sometimes imaging studies. Treatment is with replacement of the missing hormones (oral hydrocortisone and

fludrocortisone). If the disease is secondary to an another underlying condition, it may be possible to address that

directly.

Symptoms

The symptoms of Addison’s disease develop insidiously, and it may not be recognized at first. The most common symptoms

are:

  • fatigue
  • muscle weakness
  • weight loss
  • vomiting
  • diarrhea
  • headache
  • sweating
  • changes in mood and personality
  • joint and muscle pains
  • in some cases marked cravings for salt or salty foods (due to urinary losses of sodium)

Clinical Signs on Examination

  • low blood pressure that falls further when standing (orthostatic hypotension)
  • darkening (hyperpigmentation) of the skin, in most cases, 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)

In Addison’s the pituitary responds to the low levels of cortisol by increasing the output of ACTH (adrenocorticotropic

hormone the hormone which stimulates the adrenals into action). Melanocyte-stimulating hormone (MSH) shares the same

precursor molecule as ACTH, therefore an increase in ACTH production also increases MSH which leads to hyperpigmentation.

This distinguishes pituitary insufficiency from primary Addison’s since in pituitary deficiency there is insufficient ACTH

and therefore no hyperpigmentation.

Addisonian Crisis

An “Addisonian crisis” or “adrenal crisis” is a constellation of symptoms indicating 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 another form of damage to the adrenals (such as infection or trauma) in the setting

of known Addison’s disease. This situation may also develop in those on long-term oral glucocorticoids who cease taking their

medication precipitously. It is also a concern in the myxedema coma because 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
  • loss of consciousness, passing out
  • confusion
  • psychosis
  • severe loss of energy
  • convulsions

Diagnosis

Diagnosis is made by hormone teesting (cortisol and aldosterone), however as with any disease it must first be suspected.

Conditions which would raise suspicion of Addison’s are:

  • hypoglycemia, low blood sugar (worse in children)
  • 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

In suspected cases of Addison’s disease, one needs to demonstrate that adrenal hormone levels are low even after

appropriate stimulation with ADTH or the 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 may be performed to distinguish between various causes of hypoadrenalism such as renin and adrenocorticotropic

hormone (ADTH) levels, as well as medical imaging – usually in the form of ultrasound, computed tomography or magnetic

resonance imaging (MRI) of hte adrenal gland.

Causes

Causes of adrenal insufficiency are 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

Causes in this category are genetic and 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 (or related

genes, such as 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.

Ipaired steroidogenesis

To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones.

Interruptions in the delivery of cholesterol include the Smith-Lemli-Opitz syndrome and abetalipoproteinemia. Of the synthesis problems, congenital adrenal hyperplasia is the most common (21-hydroxylase, 17a-hydroxylase,

11ß-hydroxylase and 3ß-hydroxysteroid dehydrogenase), lipod CAH due to deficiency of StAR and mitochondrial DNA mutations.

Adrenal Destruction

Autoimmune destruction of the adrenal cortex (antibodies against the enzyme 21-Hydroxylase) is a common cause in teenagers and adults. Adrenal destruction is also a feature of adrenoleukodystrophy (ALD), and when the adrenal glands are involved in cancer metastasis 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 (e.g. ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g. rifampicin, phenytoin).

Maintenance Treatment

Treatment for Addison’s disease involves replacing 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 effect. 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 injections of cortisol, saline solution (isotonic IV bag as used to treat dehydration), and glucose

Pregnancy and Childbirth

Many women with Addison’s have given birth successfully and without complication, both through natural labor and through

Caesarean delivery. Both of these methods require different preventative measures relating to Addison’s medications and

dosages. Occasionally, oral intake of medications will cause debilitating nausea and vomiting, and thus the woman may be switched to injected medications until delivery. 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 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 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. Young women are most affected, outnumbering men by four to one.

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), symptoms are usually

greatly reduced or occasionally eliminated so long as the person continues their dosage schedule.

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