Adrenal crisis

From Wikipedia, the free encyclopedia
Adrenal crisis
Other namesAcute adrenal insufficiency, Addisonian crisis, Acute adrenal failure.[1]
49-year-old with an adrenal crisis. Appearance, showing lack of facial hair, dehydration, Queen Anne's sign (panel A), pale skin, muscular and weight loss, and loss of body hair (panel B).
  • /əˈdriː.nəl/[2] /ˈkraɪ.sɪs/[3]
SpecialtyEmergency medicine, Endocrinology
SymptomsDizziness, somnolence, confusion, loss of consciousness, nausea, vomiting, abdominal pain, decreased appetite, extreme exhaustion, unintended weight loss, weakness, and hypotension.[4]
ComplicationsSeizures, arrhythmias, organ damage, coma, and death.[4]
CausesAdrenal insufficiency, thyrotoxicosis, infections, trauma, pregnancy, and surgery.[4]
Risk factorsAdrenal insufficiency, polyglandular autoimmune syndromes, glucocorticoids, levothyroxine, and rifampin.[4]
Diagnostic methodACTH, basic metabolic panel, and cortisol.[4]
Differential diagnosisMyocardial infarction, trauma, stress, myxedema coma, circulatory shock, septic shock, and infection.[4]
PreventionProviding intramuscular hydrocortisone at home and using sick day rules.[4]
TreatmentSteroid replacement and fluid resuscitation.[5]
Prognosis6% mortality rate.[6]
Frequency6–8% of those with adrenal insufficiency annually.[7]

Adrenal crisis, also known as Addisonian crisis or acute adrenal insufficiency, is a serious, life-threatening complication of adrenal insufficiency. Hypotension, or hypovolemic shock, is the main symptom of adrenal crisis. Other symptoms include weakness, anorexia, nausea, vomiting, fever, fatigue, abnormal electrolytes, confusion, and coma.[8] Laboratory testing may detect lymphocytosis, eosinophilia, hyponatremia, hyperkalemia, hypoglycemia, and occasionally, hypercalcemia.[9]

The biggest trigger for adrenal crisis is gastrointestinal illness.[10] The physiological mechanisms underlying an adrenal crisis involve the loss of endogenous glucocorticoids' typical inhibitory effect on inflammatory cytokines.[9]

When a patient with adrenal insufficiency exhibits symptoms of an adrenal crisis, treatment should begin immediately.[11] To diagnose an adrenal crisis, serum cortisol, aldosterone, ACTH, renin, and dehydroepiandrosterone-sulfate should be measured.[8] A low cortisol level of less than 5 mg/dL (138 nmol/L), measured in the early morning or during a stressful period, suggests a diagnosis of adrenal insufficiency.[12]

A tailored prescription, as well as a strategy for administering additional glucocorticoids for physiological stress, are critical preventative measures. When an adult experiences an adrenal crisis, they require immediate parenteral hydrocortisone.[13]

About 6 to 8% of patients with adrenal insufficiency experience an adrenal crisis at some point each year.[7] The mortality rate linked to adrenal crises is up to 6%.[6]

Signs and symptoms[edit]

In as many as 50% of Addison's disease patients, adrenal crisis can be the first symptom of adrenal insufficiency.[14] Diagnosis is often delayed since most of the signs and symptoms of adrenal insufficiency are nonspecific and develop insidiously. Symptoms include orthostatic hypotension, lethargy, fever, nausea, fatigue, anorexia, abdominal pain, weakness, hyperpigmentation, joint pain, and weight loss. Those in an adrenal crisis often go into hypotensive shock and may exhibit sensorium alterations. They often present with gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain, which can mistakenly be diagnosed as gastroenteritis or an acute abdomen.[5]

Glucocorticoids have a permissive effect on catecholamine action, which leads to hypotension secondary to hypovolemia and hypocortisolism.[15] Hypovolemia might be resistant to inotropes 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.[5]

