Adrenal insufficiency is a condition in which the

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...

s do not produce adequate amounts of

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Withi ...

s. The adrenal gland normally secretes glucocorticoids (primarily cortisol),

mineralocorticoids Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary min ...

(primarily aldosterone), and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue,

low blood pressure Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

, depression, mood and personality changes (in mild cases) to organ failure and shock (in severe cases). An adrenal crisis may occur if the body is subjected to stress, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow. Adrenal insufficiency can be caused by dysfunction of the adrenal gland itself, whether by destruction (e.g.

Addison's disease Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adre ...

), failure of development (e.g. adrenal dysgenesis), or enzyme deficiency (e.g.

congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cort ...

). Adrenal insufficiency can also occur when the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...

or the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

do not produce adequate amounts of the hormones that assist in regulating adrenal function. This is called secondary adrenal insufficiency (when caused by lack of production of

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

(ACTH) in the pituitary gland) or tertiary adrenal insufficiency (when caused by lack of

corticotropin-releasing hormone Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that bel ...

(CRH) in the hypothalamus).

Types

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 Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...

production. Since the adrenal glands are directly affected,

mineralocorticoid Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances ( electrolyte balance and fluid balance). The primary ...

production is also reduced. Principal causes include: ** Autoimmune: e.g.

(also called autoimmune adrenalitis), which has been identified to be the cause of 80-90% of primary adrenal insufficiency cases since 1950. ** Congenital: e.g.

adrenoleukodystrophy Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the b ...

** Infection: e.g.

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, i ...

, CMV,

histoplasmosis Histoplasmosis is a fungal infection caused by '' Histoplasma capsulatum''. Symptoms of this infection vary greatly, but the disease affects primarily the lungs. Occasionally, other organs are affected; called disseminated histoplasmosis, it can ...

** Drugs: e.g. anticonvulsants,

etomidate Etomidate (USAN, INN, BAN; marketed as Amidate) is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for short procedures such as reduction of dislocated joints, tracheal intubation, cardi ...

metyrapone Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). Medical uses Metyrapone can be used in the di ...

, rifampicin ** Vascular: e.g. hemorrhage from

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

, adrenal vein thrombosis, hypercoagulable states such as

heparin-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis (the abnormal formation of blood clots ...

and

antiphospholipid syndrome Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-r ...

** Neoplasia: e.g. adenoma (tumor) of the adrenal gland ** Deposition disease: e.g.

hemochromatosis Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...

, amyloidosis,

sarcoidosis Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly a ...

Idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...

: undetermined cause * Secondary adrenal insufficiency is caused by impairment of the

, resulting in a lack of

(ACTH) production and subsequent decreased 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: **

Pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.craniopharyngioma A craniopharyngioma is a rare type of brain tumor derived from pituitary gland embryonic tissue that occurs most commonly in children, but also affects adults. It may present at any age, even in the prenatal and neonatal periods, but peak incidence ...

: Tumors in the pituitary gland can suppress production of

(ACTH). ** 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 Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a ...

). **

Sheehan's syndrome Sheehan's syndrome, also known as postpartum pituitary gland necrosis, is hypopituitarism (decreased functioning of the pituitary gland), caused by ischemic necrosis due to blood loss and hypovolemic shock during and after childbirth. Signs and ...

: Loss of blood flow to the pituitary gland following childbirth **

Pituitary apoplexy Pituitary apoplexy is bleeding into or impaired blood supply of the pituitary gland. This usually occurs in the presence of a tumor of the pituitary, although in 80% of cases this has not been diagnosed previously. The most common initial sympto ...

: Bleeding or impaired blood supply to the pituitary gland * Tertiary adrenal insufficiency is caused by impairment of the

, resulting in a lack of

(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 Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

hyperpigmentation Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Ber ...

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...

, and disorientation. Additional signs and symptoms include weakness, tiredness, dizziness,

that falls further when standing (

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

cardiovascular collapse Shock is the state of insufficient blood flow to the tissues of the body as a result of problems with the circulatory system. Initial symptoms of shock may include weakness, fast heart rate, fast breathing, sweating, anxiety, and increased thi ...

, muscle aches,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

, and

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

. These problems may develop gradually and insidiously.

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 The oral mucosa is the mucous membrane lining the inside of the mouth. It comprises stratified squamous epithelium, termed "oral epithelium", and an underlying connective tissue termed '' lamina propria''. The oral cavity has sometimes been des ...

