Cushing's disease
Introduction
Cushing's disease is a rare endocrine disorder characterized by the excessive production of adrenocorticotropic hormone (ACTH), leading to hypercortisolism. This condition is specifically caused by a pituitary adenoma, a benign tumor of the pituitary gland, which results in the overproduction of ACTH. The disease is named after the American neurosurgeon Harvey Cushing, who first described it in 1912. Cushing's disease is a subset of Cushing's syndrome, which encompasses all causes of excess cortisol, including adrenal tumors and ectopic ACTH production.
Pathophysiology
Cushing's disease arises from a pituitary adenoma, which secretes excessive ACTH. ACTH stimulates the adrenal glands to produce cortisol, a glucocorticoid hormone involved in various physiological processes, including metabolism, immune response, and stress response. The chronic overproduction of cortisol leads to the clinical manifestations of Cushing's disease. The feedback mechanism that normally regulates cortisol production is disrupted, as the pituitary adenoma is insensitive to the inhibitory effects of high cortisol levels.
Pituitary Adenomas
Pituitary adenomas are classified based on their size and hormone production. Microadenomas are less than 10 mm in diameter, while macroadenomas are 10 mm or larger. In Cushing's disease, the adenomas are typically microadenomas, although macroadenomas can also occur. These tumors are usually benign and slow-growing, but their location within the pituitary gland can lead to significant clinical symptoms due to hormone overproduction and potential compression of surrounding structures.
Clinical Manifestations
The clinical manifestations of Cushing's disease are primarily due to the effects of chronic hypercortisolism. These symptoms can be diverse and affect multiple organ systems.
Metabolic Effects
Patients with Cushing's disease often present with central obesity, characterized by fat deposition in the face (moon face), neck (buffalo hump), and trunk. Peripheral muscle wasting and weakness are common due to protein catabolism. Hyperglycemia and insulin resistance can lead to diabetes mellitus. Dyslipidemia, characterized by elevated triglycerides and low high-density lipoprotein (HDL) cholesterol, is also frequently observed.
Cardiovascular Effects
Hypertension is a common feature of Cushing's disease, resulting from the mineralocorticoid effects of cortisol and increased vascular sensitivity to catecholamines. Patients are at increased risk for cardiovascular disease, including myocardial infarction and stroke, due to the combined effects of hypertension, dyslipidemia, and hyperglycemia.
Musculoskeletal Effects
Osteoporosis is a significant complication of Cushing's disease, resulting from the inhibitory effects of cortisol on bone formation and increased bone resorption. Patients may experience fractures, particularly in the vertebrae and ribs. Proximal muscle weakness is also common due to the catabolic effects of cortisol on muscle tissue.
Dermatological Effects
Skin changes are prominent in Cushing's disease. Patients often have thin, fragile skin that bruises easily. Purple striae (stretch marks) are commonly seen on the abdomen, thighs, and breasts. Acne and hirsutism (excessive hair growth) may also occur due to the androgenic effects of cortisol.
Neuropsychiatric Effects
Cushing's disease can have significant neuropsychiatric effects, including depression, anxiety, cognitive impairment, and emotional lability. These symptoms are thought to result from the direct effects of cortisol on the brain and the psychological impact of chronic illness.
Diagnosis
The diagnosis of Cushing's disease involves a combination of clinical evaluation, biochemical testing, and imaging studies.
Biochemical Testing
Initial biochemical testing aims to confirm hypercortisolism. This can be achieved through several methods:
- 24-hour urinary free cortisol (UFC) measurement: Elevated UFC levels indicate increased cortisol production.
- Late-night salivary cortisol: Elevated levels suggest loss of the normal diurnal variation of cortisol secretion.
- Low-dose dexamethasone suppression test (LDDST): Failure to suppress cortisol production after administration of dexamethasone indicates autonomous cortisol production.
Once hypercortisolism is confirmed, further testing is required to determine the source of excess ACTH. This includes:
- Plasma ACTH levels: Elevated ACTH levels suggest a pituitary or ectopic source, while low levels indicate an adrenal source.
- High-dose dexamethasone suppression test (HDDST): Suppression of cortisol production with high-dose dexamethasone suggests a pituitary source (Cushing's disease), while lack of suppression suggests an ectopic source.
Imaging Studies
Magnetic resonance imaging (MRI) of the pituitary gland is the preferred imaging modality to identify pituitary adenomas. In cases where MRI is inconclusive, inferior petrosal sinus sampling (IPSS) may be performed to differentiate between pituitary and ectopic sources of ACTH.
Treatment
The primary treatment for Cushing's disease is the surgical removal of the pituitary adenoma. Medical therapy and radiation therapy are considered in cases where surgery is not feasible or is unsuccessful.
Surgical Treatment
Transsphenoidal surgery is the standard surgical approach for pituitary adenomas. This minimally invasive procedure involves accessing the pituitary gland through the sphenoid sinus. The goal is to remove the adenoma while preserving normal pituitary function. Surgical success rates are higher for microadenomas compared to macroadenomas.
Medical Therapy
Medical therapy is used as an adjunct to surgery or as primary treatment in patients who are not surgical candidates. Medications include:
- Steroidogenesis inhibitors (e.g., ketoconazole, metyrapone): These drugs inhibit cortisol synthesis in the adrenal glands.
- Pituitary-directed drugs (e.g., pasireotide, cabergoline): These drugs reduce ACTH production by the pituitary adenoma.
- Glucocorticoid receptor antagonists (e.g., mifepristone): These drugs block the effects of cortisol at the receptor level.
Radiation Therapy
Radiation therapy is considered for patients with persistent or recurrent disease after surgery. Stereotactic radiosurgery (e.g., Gamma Knife) is a precise form of radiation that targets the pituitary adenoma while minimizing damage to surrounding tissues.
Prognosis
The prognosis of Cushing's disease depends on several factors, including the size and invasiveness of the pituitary adenoma, the success of surgical treatment, and the presence of comorbid conditions. Early diagnosis and effective treatment are associated with better outcomes. However, patients may experience long-term complications, such as persistent hypercortisolism, hypopituitarism, and increased cardiovascular risk.