Adrenal insufficiency

There are three major types of adrenal insufficiency, depending on the affected organ. • Primary adrenal insufficiency is due to impairment of the adrenal glands, resulting in a lack of glucocorticoid production. Since the adrenal glands are directly affected, mineralocorticoid production is also reduced. Principal causes include: • Autoimmune: e.g., Addison's disease (also called autoimmune adrenalitis), which has been identified to be the cause of 80–90% of primary adrenal insufficiency cases since 1950. • Surgery or radiation: Pituitary gland surgery and/or radiation can lead to destruction of ACTH-producing tissue. • Exogenous corticosteroid use: Exogenous corticosteroids suppress the stimulation of the hypothalamus and the pituitary gland to secrete CRH and ACTH, respectively. These cases may present with symptoms of cortisol excess (see Cushing's syndrome). • Sheehan's syndrome: Loss of blood flow to the pituitary gland following childbirth • Pituitary apoplexy: Bleeding or impaired blood supply to the pituitary gland • Tertiary adrenal insufficiency is caused by impairment of the hypothalamus, resulting in a lack of corticotropin-releasing hormone (CRH) production, causing downstream reduction in ACTH production and subsequently decreasing adrenal stimulation. Since the adrenal glands are not directly affected, the effect on mineralocorticoid production is minimal, as ACTH primarily affects glucocorticoid production. Principal causes include: • Sudden withdrawal from long-term exogenous steroid use • Brain tumors ==Signs and symptoms==

Signs and symptoms include: hypoglycemia, hyperpigmentation, dehydration, weight loss, and disorientation. Additional signs and symptoms include weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), cardiovascular collapse, muscle aches, nausea, vomiting, and diarrhea. These problems may develop gradually and insidiously. Addison's disease can present with tanning of the skin that may be patchy or even all over the body. Characteristic sites of tanning are skin creases (e.g., of the hands) and the inside of the cheek (buccal mucosa). Goitre and vitiligo may also be present. Hyponatremia is a sign of secondary insufficiency. ==Pathophysiology==

When functioning normally, the adrenal glands secrete glucocorticoids (primarily cortisol) in the zona fasciculata and mineralocorticoids (primarily aldosterone) in the zona glomerulosa to regulate metabolism, blood pressure, and electrolyte balance. Adrenal hormone production is controlled by the hypothalamic–pituitary–adrenal axis, in which the hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to produce cortisol. The overproduction of α-MSH leads to the characteristic hyperpigmentation of Addison's disease. Aldosterone deficiency Although the production of aldosterone occurs within the adrenal cortex, it is not induced by adrenocorticotropic (ACTH); instead, it is regulated by the renin–angiotensin–aldosterone system (RAAS). Renin production in the juxtaglomerular cells of the kidney is induced by decreased arterial blood pressure, decreased sodium content in the distal convoluted tubule, and increased sympathetic tone. == Causes ==

Causes of acute adrenal insufficiency are mainly sudden withdrawal of long-term corticosteroid therapy, Waterhouse–Friderichsen syndrome, and stress in people with underlying chronic adrenal insufficiency. The latter is termed critical illness–related corticosteroid insufficiency. For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis (Addison's Disease), tuberculosis, AIDS, and metastatic disease. Adrenal destruction Autoimmune adrenalitis (Addison's disease) is the most common cause of primary adrenal insufficiency in the industrialised world, causing 80–90% of cases since 1950. This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected. Autoimmune adrenalitis may be part of type 2 autoimmune polyglandular syndrome, which can include type 1 diabetes, hyperthyroidism, and autoimmune thyroid disease (also known as autoimmune thyroiditis, Hashimoto's thyroiditis, and Hashimoto's disease). Hypogonadism may also present with this syndrome. Other diseases that are more common in people with autoimmune adrenalitis include premature ovarian failure, celiac disease, and autoimmune gastritis with pernicious anemia. Adrenal destruction is a feature of adrenoleukodystrophy (ALD). Destruction also occurs 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 which can spread to the adrenal cortex (tuberculosis, histoplasmosis, coccidioidomycosis), or the deposition of abnormal protein in amyloidosis. 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. Use of steroids joint injections may also result in adrenal suppression after discontinuation. 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 (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. ==Diagnosis==

The first step of diagnosing adrenal insufficiency is confirming inappropriately low cortisol secretion. To confirm inappropriately low cortisol secretion, testing may include baseline morning cortisol level in the blood or morning cortisol level in the saliva. Cortisol levels typically peak in the morning; thus, low values indicate true adrenal insufficiency. Urinary free cortisol can also be measured, but is not necessary for diagnosis. To determine the origin of dysfunction, the ACTH stimulation test is the best initial test as it can differentiate between primary and secondary adrenal insufficiency. If cortisol levels remain low following ACTH stimulation, then the diagnosis is primary adrenal insufficiency. If cortisol levels increase following ACTH stimulation, then the diagnosis is either secondary or tertiary adrenal insufficiency. The corticotropin-releasing hormone test can then differentiate between secondary and tertiary adrenal insufficiency. Additional testing can include basal plasma ACTH, renin, and aldosterone concentrations, as well as a blood chemistry panel to check for electrolyte imbalances. Depending on the type of adrenal insufficiency, there are several possible causes and therefore many different avenues of testing (see Causes above). For primary adrenal insufficiency, the most common cause is autoimmune adrenalitis (Addison's disease); therefore, 21-hydroxylase autoantibodies should be checked. Structural abnormalities of the adrenal glands can be detected on CT imaging. For secondary and tertiary adrenal insufficiency, an MRI of the brain can be obtained to detect structural abnormalities such as masses, metastasis, hemorrhage, infarction, or infection. Effects ==Treatment==

In general, the treatment of adrenal insufficiency requires replacement of deficient hormones, as well as treatment of any underlying cause. All types of adrenal insufficiency will require glucocorticoid repletion. Many cases (typically, primary adrenal insufficiency) will also require mineralocorticoid repletion. In rarer cases, repletion of androgens may also be indicated, typically in female patients with mood disturbances and changes in well-being. • Adrenal crisis (acute) treatment • Intravenous fluids • Intravenous glucocorticoids • typically hydrocortisone (Cortef) but dexamethasone (Decadron) may be used if diagnostic studies are necessary, as dexamethasone does not affect testing results • Supportive measures and correction of any additional issues such as electrolyte abnormalities • Chronic adrenal insufficiency treatment • Glucocorticoid deficiency (low cortisol) • Oral glucocorticoids • Hydrocortisone (brand name: Cortef), or • Prednisone (brand name: Deltasone), or • Dexamethasone (brand name: Decadron) • Mineralocorticoid deficiency (low aldosterone) treatment • Oral mineralocorticoids • Fludrocortisone (brand name: Florinef) • Sex hormone deficiency (low androgen) • Oral androgens • Dehydroepiandrosterone (DHEA) == Prognosis ==

Primary adrenal insufficiency predisposes to a higher risk of death, mostly due to infection, cardiovascular disease, and adrenal crisis. Delayed diagnosis can impair quality of life, and lack of treatment brings high mortality. However, with proper diagnosis, monitoring, and treatment, people with adrenal insufficiency can live normally. == Epidemiology ==

The most common cause of primary adrenal insufficiency (Addison's disease) overall is autoimmune adrenalitis. In children, congenital adrenal hyperplasia (CAH) is the most common cause of adrenal insufficiency, with an incidence of 1 in 14,200 live births. == See also ==