Cushing's disease
Definition
Pituitary corticotroph adenomas secrete inappropriate amounts of ACTH, which results in disorderly and excessive production of cortisol by the adrenal gland 1).
Cushing's disease (also known as Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease) is a cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from Pituitary Corticotroph adenoma.
Pituitary corticotroph adenoma (Functional ACTH-PAs (Cushing's disease) are the most common cause of Cushing's syndrome (hypercortisolemia from any source) and account for an estimated 70% of all cases 2).
It's important to note that Cushing's disease is different from Cushing's syndrome, which refers to the condition of having excess cortisol in the body, regardless of the cause.
Epidemiology
Classification
Etiology
Pathogenesis
Pathophysiology
The pathophysiology of Cushing’s disease involves complex disruptions in the hypothalamic-pituitary-adrenal (HPA) axis, leading to excess cortisol production. The core elements of this pathophysiology include:
1. Overproduction of ACTH: Cushing's disease is characterized by a pituitary corticotroph adenoma that secretes excessive amounts of adrenocorticotropic hormone (ACTH). In a normal HPA axis, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to produce ACTH. ACTH then stimulates the adrenal glands to produce cortisol. In Cushing’s disease, the pituitary adenoma produces unregulated, excessive ACTH, independent of CRH stimulation, leading to increased cortisol secretion by the adrenal glands. 2. Increased Cortisol Production: The excess ACTH leads to continuous stimulation of the adrenal cortex, causing hypercortisolemia (elevated cortisol levels in the blood). Cortisol normally follows a diurnal rhythm, with higher levels in the morning and lower levels at night. In Cushing's disease, this rhythm is disrupted, resulting in persistently high cortisol levels throughout the day. 3. Loss of Negative Feedback: Normally, high levels of cortisol provide negative feedback to the hypothalamus and pituitary gland, reducing the release of CRH and ACTH. However, in Cushing’s disease, the pituitary adenoma does not respond to this negative feedback, leading to continued ACTH and cortisol overproduction. 4. Adrenal Hyperplasia: Chronic ACTH stimulation causes bilateral adrenal hyperplasia (enlargement of the adrenal glands), which further amplifies cortisol production. The adrenal cortex becomes hypertrophic due to persistent stimulation by ACTH, leading to increased glucocorticoid synthesis. 5. Systemic Effects of Excess Cortisol: The elevated cortisol levels lead to a variety of systemic manifestations, which are characteristic of Cushing’s syndrome. These include:
Metabolic effects: Increased gluconeogenesis, causing hyperglycemia and potential diabetes. Increased lipolysis, leading to central obesity, with fat deposition in the face (moon face), neck (buffalo hump), and abdomen. Muscle catabolism and protein breakdown, leading to muscle weakness, thin skin, and easy bruising. Cardiovascular effects: Hypertension is common due to cortisol’s effects on sodium retention and activation of the renin-angiotensin-aldosterone system (RAAS). Immune suppression: Cortisol has strong anti-inflammatory and immunosuppressive effects, leading to increased susceptibility to infections and delayed wound healing. Bone effects: Osteoporosis due to increased bone resorption and decreased bone formation. Psychological effects: Mood changes, including depression, anxiety, and even psychosis. 6. ACTH-Dependent Cortisol Excess vs. Other Forms of Cushing’s Syndrome: In Cushing’s disease, the cortisol excess is ACTH-dependent because the primary pathology is in the pituitary gland. This contrasts with ACTH-independent Cushing’s syndrome, where cortisol excess is due to autonomous cortisol production from adrenal tumors or hyperplasia. 7. Ectopic ACTH Syndrome (Differentiation): Ectopic ACTH syndrome is another ACTH-dependent cause of Cushing’s syndrome, often resulting from ACTH secretion by non-pituitary tumors (e.g., small-cell lung carcinoma). Differentiating Cushing’s disease from ectopic ACTH syndrome can be challenging but is important in determining the source of ACTH overproduction. Summary of Key Pathophysiological Steps: Pituitary adenoma produces excess ACTH. ACTH overstimulates adrenal glands, causing increased cortisol production. Loss of negative feedback leads to continuous ACTH and cortisol secretion. Systemic effects of cortisol excess cause metabolic, cardiovascular, musculoskeletal, immune, and psychological complications. In summary, Cushing's disease results from a pituitary adenoma that disrupts the normal HPA axis, leading to excessive cortisol production and widespread systemic effects.