Hyponatremia in primary adrenal insufficiency is caused by concurrent aldosterone deficiency, resulting in volume depletion, natriuresis, and hyperkalemia.[16] Additional biochemical characteristics include hypercalcemia, which is a result of increased bone resorption and reduced renal excretion of calcium, and hypoglycemia, which occurs rarely.[17]


An absolute or relative lack of cortisol, causes adrenal crises as there is not enough tissue glucocorticoid activity to preserve homeostasis.[9]

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, secondary adrenal insufficiency due to ACTH deficiency caused by conditions affecting the hypothalamus or pituitary gland, or tertiary adrenal insufficiency caused by excessive glucocorticoid exposure. Adrenal insufficiency can be caused by autoimmune disorders such as autoimmune adrenalitis, autoimmune polyglandular syndrome, and lymphocytic hypophysitis, congenital disorders such as congenital adrenal hyperplasia, adrenoleukodystrophy, familial glucocorticoid deficiency, combined pituitary hormone deficiency, and POMC mutation. Adrenal insufficiency can also be caused by pituitary or adrenal gland surgeries. Infections such as tuberculosis, histoplasmosis, HIV, and CMV can also cause adrenal insufficiency. Infiltrative disorders like sarcoidosis, amyloidosis, and haemochromatosis have been known to cause adrenal insufficiency. Hemorrhages in the pituitary and adrenal glands, Waterhouse-Friderichsen syndrome, vasculitis, pituitary apoplexy, and Sheehan’s syndrome are vascular disorders that can cause adrenal insufficiency. Tumors on the pituitary gland or cancer metastasis can also cause adrenal insufficiency.[18]

Exogenous steroid use is the most frequent cause of adrenal insufficiency,[11] and patients who use these drugs also run the risk of experiencing an adrenal crisis. Adrenal crisis can result from abrupt, and frequently unintentional, steroid withdrawal.[5] The hypothalamus-pituitary-adrenal axis has been reported to be suppressed by the use of glucocorticoids in rectal,[19] paraspinal,[20] intradermal,[21] intraarticular,[22] injectable,[23] nasal,[24] inhaled,[25] or topical preparations.[26] At pharmacological dosages, medroxyprogesterone and megestrol also exhibit a notable glucocorticoid effect.[27] This risk may increase if steroids are used concurrently with ritonavir or, which inhibit the liver's CYP3A enzyme that breaks down steroids.[28][29]

There is a greater risk for adrenal suppression with longer durations, greater doses, and oral and intraarticular preparations. Nonetheless, no amount, time frame, or mode of administration can reliably predict adrenal insufficiency.[30]

Risk factors[edit]

Because of the lack of mineralocorticoids and increased risk of dehydration and hypovolemia, those with primary adrenal insufficiency might be more susceptible to adrenal crisis compared to individuals with secondary adrenal insufficiency.[6]

Individuals with secondary adrenal insufficiency who have diabetes insipidus are more likely to experience an adrenal crisis. This increased risk could be attributed to either the absence of V1-receptor-mediated vasoconstriction throughout extreme stress or the increased risk of dehydration.[31] A higher risk of adrenal crisis has been linked in some studies to other medical conditions like hypogonadism[10] and type 1 and type 2 diabetes, though the exact mechanism is unknown.[32]

Patients with adrenal insufficiency have a 50% lifetime risk of experiencing an adrenal crisis,[5] and those who have experienced an adrenal crisis in the past seem to be more susceptible to another episode.[6]


A known precipitating event can be found in over 90% of episodes of adrenal crisis.[5] The most common cause of adrenal crisis is gastrointestinal illness. This is probably because it has a direct impact on how well oral glucocorticoids are absorbed through the intestines.[6] Stress from surgery is another common cause.[32]

Those who have autoimmune polyendocrine syndrome type 2 might have concurrent thyroid and adrenal insufficiency. Levothyroxine can speed up the peripheral metabolism of cortisol and trigger an adrenal crisis in individuals with undetected adrenal insufficiency as well as those already on replacement steroids.[33] Cytochrome P-450 enzyme inducers, such as phenobarbitone, rifampicin, and phenytoin, may trigger an adrenal crisis.[34] Therefore, glucocorticoid dosages should be appropriately increased in those with tuberculosis-associated adrenal insufficiency starting rifampicin.[35]

