Adrenal crisis, also known as Addisonian crisis or acute adrenal insufficiency, is a life-threatening complication of adrenal insufficiency. Hypotension and hypovolemic shock are the main symptoms of an adrenal crisis. Other symptoms include weakness, anorexia, nausea, vomiting, fever, fatigue, abnormal electrolytes, confusion, and coma. Laboratory testing may detect low sodium, high potassium, high lymphocyte count, high eosinophils, low blood sugar, 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 glucocorticoids' typical inhibitory effect on inflammatory cytokines.
When someone with adrenal insufficiency exhibits symptoms of an adrenal crisis, treatment must begin immediately. To diagnose an adrenal crisis, serum cortisol, aldosterone, ACTH, renin, and dehydroepiandrosterone sulfate 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. 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, 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 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, 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 and coma.
During an adrenal crisis laboratory testing may show low sodium (hyponatremia), high potassium (hyperkalemia), high lymphocyte count (lymphocytosis), high eosinophils (eosinophilia), low blood sugar (hypoglycemia), and rarely high calcium (hypercalcemia). In an adrenal crisis, hypotension occurs due to low cortisol and volume depletion. Hypovolemia 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. Hyponatremia in primary adrenal insufficiency is caused by concurrent aldosterone deficiency, resulting in volume depletion, natriuresis, 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.
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, 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, or 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 also 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.
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 is suppressed by the use of glucocorticoids in rectal preparations, spinal injections, injections into the dermis, injections into the joint, nasal, inhaled, or steroids applied to the skin. At pharmacological dosages, medroxyprogesterone and megestrol also exhibit a notable glucocorticoid effect. This risk may increase if steroids are used concurrently with ritonavir which inhibits the liver's CYP3A 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 mineralocorticoids, increased risk of dehydration 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 are even more likely to experience an adrenal crisis. This increased risk could be attributed to either the absence of V1-receptor-mediated vasoconstriction 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 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 infections. 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 might have both thyroid and adrenal insufficiency. Levothyroxine can speed up the metabolism of cortisol and trigger an adrenal crisis. Several medications, including chemotherapy and immunotherapy, have been linked to an increased risk of adrenal crisis. Immune checkpoint inhibitors are known to cause endocrine problems, including hypophysitis and adrenalitis, with subsequent adrenal insufficiency. Barbiturates and adrenostatic medications may raise the risk of an adrenal crisis. Cytochrome P450 3A4 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, meaning that cortisol levels fall within several hours of cortisol deprivation. Because cortisol modulates the transcription of genes containing a glucocorticoid response element, this affects 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, anorexia, and pain. As a result, low cortisol causes changes in immune-cell levels, including lymphocytosis, eosinophilia, and neutropenia. Low levels of cortisol means that it loses its ability to work with catecholamines to reduce vascular reactivity, which causes vasodilatation and hypotension. Low cortisol has an adverse effect on the liver's metabolism, resulting in hypoglycemia, decreased gluconeogenesis, lower levels of free fatty acids and amino acids in circulation.
Loss of cortisol suppresses nuclear factor κB (NF-κB) and activator protein 1 (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. Additionally, through potassium retention and sodium and water loss, mineralocorticoid 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 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, dehydroepiandrosterone sulfate, aldosterone, 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 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.
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 frequently precedes an adrenal crisis and stress dose glucocorticoids may not always avoid an adrenal crisis.