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Emergency And Acute Medicine – Cushing Syndrome
Overview
Cushing disease refers specifically to excess adrenocorticotropic hormone (ACTH) production from a pituitary adenoma. Cushing syndrome describes the clinical state resulting from prolonged exposure to excessive glucocorticoids, regardless of the source.
Predisposing Factors
Genetic associations include multiple endocrine neoplasia type I and Carney complex, which is characterized by pigmented lentigines, atrial myxomas, and germ-cell tumors associated with Cushing disease.
Underlying Causes
The most common cause is exogenous glucocorticoid administration, whether therapeutic or surreptitious. Endogenous causes include ACTH-secreting pituitary adenomas, adrenal cortisol overproduction from adenoma, carcinoma, or micronodular disease, and ectopic ACTH production. Tumors associated with ectopic ACTH secretion include small cell lung carcinoma (most common), uterine cervical carcinoma, pancreatic islet cell tumors associated with MEN I, medullary thyroid carcinoma, pheochromocytoma, ganglioneuroma, melanoma, prostate carcinoma, and carcinoid tumors arising from the lung, pancreas, gastrointestinal tract, thymus, or ovary.
Clinical Recognition
The most critical emergency consideration is recognizing the risk of addisonian (adrenal) crisis during periods of physiologic stress. While Cushing syndrome itself is not usually an emergency diagnosis, early identification in the emergency setting may prevent significant morbidity and mortality.
In children, suspicion should be raised when obesity progresses in the absence of normal linear growth. During pregnancy, Cushing syndrome is rare but has been associated with severe preeclampsia and HELLP syndrome.
History And Physical Findings
Patients may have a prior diagnosis of Cushing disease or a history of corticosteroid use. Changes in weight, facial appearance, hirsutism, or psychiatric symptoms are important historical clues.
On examination, characteristic findings include moon facies, a dorsocervical fat pad (buffalo hump), central obesity with thin extremities, and supraclavicular fat deposition. These features are particularly concerning in stressed patients because of the risk of adrenal crisis.
Cardiovascular manifestations include uncontrolled hypertension. Neurologic findings may include stroke, pseudotumor cerebri (especially with exogenous steroid use), or spinal lipomatosis causing cord or nerve root compression. Gastrointestinal complications include peptic ulcer disease, gastrointestinal hemorrhage, pancreatitis, and fatty liver. Psychiatric manifestations are common and include mood disorders, depression, memory impairment, euphoria, and toxic psychosis.
Musculoskeletal findings include proximal muscle weakness, pathologic fractures, osteoporosis, and avascular necrosis of the humeral or femoral heads. Endocrine effects include glucose intolerance, hyperlipidemia, amenorrhea, hirsutism, or male-pattern balding in females. Hematologic changes include neutrophilia with lymphopenia and eosinopenia, increasing susceptibility to opportunistic infections. Ophthalmologic complications include cataracts and glaucoma, particularly with exogenous steroid use. Dermatologic features include wide purple striae, hyperpigmentation of the buccal mucosa due to excess ACTH, facial plethora, thin skin, poor wound healing, easy bruising, acne, and hyperhidrosis.
Essential Emergency Evaluation
Definitive diagnosis cannot be established in the emergency department. The priority is identifying patients at risk for addisonian crisis and managing concurrent life-threatening conditions such as myocardial infarction, stroke, sepsis, pathologic fractures, uncontrolled diabetes, or psychiatric emergencies requiring admission.
Diagnostic Studies
Laboratory evaluation may reveal hypokalemia with metabolic alkalosis, diminished glucose tolerance, overt diabetes, glycosuria, leukocytosis, and eosinopenia. Electrocardiography is useful to evaluate for myocardial ischemia, and chest radiography may identify tumors producing ectopic ACTH. Plain radiographs may be indicated if pathologic fractures are suspected and may show delayed bone age.
Definitive outpatient testing includes pituitary MRI, adrenal CT imaging, and dexamethasone suppression testing. Low-dose dexamethasone testing is used as a screening tool, though false positives are common. High-dose dexamethasone suppression testing may be required to confirm endogenous Cushing syndrome.
Alternative Diagnoses To Consider
Conditions that may mimic Cushing syndrome include alcohol-induced pseudo-Cushing syndrome, obesity, psychiatric disorders such as depression or panic disorder, and physiologic states including chronic stress, late pregnancy, and chronic strenuous exercise.
