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Adrenal crisis, also known as Addisonian crisis or acute adrenal insufficiency, is a life-threatening complication of
adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...
.
Hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
and
hypovolemic shock Hypovolemic shock is a form of Shock (circulatory), shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It can be caused by severe dehydration or blood loss. Hypovolemic shock is a medical emergency ...
are the main symptoms of an adrenal crisis. Other symptoms include weakness,
anorexia Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, vomiting, fever, fatigue, abnormal
electrolyte An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble Salt (chemistry), salts, acids, and Base (chemistry), bases, dissolved in a polar solven ...
s,
confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
, and coma. Laboratory testing may detect low sodium, high potassium, high lymphocyte count, high eosinophils,
low blood sugar Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes 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 tria ...
, and rarely high calcium. The biggest trigger for adrenal crisis is gastrointestinal illness. Those with primary adrenal insufficiency are at a higher risk for an adrenal crisis. The physiological mechanisms underlying an adrenal crisis involve the loss of endogenous
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 vertebra ...
s' typical inhibitory effect on inflammatory
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s. When someone with adrenal insufficiency exhibits symptoms of an adrenal crisis, treatment must begin immediately. To diagnose an adrenal crisis, serum
cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
,
aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...
,
ACTH 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 ...
,
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 reni ...
, and
dehydroepiandrosterone sulfate Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepia ...
are measured. A low cortisol level of less than 3 mg/dL, measured in the early morning or during a stressful period, suggests a diagnosis of adrenal insufficiency. A tailored prescription, and strategies for administering additional glucocorticoids for physiological stress, are critical preventative measures. When someone experiences an adrenal crisis, they require immediate parenteral
hydrocortisone Hydrocortisone is the name for the hormone cortisol when supplied as a medication. It is a corticosteroid and works as an anti-inflammatory and by immune suppression. Uses include conditions such as adrenocortical insufficiency, adrenogenit ...
. About 6–8% of those with adrenal insufficiency experience an adrenal crisis at some point each year. The mortality rate linked to adrenal crises is up to 6%.


Signs and symptoms

In as many as 50% of those with
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 adr ...
, adrenal crisis can be the first indication of adrenal insufficiency. Diagnosis is often delayed since most of the symptoms of adrenal insufficiency are nonspecific and develop insidiously. Hypotension and shock that fail to respond to
vasopressors An antihypotensive, also known as a vasopressor, is an agent that raises blood pressure by constricting blood vessels, thereby increasing systemic vascular resistance. This is different from inotropes which increase the force of cardiac contra ...
or fluid resuscitation are the main signs of an adrenal crisis. Those in an adrenal crisis can deteriorate quickly, usually within a few hours. Gastrointestinal symptoms such as nausea, vomiting, anorexia and abdominal pain are common in adrenal insufficiency and can lead to misdiagnosis. Other symptoms of an adrenal crisis include severe fatigue, dizziness, diffuse limb and back pain,
malaise In medicine, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. It is considered a vague termdescribing the state of simply not feeling well. The word has exist ...
, and weakness. Fever is a common sign of adrenal crisis resulting from either concurrent illness or the release of cytokines. Neurocognitive symptoms can vary from agitation, issues with concentration, and depression, to
delirium Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...
and
coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
. During an adrenal crisis laboratory testing may show low sodium (
hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), 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. Symp ...
), high potassium (
hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Oc ...
), high
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
count ( lymphocytosis), high
eosinophils Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
(
eosinophilia Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 billion/ L (1,500/ μL). The hypereosinophilic syndrome ...
), low blood sugar (
hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes 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 tria ...
), and rarely high calcium (
hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L def ...
). In an adrenal crisis, hypotension occurs due to low cortisol and
volume depletion Hypovolemia, also known as volume depletion or volume contraction, is a state of abnormally low extracellular fluid in the body. This may be due to either a loss of both salt and water or a decrease in blood volume. Hypovolemia refers to the loss ...
.
Hypovolemia Hypovolemia, also known as volume depletion or volume contraction, is a state of abnormally low extracellular fluid in the body. This may be due to either a loss of both salt and water or a decrease in blood volume. Hypovolemia refers to the loss ...
might be resistant to vasopressors and fluids if it is not identified. In secondary adrenal insufficiency, hyponatremia results from decreased kidney excretion of electrolyte-free water and the inability to suppress
vasopressin Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...
. Hyponatremia in primary adrenal insufficiency is caused by concurrent aldosterone deficiency, resulting in volume depletion,
natriuresis Natriuresis is the process of sodium excretion in the urine through the action of the kidneys. It is promoted by Brain natriuretic peptide, ventricular and atrial natriuretic peptides as well as calcitonin, and inhibited by chemicals such as aldost ...
, and hyperkalemia. Hypercalcemia is triggered by decreased calcium excretion and accelerated bone resorption throughout an adrenal crisis, which can be exacerbated by volume depletion. Hypovolemia and hypoglycemia can cause varying degrees of renal insufficiency due to decreased
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
.


