What is Cushing's Syndrome?

Cushing syndrome (CS), also known as hypercortisolism, was previously translated as Cushing syndrome. It is a clinical syndrome caused by the adrenal cortex's long-term secretion of polysaccharide corticosteroids due to a variety of reasons, also known as endogenous Cushing's syndrome. The high incidence age is 20 to 40 years old, and the ratio of male to female incidence is about 1: 3. According to its etiology, it can be divided into two types: adrenocorticotropic hormone (ACTH) -dependent and non-dependent. Main manifestations are full moon face, bloody appearance, concentric obesity, acne, purple stripes, hypertension, secondary diabetes and osteoporosis. In addition, long-term application of high-dose glucocorticoids or long-term alcoholism can also cause clinical manifestations similar to Cushing's syndrome, known as exogenous, drug-derived, or Cushing-like syndrome.

Basic Information

nickname: Cortisol syndrome, Cushing syndrome
English name: Cushing syndrome
Visiting department: Endocrinology

Common causes: Hypothalamic-pituitary lesions
Common symptoms: Full moon face, bloody appearance, concentric obesity, acne, purple streaks, hypertension, secondary diabetes, osteoporosis, etc.
Contagious: no

Causes of Cushing syndrome

1. Excessive ACTH secretion from the pituitary

Pituitary tumors or hypothalamic-pituitary dysfunction cause excessive ACTH secretion, stimulate bilateral adrenal hyperplasia, increase cortisol secretion, and produce corresponding clinical symptoms. It is the most common cause of Cushing's syndrome, accounting for about 60% ~ 70%, also known as Cushing's disease.

2. Primary adrenal cortical tumors

Most are benign adrenal adenomas, and a few are malignant adenocarcinomas. Tumor growth and adrenocortical hormone secretion are autonomous and not controlled by ACTH. Because the tumor secretes a large amount of corticosteroids, feedback inhibits the secretory function of the pituitary gland, reduces the plasma ACTH concentration, and the normal adrenal cortex of the non-tumor part obviously shrinks.

3.Excessive ACTH secretion from pituitary tumors

Some pituitary-adrenal tumors can secrete ACTH-like substances and cause the disease. Common are oat or small cell lung cancer, thymic cancer, pancreatic or islet cell carcinoma, pheochromocytoma, neuroblastoma, medullary thyroid carcinoma, ganglion and paraganglioma, bronchial adenocarcinoma and carcinoid, ovary Cancer, prostate cancer, etc.

4. Other

Primary pigmented nodular adrenal disease, ACTH-independent large nodular hyperplasia, and ectopic CRH syndrome are also relatively rare diseases that cause Cushing's syndrome.

Clinical manifestations of Cushing syndrome

The typical clinical manifestations of Cushing's syndrome are mainly due to the long-term excessive secretion of cortisol, which causes serious disorders of protein, fat, sugar, and electrolyte metabolism and interferes with the secretion of many other hormones. In addition, the excessive secretion of ACTH and the excessive secretion of other adrenocortical hormones can also cause corresponding clinical manifestations.

Centripetal obesity

Most are mild to moderately obese, and rarely severely obese. Some face and trunk are overweight, but the weight is in the normal range. Typical centripetal obesity means that the face and trunk are fat, but the limbs, including the hips, are not fat. The full moon face, buffalo dorsal, overhanging abdomen, and supraclavicular fossil fat pads are characteristic clinical manifestations of Cushing's syndrome. A small number of patients, especially children, may show uniform obesity.

2. Diabetes and impaired glucose tolerance

About half of the patients have impaired glucose tolerance and about 20% have dominant diabetes. Hypercortisolemia strengthens the glycogen gluconeogenesis, but also counteracts the effects of insulin, reducing the use of glucose by cells. So blood sugar rises, impaired glucose tolerance, and diabetes. Diabetes is more likely to manifest if the patient has a potential for diabetes. Ketoacidosis rarely occurs.