Emergency Management
Patients with iatrogenic Cushing syndrome may develop acute addisonian crisis during stress. These patients can also exhibit severe behavioral disturbances. The leading causes of death in untreated Cushing syndrome are infection, stroke, and myocardial infarction.
Initial management focuses on preventing adrenal crisis and treating associated complications. This includes intravenous fluids, glucose control, blood pressure management, appropriate cultures and antibiotics for suspected infection, and prompt treatment of cardiovascular or neurologic emergencies. Stress-dose steroids with hydrocortisone should be administered in patients with suspected adrenal crisis.
Medications that reduce cortisol production are rarely initiated in the emergency setting and should only be started under endocrinology guidance in patients with severe symptoms awaiting definitive therapy.
Definitive Therapy
Management depends on etiology. Exogenous steroid exposure requires gradual tapering when feasible, along with calcium, vitamin D, and estrogen supplementation if appropriate. Pituitary-dependent disease is treated with transsphenoidal surgery, with radiation reserved for refractory cases. Adrenal tumors require surgical resection, with medical therapy for unresectable metastatic disease. Ectopic ACTH-producing tumors are treated with surgical resection when possible and medical therapy otherwise.
Medications
Hydrocortisone is indicated only in adrenal crisis and is given intravenously. Additional agents such as ketoconazole, metyrapone, aminoglutethimide, mifepristone, mitotane, cyproheptadine, bromocriptine, pasireotide, or spironolactone may be used for symptomatic control under specialist supervision.
Disposition And Follow-Up
Hospital admission is required for patients with complications such as myocardial infarction, stroke, sepsis, pathologic fracture, uncontrolled diabetes, psychiatric emergencies, or impending adrenal crisis. Stable patients without these features may be discharged with close follow-up.
Referral And Long-Term Care
All patients with suspected Cushing syndrome require referral for definitive evaluation. Conditions secondary to hypercortisolism should be addressed concurrently.
Practical Insights And Common Pitfalls
Maintain a high index of suspicion in physiologically stressed patients with characteristic body habitus, especially those with supraclavicular fat pads. Early recognition is essential to prevent addisonian crisis and associated morbidity.
Overview
Cushing disease refers specifically to excess adrenocorticotropic hormone (ACTH) production from a pituitary adenoma. Cushing syndrome describes the clinical state resulting from prolonged exposure to excessive glucocorticoids, regardless of the source.
Predisposing Factors
Genetic associations include multiple endocrine neoplasia type I and Carney complex, which is characterized by pigmented lentigines, atrial myxomas, and germ-cell tumors associated with Cushing disease.
Underlying Causes
The most common cause is exogenous glucocorticoid administration, whether therapeutic or surreptitious. Endogenous causes include ACTH-secreting pituitary adenomas, adrenal cortisol overproduction from adenoma, carcinoma, or micronodular disease, and ectopic ACTH production. Tumors associated with ectopic ACTH secretion include small cell lung carcinoma (most common), uterine cervical carcinoma, pancreatic islet cell tumors associated with MEN I, medullary thyroid carcinoma, pheochromocytoma, ganglioneuroma, melanoma, prostate carcinoma, and carcinoid tumors arising from the lung, pancreas, gastrointestinal tract, thymus, or ovary.
Clinical Recognition
The most critical emergency consideration is recognizing the risk of addisonian (adrenal) crisis during periods of physiologic stress. While Cushing syndrome itself is not usually an emergency diagnosis, early identification in the emergency setting may prevent significant morbidity and mortality.
In children, suspicion should be raised when obesity progresses in the absence of normal linear growth. During pregnancy, Cushing syndrome is rare but has been associated with severe preeclampsia and HELLP syndrome.
History And Physical Findings
Patients may have a prior diagnosis of Cushing disease or a history of corticosteroid use. Changes in weight, facial appearance, hirsutism, or psychiatric symptoms are important historical clues.
On examination, characteristic findings include moon facies, a dorsocervical fat pad (buffalo hump), central obesity with thin extremities, and supraclavicular fat deposition. These features are particularly concerning in stressed patients because of the risk of adrenal crisis.
