Adrenal Crisis

Etiology

History of Adrenal Crisis

In 1855, Thomas Addison's pioneering work provided the earliest description of adrenal insufficiency, marking a significant milestone in comprehending this condition.[7] The discovery of cortisone by Hench, Kendall, and Reichstein in the late 1940s revolutionized the treatment of adrenal insufficiency, leading to a remarkable enhancement in the life expectancy of individuals affected by this condition.[8][9] 

In the 1930s, tuberculosis was the most prevalent cause of this condition, accounting for approximately 70% of cases. In recent times, autoimmune adrenalitis, or Addison disease, has emerged as the leading cause of primary adrenal insufficiency in developed countries. In contrast, tuberculosis remains the leading cause of adrenal insufficiency in developing countries.[10]

Precipitating Factors for Adrenal Crisis

An adrenal crisis most often occurs in a patient with either known primary or secondary adrenal insufficiency. Primary adrenal insufficiency occurs from loss of adrenal gland function and is characterized by low cortisol and high adrenocorticotropic hormone (ACTH). Examples of this include autoimmune destruction of the adrenal gland (Addison disease), surgical removal of the glands, or inborn errors of cortisol production (eg, congenital adrenal hyperplasia). Uncommonly, a patient will have no prior history of autoimmune disease or adrenal insufficiency but will have acquired adrenal insufficiency due to chronic infection, such as from Mycobacterium tuberculosis leading to chronic infectious adrenalitis and fibrosis, or have acute meningococcal meningitis causing Waterhouse-Friderichsen Syndrome and massive bilateral adrenal hemorrhage.[11][12][13][14]

Secondary adrenal insufficiency is most commonly caused by long-term suppression of the pituitary gland production of ACTH by exogenous glucocorticoids, leading to decreased adrenal gland stimulation. This suppression can occur with doses as low as 5 mg of prednisone for 4 weeks or more. Corticosteroid joint injections, steroid creams, and inhaled steroids can also contribute to this. Less commonly, secondary adrenal insufficiency is caused by disruption of the pituitary-adrenal axis by tumors in the pituitary/hypothalamus region. Patients with primary adrenal insufficiency are more likely than secondary causes because aldosterone can also be affected (as can sex hormones).[15]

Acute adrenal crisis can also be the initial presentation of undiagnosed adrenal insufficiency, which occurs in about 50% of patients diagnosed with Addison disease.[16][17][18] In a previous study, approximately 10% of patients exhibited no identifiable cause for their adrenal crisis.[19] The major etiologies of an adrenal crisis are as follows:

• Gastrointestinal and flu-like illnesses (the most common cause) [3][6][20]
• Bacterial, mycobacterial, fungal, parasitic, or viral, eg, COVID-19, infections [19][21]
• Trauma, pregnancy, childbirth, surgery, exposure to extreme hot or cold weather, or other stressful situations
• Significant emotional distress [19]
• Strenuous physical activity [22]
• Nonadherence to glucocorticoid replacement therapy [23]
• Abrupt cessation of chronic glucocorticoid therapy [23]
• Thyrotoxicosis (due to acceleration of cortisol metabolism)
• Levothyroxine therapy initiation in a previously untreated case of adrenal insufficiency [24]
• Antiadrenal medications, including mitotane, metyrapone, ketoconazole
• Anticancer medications, including immunotherapy with checkpoint inhibitors and tyrosine kinase inhibitors [25][26][27]

Patients with polyglandular disease (ie, thyroid and adrenal) warrant special attention, as they are at higher risk of adrenal crisis. Patients with hypothyroidism can have masked adrenal insufficiency as they are in a hypometabolic state. When the thyroid hormones are replaced, patients have higher metabolic activity, and hypotension and hypoglycemia due to adrenal insufficiency can occur. Another example is polyglandular autoimmune disease, where patients can have autoimmune destruction of the thyroid, parathyroid, adrenal glands, or pancreas.[24][28] 