Goitre A goitre, or goiter, is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly. Worldwide, over 90% of goitre cases are caused by iodine deficiency. The term is ...

and

vitiligo Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes. Signs and symptoms The only sign of vitiligo is the presence of pale patchy areas of depigmen ...

may also be present. Eosinophilia may also occur.

Hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symptoms can be a ...

is a sign of secondary insufficiency.

Pathophysiology

When functioning normally, the adrenal glands secrete

glucocorticoids Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

(primarily, cortisol) in the ''

zona fasciculata The ''zona fasciculata'' (sometimes, fascicular or fasciculate zone) constitutes the middle and also the widest zone of the adrenal cortex, sitting directly beneath the ''zona glomerulosa''. Constituent cells are organized into bundles or "fascicl ...

'' and

(primarily, aldosterone) in the ''

zona glomerulosa The ''zona glomerulosa'' (sometimes, glomerular zone) of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the renal capsule. Its cells are ovoid and arranged in clusters or arches (''glomus'' is Latin ...

'' to regulate metabolism, blood pressure, and electrolyte balance. Adrenal hormone production is controlled by the hypothalamic-pituitary-adrenal axis, in which the hypothalamus produces

(CRH), which stimulates the pituitary gland to produce

(ACTH), which stimulates the adrenal gland to produce cortisol. High levels of cortisol inhibit the production of both CRH and ACTH, forming a negative feedback loop. The types of adrenal insufficiency thus refer to the level of the axis in which the dysfunction originates: primary, secondary, and tertiary for adrenal glands, pituitary gland, and hypothalamus, respectively. In adrenal insufficiency, there is a deficiency in cortisol production which may be accompanied by a deficiency in aldosterone production (predominantly in primary adrenal insufficiency). Depending on the cause and type of adrenal insufficiency, the mechanism of the disease differs. Generally, the symptoms manifest through the systemic effects of cortisol and aldosterone. In secondary and tertiary adrenal insufficiency, there is no effect on the production of aldosterone within the ''zona glomerulosa'' as this process is regulated by the renin–angiotensin–aldosterone system (RAAS), not ACTH. Adrenal insufficiency can also affect the ''zona reticularis'' and disrupt production of androgens, which are precursors to testosterone and estrogen. This leads to a deficiency of sex hormones and can contribute to symptoms of depression and menstrual irregularities.

Cortisol deficiency

Cortisol increases blood sugar by inducing gluconeogenesis (glucose production) in the liver,

lipolysis Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...

(fat breakdown) in adipose tissue, and proteolysis (muscle breakdown) in muscle while increasing glucagon secretion and decreasing insulin secretion in the pancreas. Overall, these actions cause the body to use fat stores and muscle for energy. Deficiency results in

, with associated nausea, vomiting, fatigue, and weakness. Cortisol potentiates the effectiveness of angiotensin II and catecholamines such as

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

. Thus, a deficiency can contribute to

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...

, though this effect is most pronounced in mineralocorticoid deficiency. In primary adrenal insufficiency, the lack of negative feedback from cortisol leads to increased production of CRH and ACTH. ACTH is derived from

pro-opiomelanocortin Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the ...

(POMC), which is cleaved into ACTH as well as α-MSH, which regulates production of melanin in the skin. The overproduction of α-MSH leads to the characteristic hyperpigmentation of

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 Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...

production in the

juxtaglomerular cells Juxtaglomerular cells (JG cells), also known as juxtaglomerular granular cells are cells in the kidney that synthesize, store, and secrete the enzyme renin. They are specialized smooth muscle cells mainly in the walls of the afferent arteriol ...

of the kidney is induced by decreased arterial blood pressure, decreased sodium content in the

distal convoluted tubule The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule. Physiology It is partly responsible for the regulation of potassium, sodium, calcium, and pH. On its apical surface (lumen ...

, and increased sympathetic tone. Renin initiates the downstream sequence of cleavage of

angiotensinogen Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the a ...

angiotensin I Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the a ...

to angiotensin II, in which angiotensin II stimulates aldosterone production in the ''zona glomerulosa''. Thus, dysfunction of the pituitary gland or the hypothalamus does not affect the production of aldosterone. However, in primary adrenal insufficiency, damage to the adrenal cortex (e.g. autoimmune adrenalitis a.k.a.

