Why does adrenal crisis often present with fever?

Fever in Adrenal Crisis: Pathophysiological Mechanisms

Fever in adrenal crisis occurs primarily due to the dysregulated inflammatory response caused by cortisol deficiency, which leads to excessive pro-inflammatory cytokine release and heightened sensitivity to these cytokines. 1

Pathophysiological Mechanisms of Fever in Adrenal Crisis

Dysregulated Inflammatory Response

• Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and increases sensitivity to the toxic effects of these cytokines (e.g., tumor necrosis factor alpha) 1
• Pro-inflammatory cytokines may impair glucocorticoid receptor function, further aggravating glucocorticoid deficiency 1
• This dysregulated inflammatory response leads to fever as a cardinal symptom of adrenal crisis 2

Infection as a Precipitating Factor

• Infections are the major precipitating causes of adrenal crisis, with gastrointestinal infections being particularly common 2, 1
• The body's inability to mount an appropriate cortisol response to infection leads to an exaggerated inflammatory reaction, manifesting as fever 3
• Around half of the patients affected by adrenal crisis report a previous crisis, usually precipitated by gastroenteritis or fever 4

Cytokine-Mediated Temperature Dysregulation

• Without adequate cortisol, there is unchecked production of pyrogenic cytokines that act on the hypothalamus to raise the temperature set point 1
• This mechanism is similar to fever in other conditions but is exacerbated by the absence of cortisol's normal anti-inflammatory effects 3

Clinical Presentation of Fever in Adrenal Crisis

Fever as a Cardinal Symptom

• Fever is one of the common presenting symptoms in adrenal crisis, along with malaise, fatigue, nausea, vomiting, abdominal pain, and hypotension 3, 2
• The presence of fever may initially mislead clinicians to focus solely on infectious causes, potentially delaying recognition of underlying adrenal insufficiency 5

Associated Clinical Features

• Hyperpigmentation of skin (in primary adrenal insufficiency) due to elevated ACTH levels 2
• Hypotension and dehydration are cardinal manifestations requiring immediate intervention 6
• Neurological manifestations may include impaired cognitive function, confusion, loss of consciousness, and coma 2

Diagnostic and Treatment Implications

Recognizing Fever in the Context of Adrenal Crisis

• Fever in a patient with known adrenal insufficiency should prompt immediate consideration of adrenal crisis 3
• Laboratory findings typically include hyponatremia, hyperkalemia, increased creatinine, hypoglycemia, and sometimes mild hypercalcemia 2, 7

Treatment Approach

• Immediate administration of hydrocortisone 100 mg IV bolus, without waiting for diagnostic confirmation 6
• Begin fluid resuscitation with 0.9% saline 1L over the first hour, followed by 3-4L over 24-48 hours 3
• Continue glucocorticoid administration with hydrocortisone 100-300 mg/day, either as continuous IV infusion or divided IV/IM boluses every 6 hours 3, 6

Prevention Strategies

Patient Education

• Comprehensive education on stress dosing during illness or fever is essential 6
• Instructions to double or triple oral glucocorticoid dose during minor illness and to use parenteral hydrocortisone during severe illness 2
• Ensuring patients have emergency supplies, including injectable hydrocortisone 6

Medical Identification

• Recommend medical alert jewelry and emergency steroid card 2
• This is crucial for prompt recognition and treatment of adrenal crisis, especially when fever might otherwise be attributed solely to infection 6

Clinical Pitfalls to Avoid

• Do not delay hydrocortisone administration in suspected adrenal crisis while waiting for diagnostic confirmation 3
• Do not underestimate the significance of fever in patients with adrenal insufficiency, as it may indicate impending crisis 5
• Remember that both hypercalcemia and adrenal insufficiency may present with similar non-specific symptoms, including fever 7
• Be aware that adrenal crisis can be precipitated by medications (such as fluconazole), not just obvious stressors like infections 7