Adrenal Crisis Risk Factors

The risk factors associated with adrenal crisis are as follows:

• A known history of adrenal insufficiency or previous adrenal crisis
• Primary adrenal insufficiency diagnosis, which carries a higher risk than secondary adrenal insufficiency [16][29]
• Ongoing glucocorticoid therapy, including topical and inhalation forms, poses a risk for an adrenal crisis due to the potential suppression of the hypothalamic-pituitary-adrenal (HPA) axis if abruptly discontinued
• Medications, including levothyroxine, phenytoin, phenobarbital, rifampin, carbamazepine, St John's wort, ketoconazole, etomidate, and fluconazole, which affect cortisol metabolism or reduce its production [30][31][32]
• Anticoagulation agents, which increase the risk of adrenal hemorrhage
• Additional medications, including megestrol acetate and medroxyprogesterone [33][34][35]
• Pregnancy, particularly during the third trimester [36]
• Advanced age [3]
• The presence of comorbidities [16][29]
• Patients with type 1 diabetes [3] 
• Adrenal metastasis or adrenal hemorrhage [37][38]
• Polyglandular autoimmune syndromes 1 and 2 [39][40]

Epidemiology

Determining the exact frequency of adrenal crises in the general population poses a significant challenge. Patients with adrenal insufficiency have been estimated to experience an adrenal crisis in 6% to 8% of cases annually or 4 to 6 adrenal crises per 100 patient years in those carrying a diagnosis of adrenal insufficiency.[20] The incidence of adrenal crises remains high even among patients who have received extensive education on managing and preventing adrenal insufficiency.[19] A study revealed a 6% mortality rate associated with adrenal crises among this well-informed group of patients.[19] The annual frequency of adrenal crisis in patients with Addison disease remains at 8%.[41]

Pathophysiology

Adrenal Crisis Pathophysiology

The pathophysiology of adrenal crisis is not fully understood; however, examining the functions of glucocorticoids can provide insight into clinical manifestations. Glucocorticoids exhibit various roles in stress responses, demonstrating permissive, suppressive, stimulatory, and preparative effects.[42] For a full discussion of their function, please see StatPearls' companion review, "Physiology of Glucocorticoids."

In general, adrenal or Addisonian crisis refers to an acute status of severe cortisol and/or aldosterone deficiency. The hypothalamus releases corticotropin-releasing hormone (CRH) as a response to an environmental stressor. CRH stimulates the anterior pituitary to release ACTH, which travels through the bloodstream to the adrenal cortex and upregulates cortisol production. Cortisol is a glucocorticoid hormone synthesized from cholesterol by enzymes of the cytochrome P450 family in the zona fasciculate, the middle area of the adrenal cortex.[43]

Cortisol is the primary hormone involved in the human stress response and has multiple effects throughout the body, eg, causing vasoconstriction and inhibiting proinflammatory cytokines. This hormone helps regulate the supply of glucose in the body by triggering gluconeogenesis or stimulating glycogen synthesis in the liver, as well as producing and releasing amino acids from free fatty acids. Cortisol weakens the immune response by preventing T-cell proliferation and preventing T-cells from recognizing interleukin signals.[44] 

Aldosterone deficiency is usually seen in cases of more severe adrenal gland dysfunction involving the whole adrenal gland, eg, Addison disease.[43] Deficient levels of aldosterone cause increased renal sodium loss and potassium reabsorption, resulting in decreased intravascular volume, vascular tone, cardiac output, and renal perfusion. This, in turn, lowers arterial blood pressure, which may lead to postural hypotension, compensatory tachycardia, and eventual vascular collapse. Reduced renal perfusion causes water retention, which dilutes the extracellular fluid and causes the cells to leak potassium, leading to hyperkalemia and metabolic acidosis. Circulatory collapse impairs urinary excretion of waste products, causing elevated blood urea nitrogen and creatinine levels.