An adrenal crisis can also be brought on by emotional stress in addition to physical stress.[6]


An absolute or relative lack of cortisol, an endogenous glucocorticoid, causes adrenal crises because there is not enough tissue glucocorticoid activity to preserve homeostasis.[9]

Left: DNA-binding domains of a glucocorticoid receptor homodimer in the nucleus interacting with DNA. Right: Binding of synthetic glucocorticoid dexamethasone to ligand-binding domain of receptor in cytoplasm.

Cortisol has a 70 to 120 minute half-life meaning that cortisol levels within several hours of cortisol deprivation.[36] Because cortisol modulates the transcription of genes containing a glucocorticoid response element, it has extremely pleiotropic effects. The physiological effects of low cortisol begin with the loss of the natural inhibitory function of endogenous glucocorticoids on inflammatory cytokines. This leads to sharp rises in cytokine concentrations, which induce fever, lethargy, anorexia, and pain in the body. As a result, insufficient cortisol causes immune-cell populations to change, including lymphocytosis, eosinophilia, and neutropenia;[9] it also loses its ability to work in concert with catecholamines to reduce vascular reactivity, which causes vasodilatation and hypotension;[37] it has an adverse effect on the liver's intermediary metabolism, resulting in hypoglycemia, decreased gluconeogenesis, or both; and it lower levels of free fatty acids and amino acids in circulation.[38]

Loss of cortisol suppresses nuclear factor κB (NF-κB) and activator protein 1 (AP-1) at the cellular level, 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.[9] Additionally, through potassium retention and sodium and water loss, mineralocorticoid deficiency—which is common in primary but not in secondary adrenal insufficiency—is likely to aggravate adrenal crises.[31]


When a patient with adrenal insufficiency is known to be exhibiting symptoms of an adrenal crisis, treatment needs to start right away. When a patient is deemed medically unstable, treatment shouldn't be postponed in even when diagnosis is still pending.[11]

Change in plasma cortisol cycle (mcg/dl) over 24 hours

Adrenal insufficiency can be diagnosed with renin, dehydroepiandrosterone sulfate, aldosterone, serum cortisol, and ACTH levels which can be taken right before hydrocortisone is administered. A high cortisol level of more than 20 mg/dL (550 nmol/L) can rule out the diagnosis.[8] A low cortisol level of less than 5 mg/dL (138 nmol/L), obtained in the early morning or during a stressful period, strongly suggests the possibility of adrenal insufficiency.[12] 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.[17]

When in doubt, the patient should receive glucocorticoid therapy until they have fully recovered, at which point a safe diagnostic test, like an ACTH stimulation test, can be performed. The hypothalamic-pituitary-adrenal axis can be affected by prolonged glucocorticoid treatment, so this test should be done as soon as possible.[5]


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 should be used, preferably at home. Devices like MedicAlert bracelets and necklaces can alert caregivers to the possibility of adrenal crisis in patients who are unable to communicate verbally.[9]

Hydrocortisone 100mg vial

Although the exact dosage has been debated, it is generally agreed upon that all patients with proven adrenal insufficiency should receive 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.[39] Though there may be variations in specific regimens, most agree that stress doses for simple surgery should be quickly tapered and should not last longer than three days. This is because unneeded steroid excess can lead to infections, poor wound healing, and hyperglycemia.[5]

In those who are unable to tolerate oral medication or do not respond to stress doses, a low threshold to initiate parenteral hydrocortisone management should be used to guarantee adequate systemic absorption, since gastroenteritis frequently precedes an adrenal crisis[6] and a rise in oral glucocorticoids may not always avoid an adrenal crisis.[40]