3. Clinical manifestations caused by negative nitrogen balance

Proteolysis is accelerated and synthesis is reduced, so the body is in a state of negative nitrogen balance for a long time, and it is clinically manifested as excessive protein consumption. Muscle atrophy throughout the body, with muscle atrophy in the limbs more pronounced. Childhood growth retardation. The skin is thin and transparent due to reduced collagen. In the lower abdomen, the outside of the buttocks, the inside of the thighs, around the armpits and breasts, typical symmetrical skin purple lines can appear. Skin capillaries are more brittle and prone to ecchymosis, which is more common in the upper arms, back of hands, and inner thighs. Skin wounds do not heal easily.

4. Hypertension

Hypertension occurs in about three-quarters of Cushing's syndrome patients. Blood pressure is generally mild to moderately elevated, and the severity of the increased blood pressure also increases in the elderly. Long-term hypertension can also cause heart, kidney, and retina lesions. In severe cases, heart failure and cerebrovascular accidents can occur.

5. Osteoporosis

Osteoporosis can occur in about 50% of patients, manifested as low back pain, prone to pathological fractures, and the most common sites of fractures are ribs and thoracolumbar spine.

6. Gonadal dysfunction

Hypercortisolism not only directly affects the gonads, but also inhibits the secretion of gonadotropins from the hypothalamus and pituitary gland, so the gonad function in patients with Cushing syndrome is significantly lower. Women show menstrual disorders, secondary amenorrhea, and rarely have normal ovulation. Males show low sexual function and impotence.

Except for adrenocortical adenomas, Cushing's syndrome for other reasons has varying degrees of weak adrenal androgen, such as dehydroepiandrosterone and androstenedione. These hormones do not have strong androgen effects, but can be converted to testosterone in peripheral tissues. As a result, patients with Cushing's syndrome often have acne, hairy, and generally fine hairs, which are distributed on the face, submandibular, abdomen and lower back. About 20% of women with adrenal cortex adenocarcinoma show masculinity. Hair loss and oily scalp are common. These weak androgens also inhibit the hypothalamic-pituitary-gonadal axis, which is another cause of hypogonadism.

7. Mental symptoms

Most patients have psychiatric symptoms, but they are generally mild, manifested as euphoria, insomnia, inattention, emotional instability, irritability, irritability, anxiety, depression, and memory loss. A small number of patients develop symptoms similar to mania, depression, or schizophrenia.

8. Prone to infection

Cushing's syndrome patients have suppressed immune function and are prone to various infections, such as skin folliculitis, periodontitis, urinary infections, onychomycosis and ringworm. It is possible that the already stabilized TB lesions may be active. At the same time the infection is not easy to control and can develop into sepsis and toxemia.

9. High urinary calcium and kidney stones

In the case of hypercortisolemia, the absorption of calcium in the small intestine is affected, but bone calcium is mobilized, and a large amount of calcium ions enter the blood and are excreted from the urine. Therefore, although the blood calcium is at the lower limit or lower than normal, the urinary calcium output increases, and urinary stones are prone to occur.

10. Other

Patients with Cushing's syndrome often have a combined membrane edema, and some may have mild exophthalmos. The skin color deepens and there is pigmentation; Cortisol stimulates the bone marrow and increases the production of red blood cells. Patients can show multiple blood quality, blush, purple lips, and bruising of the tongue. Adrenal cortical adenocarcinoma or patients with severe hyperplasia or heterologous ACTH syndrome may have significant hypokalemia and hypochloric alkalosis. Very few patients have mild edema due to sodium retention.

Cushing's syndrome test

(A) screening

Screening for Cushing's syndrome is recommended for: young patients with osteoporosis, hypertension, and other clinical manifestations that are not commensurate with age; have clinical manifestations of Cushing's syndrome and are progressively worse, especially Patients with typical symptoms such as myopathy, hyperplasia, purple streaks, ecchymosis, and skin thinning; Obese children who gain weight but have a decrease in height percentile and stagnation; Patients with adrenal adrenal tumors.