Effects of Glucocorticoids on the Cardiovascular System

Glucocorticoids have a permissive effect on the functioning of adrenergic receptors in the heart and vasculature. Without glucocorticoids, catecholamines cannot exert their full impact on these receptors. Consequently, during an adrenal crisis, patients often experience hypotension and, in severe cases, may develop profound shock that remains unresponsive to fluid resuscitation and vasopressor therapy.[45] 

Effects of Glucocorticoids on the Immune System

Infectious or noninfectious stressors can trigger the activation of the immune system, leading to an elevated release of cytokines. Interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor (TNF)-α, and TNF-γ have pivotal roles in this immune response. This immune activation subsequently leads to the activation of the HPA axis, resulting in elevated glucocorticoid levels.[46][47] 

Glucocorticoids mitigate immune response by inhibiting cytokine production, release, and effects, thereby playing a crucial role in immune regulation.[48][49] During an adrenal crisis, any significant stressor can trigger an uncontrolled cytokine response, eg, inflammation, resulting in fever, widespread vasodilation, and heightened capillary permeability. This can result in hypovolemia and shock as a consequence of fluid shifting from capillaries into tissues, thereby contributing to the development of hypovolemic shock.

Consequently, during an adrenal crisis, the dysregulation of the immune response, marked by an excessive cytokine release, can result in systemic inflammation, fever, vasodilation, capillary leakage, hypovolemia, and shock.

Effects of Glucocorticoids on the Musculoskeletal System 

Bone health is also affected by glucocorticoid action and is mediated through thyroid hormones. Usually, glucocorticoids inhibit pituitary thyroid-stimulating hormone (TSH) secretion, and with glucocorticoid deficiency, increased TSH causes increased thyroid hormone, which increases bone resorption, causing hypercalcemia. Thyroid hormone is also thought to increase cortisol clearance. The exact mechanisms of hypercalcemia are not known, but several theories exist. Glucocorticoid inhibits activation of 1α-hydroxylation of vitamin D; hence, decreased glucocorticoid may cause increased intestinal calcium absorption. Another proposed theory is that glucocorticoids help preserve osteoblasts. Another possibility is that hypovolemia increases proximal tubular calcium reabsorption. Although hypercalcemia is recognized as a common complication of adrenal insufficiency/adrenal crisis, further studies are needed to delineate the mechanisms by which this occurs.[28][50][51]

Effects of Glucocorticoids on Intravascular Volume

Glucocorticoids can potentially suppress the expression and secretion of antidiuretic hormone (ADH) in the hypothalamic neurons.[52][53] During an adrenal crisis, there is an upsurge in the activity of ADH, leading to increased diuresis and volume depletion.

Effects of Glucocorticoids on the Glucose Homeostasis

Glucocorticoids increase glucose levels in response to stress through various mechanisms, including promoting glycogenolysis and stimulating gluconeogenesis.[54] In addition, glucocorticoids also induce insulin resistance, which reduces glucose uptake by the peripheral cells.[54] During an adrenal crisis, glucocorticoid deficiency hinders these normal stress responses. As a result of the glucocorticoid-deficient state, hypoglycemia can occur due to insufficient glucose production and improved peripheral utilization.

Effects of Glucocorticoids on Appetite Regulation

CRH is a potent appetite suppressant in response to stress.[55] Glucocorticoids are potent inhibitors of CRH release, which can lead to increased appetite.[52] During an adrenal crisis, the release of CRH remains uninhibited in a glucocorticoid-deficient state, leading to anorexia.

Glucocorticoids and Electrolyte Disturbances

Primary adrenal insufficiency causes mineralocorticoid deficiency due to direct destruction of the adrenal cortex. However, the cortex remains intact in secondary and tertiary adrenal insufficiency. The renin-angiotensin-aldosterone system regulates aldosterone production and secretion.[56] An isolated deficiency of ACTH secretion observed in secondary or tertiary adrenal insufficiency does not significantly affect aldosterone levels.[57][56] In primary adrenal insufficiency, aldosterone deficiency is often present, leading to volume loss, hyponatremia, and hyperkalemia.[18] 

Histopathology

The histopathology of adrenal crisis depends on the underlying cause of adrenal insufficiency. Please see StatPearls' companion review, "Adrenal Insufficiency," for further details on histopathological findings.