Causes

An adrenal crisis can be caused by adrenal insufficiency. Adrenal insufficiency can be classified into primary adrenal insufficiency caused by conditions affecting the
adrenal cortex The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...
, secondary adrenal insufficiency due to
ACTH 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 ...
deficiency caused by conditions affecting the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
or
pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
, or tertiary adrenal insufficiency caused by excessive glucocorticoid exposure. Adrenal insufficiency can be caused by autoimmune disorders such as
autoimmune adrenalitis 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 adren ...
, autoimmune polyglandular syndrome, and
lymphocytic hypophysitis Autoimmune hypophysitis is defined as inflammation of the pituitary gland due to autoimmunity. Signs and symptoms Autoimmune hypophysitis can lead to deficiencies in one or more pituitary hormones, causing central diabetes insipidus if the poste ...
, or congenital disorders such as
congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...
,
adrenoleukodystrophy Adrenoleukodystrophy (ALD) is a genetic disorder, disease linked to the X chromosome. It is a result of fatty acid buildup caused by failure of peroxisome#Metabolic functions, peroxisomal fatty acid beta oxidation which results in the accumulation ...
, familial glucocorticoid deficiency,
combined pituitary hormone deficiency Hypopituitarism is the decreased (''hypo'') secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is know ...
, and
POMC 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 ...
mutation. Adrenal insufficiency can also be caused by pituitary or adrenal gland surgeries. Infections such as
tuberculosis Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...
,
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 ...
,
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
, and CMV can also cause adrenal insufficiency. Infiltrative disorders like
sarcoidosis Sarcoidosis (; also known as Besnier–Boeck–Schaumann disease) is a disease involving abnormal collections of White blood cell, inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph n ...
,
amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weigh ...
, and
haemochromatosis Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the ...
have also been known to cause adrenal insufficiency.
Hemorrhages 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, vag ...
in the pituitary and adrenal glands,
Waterhouse–Friderichsen syndrome Waterhouse–Friderichsen syndrome (WFS) is defined as adrenal gland failure due to hemorrhages in the adrenal glands, commonly caused by sepsis. Typically, the bacteria responsible for triggering the bleeding is '' Neisseria meningitidis''. The ...
,
vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both artery, arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily c ...
,
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 sympt ...
, and
Sheehan's syndrome Sheehan's syndrome, also known as postpartum pituitary gland necrosis, occurs when the pituitary gland is damaged due to significant blood loss and hypovolemic shock (ischemic necrosis) or stroke, originally described during or after childbirth le ...
are vascular disorders that can cause adrenal insufficiency. Tumors on the pituitary gland or cancer metastasis can also cause adrenal insufficiency. Exogenous steroid use is the most frequent cause of adrenal insufficiency, and those who use steroids also run the risk of experiencing an adrenal crisis. Adrenal crisis can be triggered by abrupt, and frequently unintentional, steroid withdrawal. The
hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland ( ...
is suppressed by the use 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 vertebra ...
s in rectal preparations, spinal injections, injections into the dermis, injections into the joint,
nasal Nasal is an adjective referring to the nose, part of human or animal anatomy. It may also be shorthand for the following uses in combination: * With reference to the human nose: ** Nasal administration, a method of pharmaceutical drug delivery * ...
,
inhaled Inhalation (or inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...
, or steroids applied to the skin. At pharmacological dosages,
medroxyprogesterone Medroxyprogesterone (MP), is a progestin which is not used medically. A derivative, medroxyprogesterone acetate (MPA), is used as a medication in humans, and is far more widely known in comparison. ''Medroxyprogesterone'' is sometimes used as a ...
and
megestrol Megestrol (, ) is a progestin of the 17α-hydroxyprogesterone group which was, until recently, never marketed or used clinically. It is now used for treatments of Weight loss#Disease-related, disease-related weight loss, endometrial cancer, and ...
 also exhibit a notable
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 vertebra ...
effect. This risk may increase if steroids are used concurrently with
ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhi ...
which inhibits the liver's
CYP3A Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus. A homologous locus is found in mice. These genes encode monooxygenases which catalyze many reactions involved in the synthesis of cholesterol, steroids and other ...
enzyme that breaks down steroids. There is a greater risk for adrenal suppression with longer durations, greater doses, and oral and intraarticular preparations of steroids. Nonetheless, no amount, time frame, or mode of administration can reliably predict adrenal insufficiency.