Patients experiencing vomiting, chronic diarrhea, or an imminent adrenal crisis should receive intramuscular hydrocortisone. Patients must be prepared to administer it themselves because they can rapidly deteriorate.[39] A lot of patients may own a hydrocortisone ampoule,[41] 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.[32] Patients may experience significant physical as well as cognitive impairment during their illness, which may impair their capacity to make wise decisions or administer medicine.[42] Therefore, patients should 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.[39]

In case an individual suffering from adrenal insufficiency loses consciousness, they must receive the necessary medical attention. Reminding patients to always wear or keep a MedicAlert bracelet or just an emergency card is important.[43] A survey of 46 patients revealed that some medical professionals are reluctant to medicate the condition even when it is brought to their attention, which is a serious cause for concern. Only 54% of patients got glucocorticoid administration within 30 minutes of arrival, even though 86% of patients were promptly attended to by a medical professional within forty-five minutes of a distress call.[44] In situations when doctors are unsure about a patient's need for additional hydrocortisone, it is wise to listen to patients and their loved ones as they frequently have the most knowledge about this rare disorder.[45]


The two foundations of treatment for adrenal crisis are steroid replacement and fluid resuscitation.[5] When adrenal crisis treatment is started as soon as possible, it can be effective in preventing irreversible effects from prolonged hypotension.[9] Treatment shouldn't be postponed while doing diagnostic tests. If there is reason to suspect something, a blood sample could be taken right away for ACTH and serum cortisol testing; however, treatment needs to begin right away, regardless of the results of the assay. Once a patient has recovered clinically, it is safe to confirm the diagnosis in an acutely ill patient.[46]

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.[47] A constant infusion of hydrocortisone results in a cortisol concentration insert at a steady state.[48]

Hypovolemia 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. Over the course of the first hour, a liter of saline 0.9% must be administered. Subsequent replacement fluids should be determined by measuring the serum electrolytes and conducting frequent hemodynamic monitoring.[49] In cases of secondary adrenal insufficiency, cortisol replacement can cause water diuresis along with suppress antidiuretic hormone. When combined with sodium replacement, these effects can quickly correct hyponatremia as well as osmotic demyelination syndrome. As a result, care must be taken to adjust sodium by less than 10 mEq during the first 24 hours.[50]

It is widely acknowledged that extra mineralocorticoid treatment is not necessary at hydrocortisone dosages greater than 50 mg/day because there is adequate action within the mineralocorticoid receptor.[8] In those who have primary adrenal insufficiency, fludrocortisone needs to be started with subsequent dose tapering; for most patients, a daily dose of 50–200 mcg is adequate.[49] According to current treatment guidelines of primary adrenal insufficiency, the doses of prednisolone and dexamethasone are recommended based on their glucocorticoid potency in relation to hydrocortisone.[47]

Patients with lymphocytic hypophysitis can experience both adrenal insufficiency as well as diabetes insipidus. Whether or not a patient 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.[7]


Patients with hypoadrenalism are more likely to die from adrenal crises; the death rate from adrenal crises can amount to 6% of crisis events.[6] "Adrenal failure" accounted for 15% of deaths in a study conducted in Norway involving 130 Addison's disease patients, making it the second most common cause of death.[51] While symptoms may have gone unnoticed prior to the fatal episode, fatal adrenal crises have happened in patients who had never been diagnosed with hypoadrenalism.[52]


An adrenal crisis occurs in roughly 6–8% of those with adrenal insufficiency annually.[7] Patients with primary hypoadrenalism experience adrenal crises somewhat more frequently compared to those with secondary adrenal insufficiency.[31] This is likely due to the fact that patients with primary hypoadrenalism lack mineralocorticoid secretion and some secondary adrenal insufficiency patients retain some cortisol secretion.[53] Despite varying degrees of consequent adrenal suppression, patients with hypoadrenalism from long-term glucocorticoid therapy rarely experience adrenal crises.[54]

Special populations[edit]


T1-weighted post contrast coronal section of non-functioning pituitary adenoma. The tumor is seen extending into the right cavernous sinus.