Clinical Features
Diagnosis
Differential diagnosis
Treatment
Cushing's disease prognosis
Complications
Cushing's disease leads to numerous complications due to chronic exposure to elevated cortisol levels. These complications affect multiple organ systems and can have significant long-term health consequences. Here are the key complications:
1. Metabolic Complications: Diabetes mellitus: Chronic hypercortisolism induces insulin resistance and increases hepatic gluconeogenesis, leading to hyperglycemia and the development of type 2 diabetes. Dyslipidemia: Elevated cortisol levels increase triglycerides and LDL cholesterol while lowering HDL cholesterol, contributing to an atherogenic lipid profile. Weight gain and central obesity: Cortisol promotes fat redistribution, resulting in truncal obesity, moon face, and a buffalo hump (fat pad on the back of the neck). 2. Cardiovascular Complications: Hypertension: Chronic cortisol excess activates the renin-angiotensin-aldosterone system (RAAS) and enhances vascular sensitivity to catecholamines, leading to persistent high blood pressure. Atherosclerosis: Due to the combination of hypertension, diabetes, and dyslipidemia, there is an increased risk of atherosclerosis, which can lead to coronary artery disease, myocardial infarction, and stroke. Heart failure: Prolonged hypertension and metabolic stress can lead to left ventricular hypertrophy and ultimately, heart failure. 3. Musculoskeletal Complications: Osteoporosis: Cortisol increases bone resorption by stimulating osteoclast activity and decreases bone formation by inhibiting osteoblast function, leading to osteoporosis and an increased risk of fractures, particularly vertebral compression fractures. Muscle weakness and atrophy: Cortisol promotes protein breakdown, leading to proximal muscle weakness and muscle wasting (often seen in the upper arms and thighs). 4. Immune System Complications: Immunosuppression: Cortisol has potent anti-inflammatory effects, reducing immune function and increasing the risk of infections, including skin infections, respiratory infections, and delayed healing of wounds. Opportunistic infections: Patients may develop opportunistic infections such as pneumocystis pneumonia or fungal infections due to long-term immunosuppression. 5. Psychological and Cognitive Complications: Depression and anxiety: Chronic cortisol excess is associated with a higher risk of depressive disorders, anxiety, and mood disturbances. Cognitive impairment: Patients may experience memory problems, concentration difficulties, and emotional instability. In severe cases, this may lead to psychosis. Sleep disturbances: Disrupted diurnal rhythm of cortisol secretion often leads to insomnia and poor-quality sleep. 6. Skin and Hair Complications: Thin, fragile skin: Cortisol affects collagen production, leading to easy bruising, skin atrophy, and poor wound healing. Striae (stretch marks): Wide, purplish striae, especially on the abdomen, thighs, and breasts, are common due to the weakening of the skin and rapid weight gain. Hirsutism and acne: Cortisol excess can increase androgen production, leading to excessive hair growth (hirsutism) in women and acne. 7. Reproductive and Hormonal Complications: Menstrual irregularities: Women with Cushing’s disease often experience amenorrhea or oligomenorrhea due to disruption of the hypothalamic-pituitary-gonadal axis. Infertility: Both men and women may experience reduced fertility due to hormonal imbalances, including reduced gonadotropin secretion. Erectile dysfunction: In men, cortisol excess can lead to decreased libido and erectile dysfunction. 8. Complications from Chronic Cortisol Exposure: Glaucoma and cataracts: Chronic glucocorticoid exposure is associated with an increased risk of glaucoma and cataract formation. Peptic ulcers: Excess cortisol stimulates gastric acid secretion, increasing the risk of gastric ulcers and gastrointestinal bleeding. 9. Increased Mortality Risk: Patients with untreated or poorly controlled Cushing’s disease have an increased risk of premature mortality, primarily due to cardiovascular complications (hypertension, coronary artery disease, stroke) and metabolic disorders (diabetes). Thromboembolism: Cushing’s disease increases the risk of deep vein thrombosis (DVT) and pulmonary embolism due to hypercoagulability. 10. Post-Surgical Complications: Adrenal insufficiency: After surgery to remove a pituitary adenoma (the primary treatment for Cushing's disease), patients may develop secondary adrenal insufficiency, requiring glucocorticoid replacement therapy until the HPA axis recovers. Tumor recurrence: There is a risk of pituitary adenoma recurrence after surgery, which may necessitate further interventions such as repeat surgery, radiation therapy, or medical management. In summary, the complications of Cushing’s disease are widespread, involving metabolic, cardiovascular, musculoskeletal, immune, and psychological systems. Early diagnosis and treatment are crucial to prevent or mitigate these complications.