(Two) qualitative diagnostic tests

1. Determination of plasma cortisol levels and circadian rhythm

Cortisol is secreted by pulse in normal people, and has obvious circadian rhythm. Patients with Cushing syndrome have elevated plasma cortisol levels and disappeared circadian rhythms.

2.24h urine free cortisol (UFC) determination

The measurement of 24hUFC can avoid transient changes in blood cortisol, and it can also avoid the influence of the concentration of corticosteroid-binding globulin in the blood. It is of great value in the diagnosis of Cushing's syndrome. Keep the urine volume accurately for 24 hours, and avoid taking drugs that affect the determination of urinary cortisol.

3. Dexamethasone inhibition test

This is a necessary experiment to confirm the diagnosis of Cushing's syndrome. Whether it is the classic low-dose dexamethasone inhibition test (LDDST) or the simplified overnight method, the diagnostic compliance rate is above 90%.

4. Midnight salivary cortisol determination

Because only free cortisol is present in saliva, and is parallel to the free cortisol concentration in the blood, and is not affected by saliva flow rate, the circadian rhythm of salivary cortisol levels and the disappearance of midnight cortisol trough are Cushing's syndrome Patients have more stable biochemical changes. Its sensitivity and specificity can reach 95% to 98%.

(Three) the diagnosis of the cause

1. High-dose dexamethasone inhibition test

It is currently the main method used to determine the source of excess ACTH. After taking the drug, UFC or blood cortisol levels are inhibited by more than 50% to be positive. In patients with Cushing's disease, UFC (urinary free cortisol) or 17-hydroxycorticosteroid levels can be suppressed to less than 50% of the control day, and the diagnosis coincidence rate is about 80%. Adrenal adenoma or adenocarcinoma Patients generally cannot be suppressed below 50%; most patients with ectopic ACTH syndrome are not suppressed, except for some patients with bronchial carcinoids. The results of the overnight high-dose dexamethasone inhibition test are similar to the classical method, and have the advantages of quickness and simplicity.

2. Determination of plasma ACTH levels

Adrenocortical tumors, whether benign or malignant, have plasma ACTH levels below the lower limit of normal values, while patients with ACTH-dependent Cushing's disease and ectopic ACTH syndrome have elevated plasma ACTH levels to varying degrees. Therefore, the determination of plasma ACTH levels has a positive diagnostic significance for differentiating ACTH dependence and non-dependence, but it can only be used as a reference to identify whether the increase in ACTH secretion from pituitary or ectopic.

3. Excitation test of desmopressin (DDAVP)

Desmopressin is a V ₂ and V ₃ vasopressin receptor agonist and can be used to distinguish between Cushing's disease and ectopic ACTH syndrome. This test is an alternative to the CRH excitation test, which is less sensitive and specific than the CRH excitation test and is used when CRH reagents cannot be obtained.

4.CRH (Adrenocorticotropic Hormone Releasing Hormone) Excitation Test

After intravenous injection of synthetic sheep or human CRH to patients with pituitary Cushing's disease, blood ACTH and cortisol levels increased significantly, and the increase was more significant than that of normal people; but most patients with ectopic ACTH syndrome did not respond. Therefore, this test is of great value in the differential diagnosis of these two ACTH-dependent Cushing syndromes.

5. Bilateral inferior petrosal sinus intubation to measure ACTH or ACTH related peptide levels

It is of diagnostic significance to distinguish ectopic ACTH syndrome from pituitary Cushing's disease, and to locate ectopic ACTH-secreting tumors. It also has important significance for the positioning of pituitary ACTH tumors on the left or right side of the pituitary. It is a traumatic interventional examination and is recommended only by experienced radiologists at experienced medical centers.

6. Imaging examination

(1) Imaging examination of the saddle area Magnetic resonance or CT scan of the saddle area is very helpful for pituitary size and whether there is adenoma. MRI is superior to CT in the diagnosis of pituitary lesions. It is recommended that all patients with ACTH-dependent Cushing's syndrome undergo pituitary enhanced MRI or pituitary dynamic enhanced MRI.