) can lead to destruction of the ''zona glomerulosa'' and therefore a loss of aldosterone production. Aldosterone acts on mineralocorticoid receptors on epithelial cells lining the distal convoluted tubule, activating

epithelial sodium channels The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...

(ENaC) and the Na⁺/K⁺-ATPase pump. This results in the absorption of sodium (with resulting retention of fluid) and the excretion of potassium. Deficiency of aldosterone leads to urinary loss of sodium and effective circulating volume, as well as retention of potassium. This can cause hypotension (in severe cases,

shock Shock may refer to: Common uses Collective noun *Shock, a historic commercial term for a group of 60, see English numerals#Special names * Stook, or shock of grain, stacked sheaves Healthcare * Shock (circulatory), circulatory medical emergen ...

), dizziness (from

), dehydration, and salt craving. Differently from mineralocorticoid deficiency, glucocorticoid deficiency does not cause a negative sodium balance (in fact a positive sodium balance may occur).

Causes

Causes of acute adrenal insufficiency are mainly sudden withdrawal of long-term corticosteroid therapy,

Waterhouse–Friderichsen syndrome Waterhouse–Friderichsen syndrome (WFS) is defined as adrenal gland failure due to bleeding into the adrenal glands, commonly caused by severe bacterial infection. Typically, it is caused by '' Neisseria meningitidis''. The bacterial infection ...

, and

stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...

in people with underlying chronic adrenal insufficiency.Table 20-7 in: 8th edition. The latter is termed critical illness–related corticosteroid insufficiency. For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis (Addison's Disease),

, AIDS, and

metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

disease. Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections,

, and

. Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol. These are adrenal destruction (disease processes leading to glandular damage), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol), or adrenal dysgenesis (the gland has not formed adequately during development).

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.

Autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

destruction of the adrenal cortex is caused by an immune reaction against the enzyme

21-hydroxylase Steroid 21-hydroxylase (also known as steroid 21-monooxygenase, cytochrome P450C21, 21α-hydroxylase and less commonly 21β-hydroxylase) is an enzyme that hydroxylates steroids at the C21 position and is involved in biosynthesis of aldosterone a ...

(a phenomenon first described in 1992). This may be isolated or in the context of

autoimmune polyendocrine syndrome Autoimmune polyendocrine syndromes (APSs), also called polyglandular autoimmune syndromes (PGASs) or polyendocrine autoimmune syndromes (PASs), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one en ...

(APS type 1 or 2), in which other hormone-producing organs, such as the

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

and

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...

, may also be affected. Autoimmune adrenalitis may be part of Type 2 autoimmune polyglandular syndrome, which can include

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar ...

hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidis ...

, and autoimmune

thyroid disease Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning ...

(also known as

autoimmune thyroiditis Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it. It may ...

Hashimoto's thyroiditis Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enlarg ...

, and Hashimoto's disease).

Hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...

may also present with this syndrome. Other diseases that are more common in people with autoimmune adrenalitis include premature ovarian failure,

celiac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...

, and autoimmune

gastritis Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...

with

pernicious anemia Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic fa ...

. Adrenal destruction is a feature of

(ALD). Destruction also occurs when the adrenal glands are involved in

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...

(seeding of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cells from elsewhere in the body, especially lung),

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, v ...

(e.g. in

), particular

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...

s which can spread to the adrenal cortex (

coccidioidomycosis Coccidioidomycosis (, ), commonly known as cocci, Valley fever, as well as California fever, desert rheumatism, or San Joaquin Valley fever, is a mammalian fungal disease caused by '' Coccidioides immitis'' or ''Coccidioides posadasii''. Coccid ...

), or the deposition of abnormal protein in amyloidosis.

Impaired steroidogenesis

To form cortisol, the adrenal gland requires

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

, which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include

Smith–Lemli–Opitz syndrome Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a bro ...

and

abetalipoproteinemia Abetalipoproteinemia (also known as: Bassen-Kornzweig syndrome, microsomal triglyceride transfer protein deficiency disease, MTP deficiency, and betalipoprotein deficiency syndrome) is a disorder that interferes with the normal absorption of fat ...

. Of the synthesis problems,

is the most common (in various forms:

17α-hydroxylase Cytochrome P450 17A1 (steroid 17α-monooxygenase, 17α-hydroxylase, 17-alpha-hydroxylase, 17,20-lyase, 17,20-desmolase) is an enzyme of the hydroxylase type that in humans is encoded by the ''CYP17A1'' gene on chromosome 10. It is ubiquitously exp ...

