Addison’s disease (also chronic adrenal insufficiency, hypocortisolism, and hypocorticism)is a rare, chronic endocrine disorder where the adrenalglands do not produce sufficient steroidhormones (glucocorticoids and often mineralocorticoids).Lifelong, continuous treatment with steroid replacement therapy is required,with regular follow-up treatment and monitoring for other health problems.
Itis generally diagnosed via blood tests and medicalimaging. Treatment involves replacing the absent hormones (oral hydrocortisone andfludrocortisone).
Addison’sdisease is named after Dr. ThomasAddison, the British physician whofirst described the condition in On the Constitutional and LocalEffects of Disease of the Suprarenal Capsules (1849). Theadjective "Addisonian" describes features of the condition, andpatients suffering from Addison’s disease. While Addison's six patients in1855 all had adrenal tuberculosis, the term "Addison's disease" doesnot imply an underlying disease process.
Thesymptoms of Addison's disease develop insidiously, and it may take some time tobe recognized. The most common symptoms are fatigue, lightheadedness uponstanding or while upright,muscle weakness, fever, weight loss,difficulty in standing up, anxiety, nausea, 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 ofsodium. Affected individuals may note increased tanning since adrenal insufficiencyis manifested in the skin primarily byhyperpigmentation,specifically due to the decrease in cortisol and subsequent increase in ACTHlevels .
Becauseprimary hypocortisolism is manifested as a deficiency in glucocorticoid releasefrom the adrenal cortex, increased ACTH will be releasedby the pituitary in order to trigger release of the absent glucocorticoid; itis because of this overstimulation of ACTH that bronzing of the skin occurs. Insecondary or tertiary hypocortisolism, there is a deficiency of either CRH orACTH release by the hypothalamus or pituitary gland, respectively. The formerwill manifest as no ACTH release while the latter will manifest as physiologic(normal) ACTH release; neither will cause an overproduction of ACTH. Onexamination, the following may be noticed:
� Low bloodpressure that falls further when standing (orthostatic hypotension)
� In long-standing Addison'sDisease, the pinna of the ear may become calcified
� Most people with primaryAddison's have darkening (hyperpigmentation)of the skin, including areas not exposed to the sun; characteristic sites areskin creases (e.g. of the hands), nipple, and the inside of the cheek (buccalmucosa), also old scars may darken. This occurs because melanocyte-stimulating hormone (MSH)and adrenocorticotropic hormone (ACTH)share the same precursor molecule, Pro-opiomelanocortin (POMC). Afterproduction in anterior pituitary gland, POMC gets cleaved into Gamma-MSH, ACTHand Beta-lipotropin. The subunit ACTH undergoes further cleavage to produceAlpha-MSH, the most important MSH for skin pigmentation. In secondary andtertiary forms of Addison's, skin darkening does not occur.
� Medical conditions such as type I diabetes, autoimmune thyroid disease(Hashimoto's thyroiditis and goiter) and vitiligo oftenoccur together with Addison's (often in the setting of Autoimmune polyendocrine syndrome).Hence, symptoms and signs of any of the former conditions may also be presentin the individual with Addison's.
� The occurrence of Addison'sDisease in someone who also has Hashimoto's thyroiditis is called Schmidtsyndrome.
An"Addisonian crisis" or "adrenal crisis" is a constellationof symptoms that indicate severe adrenal insufficiency. This may be the resultof either previously undiagnosed Addison's disease, a disease process suddenlyaffecting adrenal function (such as adrenal hemorrhage), or anintercurrent problem (e.g. infection, trauma) in someone known to haveAddison's disease. It is a medicalemergency and potentially life-threatening situation requiringimmediate emergency treatment.
� Sudden penetrating pain inthe legs, lower back or abdomen
� Severe vomiting and diarrhea,resulting in dehydration
� Low bloodpressure
� Syncope (loss of consciousness and abilityto stand)
� Hypoglycemia (reducedlevel of blood glucose)
� Confusion, psychosis,slurred speech
� Severe lethargy
� Hyperkalemia (elevatedpotassium level in the blood)
� Hypercalcemia (elevatedcalcium level in the blood)
Causesof adrenal insufficiency can be grouped by the way they cause the adrenals toproduce insufficient cortisol. These are adrenal dysgenesis (thegland has not formed adequately during development), impaired steroidogenesis (thegland is present but is biochemically unable to produce cortisol) or adrenaldestruction (disease processes leading to the gland being damaged).
Allcauses in this category are genetic, and generally very rare. These include mutations tothe 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 orAllgrove syndrome). DAX-1 mutations may cluster in a syndromewith glycerol kinase deficiency with a numberof other symptoms when DAX-1 is deleted together with a numberof other genes.
Toform cortisol, the adrenal gland requires cholesterol,which is then converted biochemically into steroid hormones. Interruptions inthe delivery of cholesterol include Smith-Lemli-Opitz syndromeand abetalipoproteinemia.
Ofthe synthesis problems, congenital adrenal hyperplasia isthe most common (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase and 3β-hydroxysteroiddehydrogenase), lipoid CAH due todeficiency of StAR and mitochondrialDNA mutations. Somemedications interfere with steroid synthesis enzymes (e.g. ketoconazole),while others accelerate the normal breakdown of hormones by the liver (e.g. rifampicin, phenytoin).
Autoimmune adrenalitis is the mostcommon cause of Addison's disease in the industrialized world. Autoimmune destructionof the adrenal cortex is cause by an immunereaction against the enzyme 21-hydroxylase (aphenomenon first described in 1992). This may be isolated or in thecontext of autoimmune polyendocrine syndrome (APStype 1 or 2), in which other hormone-producing organs such as the thyroid and pancreas mayalso be affected.
Adrenaldestruction is also a feature of adrenoleukodystrophy (ALD), and when theadrenal glands are involved in metastasis (seedingof cancer cellsfrom elsewhere in the body, especially lung),hemorrhage (e.g.in Waterhouse-Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), deposition of abnormalprotein inamyloidosis.
Routineinvestigations may show:
� Hypoglycemia,low blood sugar (worsein children due to loss of glucocorticoid's glucogenic effects)
� Hyponatremia (lowblood sodium levels), due to the kidney's inability to excrete free water inthe absence of sufficient cortisol, and also the effect of Corticotropin-releasing hormone tostimulate secretion of ADH. That hyponatremia occurs even when theadrenal insufficiency is due to pituitary disease(in which aldosterone deficiency is not a feature),underscores the fact that hyponatremia in Addison's disease is not due to lackof aldosterone.
� Hyperkalemia (raisedblood potassium levels),due to loss of production of the hormone aldosterone
� Eosinophilia and lymphocytosis (increasednumber of eosinophils or lymphocytes,two types of white blood cells)
� Metabolic acidosis (increased bloodacidity), also due to loss of the hormone aldosterone becausesodium reabsorption in the distal tubule islinked with acid/hydrogen ion (H ) secretion. Low levels of aldosteronestimulation of the renal distal tubule leads to sodium wasting in the urine andH retention in the serum.