History and Physical

When evaluating a patient suspected of adrenal crisis, clinicians must thoroughly review the patient's medical history and past surgical history. If the patient is on chronic steroid therapy, compliance with medication is essential, as an adrenal crisis can be precipitated by both the abrupt cessation of steroids or if the patient had an acute stress event and did not increase their steroid dose enough. Additional historical elements that may assist with diagnosis include recent illnesses (eg, gastroenteritis), surgeries, traumatic injuries, or other stressors. Family or a personal history of autoimmune diseases (eg, hypothyroidism or diabetes mellitus) raises the likelihood of other concurrent undiagnosed Addison disease. In addition, clinicians should review the patient's list of home medications and supplements, including inhaled steroids for asthma or COPD, topical steroid creams, and intra-articular injections, as knowing if a patient has a history of adrenal insufficiency or has been on maintenance steroids for any reason is crucial.[58][59]

Identifying any precipitating factors that may trigger an adrenal crisis in individuals is essential. Evaluating other autoimmune diseases in patients while obtaining their history is crucial, as individuals with autoimmune polyglandular endocrinopathy can manifest multiple autoimmune disorders. Furthermore, recurrent hypoglycemia in patients with type 1 diabetes on insulin can indicate adrenal insufficiency. Patients with adrenal crisis usually present with an unexplained shock resistant to standard fluid resuscitation and vasopressor therapy.[60] Given the significant mortality of an adrenal crisis, early recognition and treatment with glucocorticoids and mineralocorticoids (if warranted) is crucial. 

Initial clinical manifestations of adrenal crisis can be nonspecific, including weakness, fatigue, nausea, vomiting, fever, lower chest or abdominal pain, anorexia, back pain, dizziness, somnolence, and confusion. Without appropriate treatment, these symptoms can worsen, quickly developing into hypotension, altered mental status, and obtundation.[3][61] In children, adrenal crises can manifest as weight loss with failure to thrive and are accompanied by other features, including hypoglycemic crises, which may result in seizures. Less frequently observed presentations in individuals of all age groups range from an acute abdomen resembling a surgical emergency to nonspecific symptoms, including salt cravings, amenorrhea, loss of libido, and depression. 

Physical Examination

Assessing a patient's vital signs when evaluating for an adrenal crisis is essential. Patients experiencing an adrenal crisis may exhibit several symptoms, including fever, tachycardia, and orthostatic hypotension.[61] During physical examination, patients may appear visibly unwell. Individuals with primary adrenal insufficiency might display findings including skin and buccal mucosa hyperpigmentation and scarring.[62] Cushingoid signs may also be present, eg, facial fullness, dorsocervical fat pad, truncal obesity with striae, and hirsutism in those who take chronic steroids. Abdominal symptoms may take on features of acute abdomen.[63] Patients may have hyperpyrexia, with temperatures reaching 105 °F (40.5 °C) or higher.[5][20][41] As the patient's cortisol stores are depleted, they will eventually develop circulatory collapse with cyanosis and shock and eventual coma and death if not treated.

Evaluation

Initial laboratory testing should include serum chemistry, complete blood count with differential, cortisol level, ACTH, aldosterone, renin, and thyroid function.[63] In the context of an adrenal crisis, several laboratory abnormalities may be present. However, the classic laboratory findings associated with adrenal crisis include the following:

• Hyponatremia resulting from mineralocorticoid deficiency
• Hyperkalemia resulting from mineralocorticoid deficiency
• Hypoglycemia, stemming from decreased gluconeogenesis and glycogenolysis (more prevalent in children)
• Low or low normal ACTH levels, as observed in secondary adrenal insufficiency
• High or high normal ACTH levels, as observed in primary adrenal insufficiency
• Hypercalcemia, resulting from hypovolemia, increased 1,25 Vitamin D, or bone metabolism alterations (Please refer to the Pathophysiology section for more information)
• Elevated creatinine levels, attributed to prerenal failure
• High renin levels, as typically seen in primary adrenal insufficiency due to increased urinary sodium loss and reduced blood volume
• Normocytic normochromic anemia, lymphocytosis, and eosinophilia, resulting from glucocorticoid deficiency
• Increased TSH levels [15]

An acutely stressful event such as sepsis typically stimulates cortisol production, which decreases eosinophil counts. However, patients with adrenal insufficiency cannot increase their cortisol reserves. Thus, normal or increased eosinophil counts in an unstable patient raise the possibility of an adrenal etiology. Increased TSH levels can occur due to coexisting hypothyroidism in autoimmune polyglandular endocrinopathy or the absence of cortisol's inhibitory effect on TSH production. Per the Society for Endocrine Emergency Guidelines, thyroid hormone should not be replaced unless the TSH level is >10 mU/L.[15]

The treatment of adrenal crises should never be delayed to obtain blood work to determine the underlying etiology. Prompt administration of hydrocortisone is of the utmost importance in managing adrenal crises. However, if no delay in treatment is anticipated, blood work can be performed quickly before initiating hydrocortisone administration. In situations with diagnostic uncertainty and borderline cortisol levels, performing an ACTH stimulation test in the acute setting is not recommended until the patient's condition has stabilized.[64]

Additional Diagnostic Studies 

An electrocardiogram (ECG) may show peaked T waves from hyperkalemia or short QT interval from hypercalcemia. A chest radiograph, urine studies, and blood cultures should be ordered to evaluate for any infection. A computed tomography (CT) scan of the abdomen may show hemorrhage in the adrenals, calcification of the adrenals as seen with tuberculosis, or metastasis. In cases of secondary adrenal insufficiency, a head CT scan may show the destruction of the pituitary (ie, empty sella syndrome) or a pituitary mass lesion.[65]

Treatment / Management

An adrenal crisis requires prompt identification and treatment. This medical emergency necessitates maximal supportive care and monitoring in the intensive care unit. The administration of glucocorticoids, specifically hydrocortisone, constitutes the definitive treatment for adrenal crisis. In patients with known adrenal insufficiency, symptoms consistent with an adrenal crisis should be sufficient to initiate treatment. If a patient is medically unstable and is strongly suspected of adrenal insufficiency or crisis, stress dose steroids should be administered promptly.[66] The administrative dosing of stress dose steroids and fluid resuscitation differs in children from adults (see Table. Emergent Adrenal Crisis Management Guidelines). 

Table. Emergent Adrenal Crisis Management Guidelines

In cases of adrenal crisis, involving an endocrinologist as soon as possible is crucial to ensure appropriate management of the condition and guidance in patient care. Recent evidence indicates that continuous infusion is a superior delivery method for hydrocortisone in the management of adrenal crises when compared to intermittent boluses.[68] Continuous hydrocortisone infusion has shown better maintenance of cortisol levels within the therapeutic range. Once there is clinical improvement, initiating a gradual tapering of steroids is advisable.[69] This approach helps prevent abrupt discontinuation and enables a smoother transition to lower doses. 

The necessity for mineralocorticoid replacement should be assessed individually and in consultation with an endocrinologist. Mineralocorticoid replacement is unnecessary if the glucocorticoid doses administered to patients exceed 50 mg.[70] In situations where hydrocortisone is unavailable, the following alternative parenteral glucocorticoids can be considered:[3][31](A1)

• Prednisolone: A preferred alternative treatment, prednisolone is administered as an initial bolus of 25 mg, followed by 2 additional 25 mg doses within the first 24 hours. Subsequently, this regimen should be continued with a daily dose of 50 mg of prednisone.
• Methylprednisolone: This can be administered at a dosage of 40 mg every 24 hours.
• Dexamethasone: This alternative is the least preferred, with a recommended dosage of 4 mg every 24 hours.