Risk factors

Because of the lack of
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 ...
s, increased risk of
dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
and hypovolemia, those with primary adrenal insufficiency are at a higher risk of developing an adrenal crisis compared to those with secondary adrenal insufficiency. People who have both secondary adrenal insufficiency and
diabetes insipidus Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...
are even more likely to experience an adrenal crisis. This increased risk could be attributed to either the absence of V1-receptor-mediated
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 vesse ...
in times of stress or the increased risk of dehydration. A higher risk of adrenal crisis has been linked to other medical conditions such as
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
and asthma, though the exact mechanism is unknown. Those with adrenal insufficiency have a 50% risk of experiencing an adrenal crisis within their life, and those who have experienced an adrenal crisis in the past are more susceptible to re-developing adrenal crisis.


Triggers

A known precipitating event can be found in over 90% of episodes of adrenal crisis. The most common cause of adrenal crisis is infections, specifically
gastrointestinal infection Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the Human gastrointestinal tract, gastrointestinal tract, namely the esophagus, stomach, small intestine, large intestine and rectum; and the accessory or ...
s. Adrenal crises can also be caused by major surgery, dental operations, pregnancy/labour, extreme weather, serious injury/accidents, intense physical activity, vaccines, and emotional stress. Those who have
autoimmune polyendocrine syndrome type 2 Autoimmune polyendocrine syndrome type 2, a form of autoimmune polyendocrine syndrome also known as APS-II, or PAS II, is the most common form of the polyglandular failure syndromes. PAS II is defined as the association between autoimmune Addiso ...
might have both
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
and adrenal insufficiency.
Levothyroxine Levothyroxine, also known as -thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to tre ...
can speed up the metabolism of cortisol and trigger an adrenal crisis. Several medications, including
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
and
immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
, have been linked to an increased risk of adrenal crisis.
Immune checkpoint inhibitor Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno ...
s are known to cause endocrine problems, including hypophysitis and adrenalitis, with subsequent adrenal insufficiency.
Barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...
s and adrenostatic medications may raise the risk of an adrenal crisis.
Cytochrome P450 3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It oxidizes small foreign organic molecules (xenobiotics), such as t ...
inducers boost hydrocortisone metabolism, leading to a higher demand for hydrocortisone since hydrocortisone is being metabolized faster.


Mechanism

An absolute or relative lack of cortisol causes adrenal crises since there is not enough tissue glucocorticoid activity to preserve homeostasis. Cortisol has a 70 to 120-minute
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
, meaning that cortisol levels fall within several hours of cortisol deprivation. Because cortisol modulates the transcription of genes containing a glucocorticoid response element, this effects many different genes. The physiological effects of low cortisol begin with the loss of the natural inhibitory function of glucocorticoids on inflammatory cytokines. This leads to sharp rises in cytokine concentrations, which can induce fever,
lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness, or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overw ...
,
anorexia Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...
, and pain. As a result, low cortisol causes changes in immune-cell levels, including lymphocytosis, eosinophilia, and
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
. Low levels of cortisol means that it loses its ability to work with
catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...
s to reduce vascular reactivity, which causes
vasodilatation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel ...
and hypotension. Low cortisol has an adverse effect on the liver's metabolism, resulting in hypoglycemia, decreased gluconeogenesis, lower levels of
free fatty acids In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
and
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s in circulation. Loss of cortisol suppresses nuclear factor κB (NF-κB) and
activator protein 1 Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular process ...
(AP-1), which allows genes that generate inflammatory proteins to be activated without restriction. This is because cortisol normally inhibits NF-κB's binding to the
glucocorticoid receptor The glucocorticoid receptor (GR or GCR) also known by its gene name ''NR3C1'' ( nuclear receptor subfamily 3, group C, member 1) is the steroid receptor for glucocorticoids such as cortisol. The GR is expressed in almost every cell in the bod ...
. Additionally, through potassium retention and sodium and water loss,
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 ...
deficiency is likely to aggravate adrenal crises.