All age groups are susceptible to misclassification of an adrenal crisis diagnosis,[7] but older patients may be more vulnerable if relative hypotension is not evaluated, given the age-related rise in blood pressure.[55] It is possible to confuse hyponatremia—a common sign of adrenal insufficiency or adrenal crisis—with the syndrome of inappropriate antidiuretic hormone secretion, which is frequently brought on by disease, drugs, or aging itself.[56]

The treatment of pituitary tumors and the widespread use of opioids for both malignant and increasingly non-malignant pain, as well as exogenous glucocorticoid therapy for the numerous inflammatory as well as malignant conditions that become more common in people over 60, are the main causes of a new diagnosis of adrenal insufficiency in older adults.[57][54] Adrenal crisis is more likely to occur in older people.[58] Urinary tract infections, particularly in older women, are often linked to an adrenal crisis, as is pneumonia as well as a flare-up of chronic respiratory disease.[59] Cellulitis is linked to adrenal crises within this age range and may be more prevalent in patients with fragile skin who have been exposed to higher doses of glucocorticoids.[60] Older adults frequently experience falls and fractures, which may be linked to postural hypotension, especially in those who have primary adrenal insufficiency.[61]

Older patients have a higher mortality rate from adrenal crisis, at least in part due to the existence of comorbidities that make treatment more difficult.[62]

While studies on the prevalence of adrenal crisis in older adults are scarce, one population-based investigation into hospital admissions for adrenal crisis found that the incidence increased with age in older patients, 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.[60]


Most cases of adrenal insufficiency in pregnancy are identified before conception. Because the symptoms of hyperemesis gravidarum (fatigue, vomiting, nausea, and mild hypotension) and normal pregnancy (nausea and vomiting) overlap, there is usually little clinical indication of adrenal insufficiency during pregnancy.[63] Adrenal insufficiency during pregnancy has only been documented in 100 cases as of 2018.[64]

Untreated adrenal crisis can cause severe morbidity in both the mother and the fetus, such as inadequate wound healing, infection, venous thromboembolism, extended hospital stays, preterm birth, fetal intrauterine growth restriction, and an increased risk of cesarean delivery.[65] The occurrence of adrenal crisis during pregnancy is uncommon, even in patients 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 patients. In a different study only 1.1% of the 93 patients in the study who had a known insufficiency experienced an adrenal crisis during pregnancy.[66]


Fluorodeoxyglucose Positron emission tomographyCT scan shows enlarged adrenals with masses. Genetic and biochemical workup was consistent with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

A common finding in children experiencing an adrenal crisis is hypoglycemia. This could be linked to seizures, which are extremely dangerous and can result in permanent brain damage or even death.[67] Due to issues with adrenomedullary development as well as epinephrine production, hypoglycemia, and hemodynamic disturbance may be more prominent in the context of acute adrenal insufficiency in congenital conditions, including congenital adrenal hyperplasia, compared to other forms of primary adrenal insufficiency.[68] The severity of the enzyme impairment is correlated with the degree of adrenomedullary dysfunction.[69] Severe hyperkalemia has also been linked to potentially fatal cardiac arrhythmias.[70] Because the renal tubules' function is still developing in infants and early children with primary adrenal insufficiency, hyponatremia is of particular concern.[68]

Studies have demonstrated that younger children with congenital adrenal hyperplasia experience adrenal crisis events more frequently than older children and adolescents.[71] Furthermore, research on congenital adrenal hyperplasia in children shows that individuals with more severe salt-wasting types have a higher chance of needing to be hospitalized.[72] There are differences in the incidence of adrenal crises between the sexes, and these differences change with age.[73] Psychosocial factors have the potential to alter the baseline adrenal crisis risk as well, especially as patients transition from parental treatment oversight to self-management in adolescence.[74] Management in this age group is further complicated by changes in cortisol pharmacokinetics, 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.[75]

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 for every 100 patient years in children with adrenal insufficiency; incidences may be higher in specific countries. Adrenal crisis among kids results in death in about 1/200 cases.[13]

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