In patients with an infectious process as the precipitating event for adrenal crisis, prompt administration of appropriate antibiotics is necessary to address the underlying infection. 

Differential Diagnosis

An adrenal crisis is rarely an isolated event and has a wide array of differential diagnoses, depending on the presentation and underlying etiology. Although symptoms such as altered mental status, abdominal pain, nausea, vomiting, and fever are frequently encountered during presentations, hypotension typically remains the most significant feature. An adrenal crisis should be considered the primary differential diagnosis for patients with a known history of adrenal insufficiency and experiencing related symptoms.[71] 

Further investigation is necessary to determine the underlying cause of the adrenal crisis and potential secondary triggers. In patients without a known adrenal pathology and exhibiting hypotension resistant to fluid administration and vasopressor support, the diagnosis of adrenal crisis should be strongly considered.[5] Differential diagnoses that should also be considered include: 

• Shock
  • Cardiogenic
  • Obstructive
  • Distributive
  • Hypovolemic
  • Septic
• Cardiac
  • Acute myocardial infarction
• Endocrine
  • Thyrotoxicosis
  • Diabetic ketoacidosis
  • Hyperosmolar hyperglycemic state
  • Myxedema coma
  • Pituitary adenoma
• Gastrointestinal
  • Dehydration
  • Gastroenteritis
  • Poor oral intake
  • Acute abdomen (eg, appendicitis, diverticulitis, obstruction)
• Hematology and oncology
  • History of melanoma, breast cancers, or immunotherapy with a checkpoint inhibitor
  • Malignancy
• Obstetrics
  • Pregnancy
  • Hyperemesis gravidarum
• Infectious
  • Acute localized or systemic infection
• Stressors
  • Trauma 
  • Recent surgery
  • Psychological stress

Prognosis

Despite the potential for successful treatment with prompt administration of glucocorticoids, the associated mortality rate remains unacceptably high for adrenal crisis. Due to its rarity, many healthcare professionals may have limited familiarity with the presentation and management of adrenal crises. A retrospective study in the United Kingdom revealed that adrenal crisis contributed to 10% of the deaths in patients with primary and secondary adrenal insufficiency.[72] 

Patients whose adrenal crisis is quickly identified and given prompt treatment with IV fluids and parenteral steroids have a good prognosis and recovery. Those who are critically ill with significantly altered mental status, advanced endocrinopathies (eg, severe diabetes and uncontrolled thyroid disease), or multiple comorbidities have an increased risk of mortality and residual disability. The patient may need physical or occupational therapy and rehabilitation to regain independent function. 

Complications

An adrenal crisis can result in fatal outcomes, even with timely recognition and appropriate treatment.[2] Besides the risk of death, adrenal crisis is associated with other potential complications. Electrolyte abnormalities, such as hyponatremia, hyperkalemia, and hypoglycemia, can lead to various complications, including seizures, arrhythmias, and coma.[71] If left untreated, hypotension can lead to hypoperfusion, potentially resulting in multiple organ failure. Furthermore, the precipitating disease or event that triggered the adrenal crisis can introduce additional complications.[62]

Despite receiving steroid replacement therapy, individuals who have experienced adrenal crises often face significant challenges in their quality of life. Studies have indicated that many individuals suffer from disabilities and are unable to work due to conditions such as depression and chronic fatigue, thereby leading to a poor quality of life.[73] 

Adrenal crises continue to maintain an unacceptably high mortality rate. Although the exact cause of mortality may not be apparent in all cases, experts believe it to be attributed to respiratory infections, adverse cardiovascular events, and stroke.[1] Despite extensive efforts in patient education, the incidence of adrenal crisis–related mortality remains significant. A study involving 423 participants reported an adrenal crisis–related mortality rate as high as 6%.[19] In a previous study, patient satisfaction with managing adrenal crises in the emergency setting was as low as 66%.[74]