Diagnosis

When a person with adrenal insufficiency is known to be exhibiting symptoms of an adrenal crisis, treatment begins before diagnostic testing. When adrenal insufficiency is suspected a blood sample can be collected to test serum cortisol and
ACTH 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 ...
levels, while treatment begins during the wait for results. Once an acutely ill person has recovered, the diagnosis can be confirmed. Adrenal insufficiency can be diagnosed by testing
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 reni ...
,
dehydroepiandrosterone sulfate Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepia ...
,
aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...
, serum cortisol, and ACTH levels. A high cortisol level of more than 13 to 15 mg/dL can rule out the diagnosis. A low cortisol level of less than 3 mg/dL, obtained in the early morning or during a stressful period, strongly suggests the possibility of adrenal insufficiency. In instances of primary adrenal insufficiency, there is a correspondingly high ACTH level; in contrast, low or inappropriately normal ACTH correlates with tertiary or secondary adrenal insufficiency.


Prevention

A customized prescription as well as a plan for the administration of additional glucocorticoids for physiological stress are important preventative measures. If oral glucocorticoids are not an option, parenteral hydrocortisone can be used, preferably at home. Devices like
MedicAlert The MedicAlert Foundation is a non-profit company founded in 1956 and headquartered in Turlock, California. It maintains a database of members' medical information that is made available to medical authorities in the event of a medical emergency ...
bracelets and necklaces can alert caregivers to the possibility of adrenal crisis in those who are unable to communicate verbally. Although the exact dosage has been debated, it is generally agreed upon that anyone with proven adrenal insufficiency receives glucocorticoid replacement during stressful times. The recommended amounts of glucocorticoid replacement are dependent on the anticipated stress, and the current guidelines depend on expert opinion. Though there may be variations in specific regimens, most agree that stress doses for simple surgery is quickly tapered and does not last longer than three days. This is because unneeded steroid excess can lead to infections, poor wound healing, and
hyperglycemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluc ...
. In those who are unable to tolerate oral medication or do not respond to stress doses, a low threshold to initiate parenteral hydrocortisone management can be used to guarantee adequate systemic absorption, since
gastroenteritis Gastroenteritis, also known as infectious diarrhea, is an inflammation of the Human gastrointestinal tract, gastrointestinal tract including the stomach and intestine. Symptoms may include diarrhea, vomiting, and abdominal pain. Fever, lack of ...
frequently precedes an adrenal crisis and stress dose glucocorticoids may not always avoid an adrenal crisis. Those experiencing vomiting, chronic diarrhea, or an imminent adrenal crisis receive
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
hydrocortisone. Individuals must be prepared to administer it themselves because they can rapidly deteriorate. Those with adrenal insufficiency may own a hydrocortisone ampoule, but not all have practiced the injection, and most will depend on medical professionals to give it to them in the event of an adrenal crisis episode. Individuals may experience significant physical as well as
cognitive impairment Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...
during their illness, which may impair their capacity to make wise decisions or administer medicine. Therefore, everyone with adrenal insufficiency can receive training on intramuscular hydrocortisone use and education on how to recognize an adrenal crisis, as well as assistance from a close family member or friend. In case an individual suffering from adrenal insufficiency loses consciousness, they must receive the necessary medical attention. A survey of 46 people with adrenal insufficiency revealed that some medical professionals are reluctant to medicate the condition even when it is brought to their attention. Only 54% of those with adrenal insufficiency got glucocorticoid administration within 30 minutes of arrival, even though 86% of those with adrenal insufficiency were promptly attended to by a medical professional within forty-five minutes of a distress call.