Cardiovascular manifestations include uncontrolled hypertension. Neurologic findings may include stroke, pseudotumor cerebri (especially with exogenous steroid use), or spinal lipomatosis causing cord or nerve root compression. Gastrointestinal complications include peptic ulcer disease, gastrointestinal hemorrhage, pancreatitis, and fatty liver. Psychiatric manifestations are common and include mood disorders, depression, memory impairment, euphoria, and toxic psychosis.
Musculoskeletal findings include proximal muscle weakness, pathologic fractures, osteoporosis, and avascular necrosis of the humeral or femoral heads. Endocrine effects include glucose intolerance, hyperlipidemia, amenorrhea, hirsutism, or male-pattern balding in females. Hematologic changes include neutrophilia with lymphopenia and eosinopenia, increasing susceptibility to opportunistic infections. Ophthalmologic complications include cataracts and glaucoma, particularly with exogenous steroid use. Dermatologic features include wide purple striae, hyperpigmentation of the buccal mucosa due to excess ACTH, facial plethora, thin skin, poor wound healing, easy bruising, acne, and hyperhidrosis.
Essential Emergency Evaluation
Definitive diagnosis cannot be established in the emergency department. The priority is identifying patients at risk for addisonian crisis and managing concurrent life-threatening conditions such as myocardial infarction, stroke, sepsis, pathologic fractures, uncontrolled diabetes, or psychiatric emergencies requiring admission.
Diagnostic Studies
Laboratory evaluation may reveal hypokalemia with metabolic alkalosis, diminished glucose tolerance, overt diabetes, glycosuria, leukocytosis, and eosinopenia. Electrocardiography is useful to evaluate for myocardial ischemia, and chest radiography may identify tumors producing ectopic ACTH. Plain radiographs may be indicated if pathologic fractures are suspected and may show delayed bone age.
Definitive outpatient testing includes pituitary MRI, adrenal CT imaging, and dexamethasone suppression testing. Low-dose dexamethasone testing is used as a screening tool, though false positives are common. High-dose dexamethasone suppression testing may be required to confirm endogenous Cushing syndrome.
Alternative Diagnoses To Consider
Conditions that may mimic Cushing syndrome include alcohol-induced pseudo-Cushing syndrome, obesity, psychiatric disorders such as depression or panic disorder, and physiologic states including chronic stress, late pregnancy, and chronic strenuous exercise.
Emergency Management
Patients with iatrogenic Cushing syndrome may develop acute addisonian crisis during stress. These patients can also exhibit severe behavioral disturbances. The leading causes of death in untreated Cushing syndrome are infection, stroke, and myocardial infarction.
Initial management focuses on preventing adrenal crisis and treating associated complications. This includes intravenous fluids, glucose control, blood pressure management, appropriate cultures and antibiotics for suspected infection, and prompt treatment of cardiovascular or neurologic emergencies. Stress-dose steroids with hydrocortisone should be administered in patients with suspected adrenal crisis.
Medications that reduce cortisol production are rarely initiated in the emergency setting and should only be started under endocrinology guidance in patients with severe symptoms awaiting definitive therapy.
Definitive Therapy
Management depends on etiology. Exogenous steroid exposure requires gradual tapering when feasible, along with calcium, vitamin D, and estrogen supplementation if appropriate. Pituitary-dependent disease is treated with transsphenoidal surgery, with radiation reserved for refractory cases. Adrenal tumors require surgical resection, with medical therapy for unresectable metastatic disease. Ectopic ACTH-producing tumors are treated with surgical resection when possible and medical therapy otherwise.
Medications
Hydrocortisone is indicated only in adrenal crisis and is given intravenously. Additional agents such as ketoconazole, metyrapone, aminoglutethimide, mifepristone, mitotane, cyproheptadine, bromocriptine, pasireotide, or spironolactone may be used for symptomatic control under specialist supervision.
Disposition And Follow-Up
Hospital admission is required for patients with complications such as myocardial infarction, stroke, sepsis, pathologic fracture, uncontrolled diabetes, psychiatric emergencies, or impending adrenal crisis. Stable patients without these features may be discharged with close follow-up.
Referral And Long-Term Care
All patients with suspected Cushing syndrome require referral for definitive evaluation. Conditions secondary to hypercortisolism should be addressed concurrently.
Practical Insights And Common Pitfalls
Maintain a high index of suspicion in physiologically stressed patients with characteristic body habitus, especially those with supraclavicular fat pads. Early recognition is essential to prevent addisonian crisis and associated morbidity.
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