Multicenter retrospective cohort studies
Despite growing interest in how patient frailty affects outcomes (eg, in neuro-oncology), its role after transsphenoidal surgery for Cushing disease (CD) remains unclear. They evaluated the effect of frailty on CD outcomes using the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) data set from a collaboration of US academic pituitary centers.
Data on consecutive surgically treated patients with CD (2011-2023) were compiled using the 11-factor modified frailty index. Patients were classified as fit (score, 0-1), managing well (score, 2-3), and mildly frail (score, 4-5). Univariable and multivariable analyses were conducted to examine outcomes.
Data were analyzed for 318 patients (193 fit, 113 managing well, 12 mildly frail). Compared with fit and managing well patients, mildly frail patients were older (mean ± SD 39.7 ± 14.2 and 48.9 ± 12.2 vs 49.4 ± 8.9 years, P < .001) but did not different by sex, race, and other factors. They had significantly longer hospitalizations (3.7 ± 2.0 and 4.5 ± 3.5 vs 5.3 ± 3.5 days, P = .02), even after multivariable analysis (β = 1.01, P = .007) adjusted for known predictors of prolonged hospitalization (age, Knosp grade, surgeon experience, American Society of Anesthesiologists grade, complications, frailty). Patients with mild frailty were more commonly discharged to skilled nursing facilities (0.5% [1/192] and 4.5% [5/112] vs 25% [3/12], P < .001). Most patients underwent gross total resection (84.4% [163/193] and 79.6% [90/113] vs 83% [10/12]). No difference in overall complications was observed; however, venous thromboembolism was more common in mildly frail (8%, 1/12) than in fit (0.5%, 1/193) and managing well (2.7%, 3/113) patients ( P = .04). No difference was found in 90-day readmission rates.
These results demonstrate that mild frailty predicts CD surgical outcomes and may inform preoperative risk stratification. Frailty-influenced outcomes other than age and tumor characteristics may be useful for prognostication. Future studies can help identify strategies to reduce the disease burden for frail patients with hypercortisolemia 3).
Case series
Case reports
A study reports a rare case of a 50-year-old female patient who presented with typical clinical features of Cushing's disease and was diagnosed with isolated double ACTH-secreting pituitary neuroendocrine tumors. Endocrinological examination revealed an ACTH-producing pituitary neuroendocrine tumor, and preoperative magnetic resonance imaging (MRI) demonstrated a microadenoma with a lower intensity on the right side of the pituitary gland. The patient underwent endoscopic endonasal transsphenoidal surgery, which revealed another pituitary tumor in the left side of the pituitary gland. The two, clearly separated, pituitary neuroendocrine tumors identified in the same gland were completely resected. Immunohistochemistry and pathology revealed that the clearly separated double pituitary neuroendocrine tumors were positive for ACTH, thyroid-stimulating, growth and prolactin hormones. Postoperatively, the levels of ACTH and cortisol hormone decreased rapidly. The case reported in the present study is considerably rare, due to the presence of a second pituitary neuroendocrine tumor in the same gland, which was not detected by preoperative MRI scan, but was noticed during surgery. Intraoperative evaluation may be important in the identification of double or multiple pituitary neuroendocrine tumors 4).