Treatment

The two foundations of treatment for adrenal crisis are steroid replacement and
fluid resuscitation Fluid replacement or fluid resuscitation is the medical practice of replenishing bodily fluid lost through sweating, bleeding, fluid shifts or other pathologic processes. Fluids can be replaced with oral rehydration therapy (drinking), intravenous ...
. When adrenal crisis treatment is started as soon as possible, it can be effective in preventing irreversible effects from prolonged hypotension. Treatment should not be postponed while doing diagnostic tests. If there is reason to suspect something, a blood sample could be taken right away for
ACTH 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 ...
and serum cortisol testing; however, treatment needs to begin right away, regardless of the results of the assay. Once someone has recovered clinically, it is safe to confirm the diagnosis in an acutely ill person. In cases of emergency, parenteral hydrocortisone can be given as soon as possible by intramuscular (IM) injection while IV access is being established, or as a bolus injection of 100 mg of intravenous (IV) hydrocortisone. After this bolus, 200 mg of hydrocortisone should be administered every 24 hours, either continuously by IV infusion or, if that is not possible, in doses of 50 mg of hydrocortisone per IV/IM injection every 6 hours.
Hypovolemia Hypovolemia, also known as volume depletion or volume contraction, is a state of abnormally low extracellular fluid in the body. This may be due to either a loss of both salt and water or a decrease in blood volume. Hypovolemia refers to the loss ...
and hyponatremia can be corrected with intravenous fluid resuscitation using isotonic sodium chloride 0.9%; the hypoglycemia may also need to be corrected with intravenous
dextrose Glucose is a sugar with the molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae during photosynthesis from water an ...
. Over the course of the first hour, a liter of
saline Saline may refer to: Salt-related * Saline (medicine), a liquid with salt content to match the human body * Saline water, non-medicinal salt water * Saline, a historical term (especially American) for a salt works or saltern Places United States ...
0.9% must be administered. Subsequent replacement fluids should be determined by measuring the serum
electrolyte An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble Salt (chemistry), salts, acids, and Base (chemistry), bases, dissolved in a polar solven ...
s and conducting frequent
hemodynamic Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously ...
monitoring. In cases of secondary adrenal insufficiency, cortisol replacement can cause water
diuresis Diuresis () is the excretion of urine, especially when excessive (polyuria). The term collectively denotes the physiologic processes underpinning increased urine production by the kidneys during maintenance of fluid balance. In healthy people, ...
and suppress
antidiuretic hormone Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...
. When combined with
sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
replacement, these effects can quickly correct hyponatremia as well as
osmotic demyelination syndrome Central pontine myelinolysis (CPM) is a neurological condition involving severe damage to the myelin sheath of nerve cells in the ''pons'' (an area of the brainstem). It is predominately iatrogenic (treatment-induced), and is characterized by acu ...
. As a result, care must be taken to adjust
sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
by less than 10 mEq during the first 24 hours. It is widely acknowledged that extra
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 ...
treatment is not necessary at hydrocortisone dosages greater than 50 mg/day because there is adequate action within the
mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...
. In those who have primary adrenal insufficiency,
fludrocortisone Fludrocortisone, sold under the brand name Florinef among others, is a corticosteroid used to treat congenital adrenal hyperplasia, postural hypotension, and adrenal insufficiency. In adrenal insufficiency, it is generally taken together wit ...
needs to be started with subsequent dose tapering; for most people, a daily dose of 50–200 mcg is adequate. Those with lymphocytic hypophysitis can experience both adrenal insufficiency as well as
diabetes insipidus Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...
. Whether or not a someone is receiving treatment for diabetes insipidus, fluid administration should be done carefully because too much fluid can lead to hypernatremia and too little water can cause hyponatremia. Hyponatremia is typically maintained with careful synchronization of urine output and a normal saline infusion.


Outlook

People with adrenal insufficiency are more likely to die from an adrenal crisis than other causes of death; the death rate from adrenal crises can amount to 6%. While symptoms may have gone unnoticed prior to the fatal episode, fatal adrenal crises have happened in those who had never been diagnosed with hypoadrenalism.


Epidemiology

An adrenal crisis occurs in roughly 6–8% of those with adrenal insufficiency annually. Those with primary hypoadrenalism experience adrenal crises somewhat more frequently compared to those with secondary adrenal insufficiency. This is likely due to the fact that those with primary hypoadrenalism lack
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 ...
secretion and some with secondary adrenal insufficiency retain some cortisol secretion. Despite varying degrees of consequent adrenal suppression, those with
hypoadrenalism Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...
from long-term glucocorticoid therapy rarely experience adrenal crises.