, 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 The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

(e.g. rifampicin,

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...

). Adrenal insufficiency can also result when a patient has a brain mass in the pituitary gland (e.g.

pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.craniopharyngioma A craniopharyngioma is a rare type of brain tumor derived from pituitary gland embryonic tissue that occurs most commonly in children, but also affects adults. It may present at any age, even in the prenatal and neonatal periods, but peak incidence ...

) which can take up space and interfere with the secretion of pituitary hormones such as ACTH, therefore leading to decreased adrenal stimulation (secondary adrenal insufficiency). The same can occur with masses in the hypothalamus (tertiary adrenal insufficiency).

Corticosteroid withdrawal

Use of high-dose steroids for more than a week begins to produce suppression of the person's

adrenal glands The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...

because the exogenous

suppress release of hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH). With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid. During this recovery time, the person is vulnerable to adrenal insufficiency during times of stress, such as illness, due to both adrenal atrophy and suppression of CRH and ACTH release. Use of steroids

joint injection In medicine, a joint injection (intra-articular injection) is a procedure used in the treatment of inflammatory joint conditions, such as rheumatoid arthritis, psoriatic arthritis, gout, tendinitis, bursitis, Carpal Tunnel Syndrome, and occasiona ...

s 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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

, congenital adrenal hypoplasia due to ''DAX-1'' gene mutations and mutations to the

ACTH receptor The adrenocorticotropic hormone receptor or ACTH receptor also known as the melanocortin receptor 2 or MC2 receptor is a type of melanocortin receptor (type 2) which is specific for ACTH. A G protein–coupled receptor located on the external ...

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. This is followed by determining the origin of dysfunction (adrenal glands, pituitary gland, or hypothalamus) and therefore the type of adrenal insufficiency (primary, secondary, or tertiary). After narrowing down the source, further testing can elucidate the cause of insufficiency. If a patient is suspected to be experiencing an acute adrenal crisis, immediate treatment with IV corticosteroids is imperative and should not be delayed for any testing, as the patient's health can deteriorate rapidly and result in death without replacing the corticosteroids. Dexamethasone should be used as the corticosteroid of choice in these cases as it is the only corticosteroid that will not affect diagnostic test results. To confirm inappropriately low cortisol secretion, testing can 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 are not necessary for diagnosis. To determine the origin of dysfunction, the

ACTH stimulation test The ACTH test (also called the cosyntropin, tetracosactide, or Synacthen test) is a medical test usually requested and interpreted by endocrinologists to assess the functioning of the adrenal glands' stress response by measuring the adrenal respon ...

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 many possible causes and therefore many different avenues of testing (see Causes above). For primary adrenal insufficiency, the most common cause is autoimmune adrenalitis (

); 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 Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthm ...

(Cortef) but

dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...

(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 Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthm ...

(brand name: Cortef), or ****

Prednisone Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and ad ...

(brand name: Deltasone), or ****

Dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...

(brand name: Decadron) ** Mineralocorticoid deficiency (low aldosterone) treatment *** Oral mineralocorticoids ****

Fludrocortisone Fludrocortisone, sold under the brand name Florinef, among others, is a corticosteroid used to treat adrenogenital syndrome, postural hypotension, and adrenal insufficiency. In adrenal insufficiency, it is generally taken together with hydroc ...

(brand name: Florinef) ** Sex hormone deficiency (low androgen) *** Oral androgens ****

Dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It fun ...

(DHEA)

Prognosis

Primary adrenal insufficiency predisposes to 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 overall is autoimmune adrenalitis (Addison's disease). It is estimated that about 144 million people in the developed world have Addison's disease. In children,

(CAH) is the most common cause of adrenal insufficiency, with an incidence 1 in 14,200 live births.

References

External links

{{DEFAULTSORT:Adrenal Insufficiency Adrenal gland disorders de:Nebennierenrindeninsuffizienz

Types

Signs and symptoms

Pathophysiology

Cortisol deficiency

Aldosterone deficiency

Causes

Adrenal destruction

Impaired steroidogenesis

Corticosteroid withdrawal

Adrenal dysgenesis

Diagnosis

Effects

Treatment

Prognosis

Epidemiology

See also

References

Further reading

External links