Special populations


Geriatrics

All age groups are susceptible to misclassification of an adrenal crisis diagnosis, but older people may be more vulnerable if relative hypotension is not evaluated, given the age-related rise in blood pressure. It is possible to confuse hyponatremia, a common sign of adrenal insufficiency or adrenal crisis, with the
syndrome of inappropriate antidiuretic hormone secretion Syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as the syndrome of inappropriate antidiuresis (SIAD), is characterized by a physiologically inappropriate release of Vasopressin, antidiuretic hormone (ADH) either from ...
, which is frequently brought on by disease, drugs, or aging itself. The treatment of
pituitary tumors 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.opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
s for pain, as well as exogenous glucocorticoid therapy for the numerous conditions that become more common in people over 60, are the main causes of a new diagnosis of adrenal insufficiency in older adults. Adrenal crisis is more likely to occur in older people.
Urinary tract infection A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra (urethritis) while upper urinary tract infections affect the kidney (pyel ...
s, particularly in older women, are often linked to an adrenal crisis, as is
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
as well as a flare-up of
COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...
.
Cellulitis Cellulitis is usually a bacterial infection involving the inner layers of the skin. It specifically affects the dermis and subcutaneous fat. Signs and symptoms include an area of redness which increases in size over a few days. The borders of ...
is linked to adrenal crises within this age range and may be more prevalent in those with fragile skin who have been exposed to higher doses of glucocorticoids. Older adults, especially those who have primary adrenal insufficiency, frequently experience falls and fractures, which may be linked to
postural hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...
. Older people have a higher mortality rate from adrenal crisis, at least in part due to the existence of comorbidities that make treatment more difficult. While studies on the prevalence of adrenal crisis in older adults are limited, one population-based study into hospital admissions for adrenal crisis found that the incidence increased with age in older individuals, going from 24.3 (60–69 years) to 35.2 (70–79 years) and 45.8 (80+ years) per million per year. This is significantly higher compared to the general adult admission rate, which is 15.0 per million annually in the same population.


Pregnancy

Most cases of adrenal insufficiency are identified before conception. Because the symptoms of
hyperemesis gravidarum Hyperemesis gravidarum (HG) is a pregnancy complication that is characterized by severe nausea, vomiting, weight loss, and possibly dehydration. Feeling faint may also occur. It is considered a more severe form of morning sickness. Symptoms ...
(fatigue, vomiting, nausea, and mild hypotension) and normal pregnancy (nausea and vomiting) overlap, there is usually little clinical indication of adrenal insufficiency during pregnancy. Untreated adrenal crisis can cause severe morbidity in both the mother and the fetus, such as inadequate wound healing, infection,
venous thromboembolism Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lun ...
, extended hospital stays, preterm birth, fetal intrauterine growth restriction, and an increased risk of
cesarean delivery Caesarean section, also known as C-section, cesarean, or caesarean delivery, is the surgical procedure by which one or more babies are delivered through an incision in the mother's abdomen. It is often performed because vaginal delivery would ...
. The occurrence of adrenal crisis during pregnancy is uncommon, even in people who have a documented history of adrenal insufficiency. In one study, pregnancy was identified as a trigger for adrenal crisis in 0.2% of the 423 participants. In a different study, only 1.1% of the 93 participants in the study who had a known insufficiency experienced an adrenal crisis during pregnancy.


Children

A common finding in children experiencing an adrenal crisis is hypoglycemia. This can lead to seizures, which can result in permanent brain damage or even death. Due to issues with
adrenomedullary 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 which ...
development as well as
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
production, hypoglycemia may be more prominent in the context of acute adrenal insufficiency in congenital conditions, including
congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...
, compared to other forms of primary adrenal insufficiency. The severity of the enzyme impairment is correlated with the degree of adrenomedullary dysfunction. Severe hyperkalemia has also been linked to potentially fatal cardiac
arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
s. Studies have demonstrated that younger children with congenital adrenal hyperplasia experience adrenal crisis events more frequently than older children and adolescents. Psychosocial factors can alter the baseline adrenal crisis risk, especially as the transition from parental treatment oversight to self-management in adolescence. Management in this age group is further complicated by changes in cortisol
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
, resulting in an increased clearance as well as volume without a change to the cortisol half-life that has been shown during the pubertal period. There is still a significant morbidity and death associated with adrenal insufficiency in newborns and early children. It has been estimated that 5–10 episodes of adrenal crisis occur every 100 years in those with adrenal insufficiency; incidences may be higher in specific countries. Adrenal crisis among kids results in death in about 1/200 cases.


See also

* Stress dose *
Adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...


References


Citations


Sources

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Further reading

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External links

* * {{Shock types Medical emergencies Adrenal gland disorders