(2) Adrenal imaging examinations include B-ultrasound, CT, magnetic resonance, and radioiodized cholesterol iodine scans. Bilateral adrenal CT thin-layer (2 to 3 mm) enhanced scans are preferred.

(3) Imaging examination of ectopic ACTH syndrome lesions Since most tumors that cause ectopic ACTH syndrome are located in the lung or mediastinum, chest X-ray and CT scans are necessary. Somatostatin receptor imaging can also be used for tumor localization of ectopic ACTH syndrome.

Cushing's syndrome diagnosis

The diagnosis of cortisol is divided into three aspects: determining the diagnosis of the disease, the diagnosis of the cause, and the diagnosis of the location.

1. Determine the diagnosis

Mainly based on typical clinical symptoms and signs. Such as concentric obesity, purple stripes, increased hair, sexual dysfunction, fatigue, etc. Coupled with a significant increase in urinary 17-hydroxycorticosteroid excretion, low-dose flumetasone inhibition test cannot be suppressed and blood 11-hydroxycorticosteroids are higher than normal levels and lose the circadian rhythm to diagnose cortisol. Early mild cases should be distinguished from simple obesity.

2. Etiology diagnosis

That is, the difference is cortical hyperplasia caused by adrenocortical adenoma, adenocarcinoma, pituitary tumor, non-pituitary tumor or heterogeneous ACTH-secreting tumor.

3. Location diagnosis

Mainly the location of adrenal cortical tumors for surgical resection. However, at the same time of positioning, the diagnosis of the cause is often solved.

Cushing's syndrome treatment

Cushing's disease

(1) Surgical treatment Selective transsphenoidal or transcranial pituitary adenoma removal is the preferred treatment method, and the postoperative remission rate is 65% to 90%. For those who do not respond or relapse after surgery, pituitary surgery or adrenalectomy can be performed again. Bilateral adrenal resection or subtotal resection is an effective method for rapid control of hypercortisolism, but surgery will cause permanent adrenal insufficiency, and adrenal corticosteroid replacement therapy will be required for life. Because of the risk of Nelson syndrome after surgery, pituitary radiation therapy should be followed.

(2) Radiation therapy of pituitary gland In 20% of cases, a long-lasting effect can be obtained. However, most cases have poor curative effects and are prone to relapse, so they are generally not the first choice. They can be used as an adjuvant treatment after surgery to reduce postoperative recurrence or avoid Nelson syndrome.

(3) Drug therapy Steroid synthesis inhibitors can inhibit cortisol synthesis, but they have no direct therapeutic effect on tumors and cannot restore the normal function of the HPA axis. Commonly used drugs Mitotan (dichlorobenzene dichloroethane), Aminutamib, Mitirapone (Metoprolone), Ketoconazole, Etomidate. Close monitoring is required during medication. Mifepristone, a glucocorticoid receptor antagonist, can relieve clinical symptoms, but has little effect on pituitary and adrenal lesions, and is suitable for patients who cannot be operated on.

2. Ectopic ACTH syndrome

The treatment method and effect depend on the type, stage and location of the primary tumor. Benign tumors such as thymoma and pheochromocytoma can be cured by surgery. However, most tumors that cause ectopic ACTH syndrome are malignant, and treatment is very difficult.

3. Adrenal cortex adenoma

Laparoscopic surgery is preferred to remove the affected adenoma. Due to hypercortisolemia, the hypothalamus-pituitary axis and the contralateral adrenal glands are inhibited for a long time. Significant adrenal insufficiency symptoms will appear during and after surgery. Short-term replacement of corticosteroids.

4. Adrenal cortical adenocarcinoma

Including surgical treatment, chemotherapy and local radiotherapy, the appropriate treatment method is selected according to the different stages of the tumor. Postoperative glucocorticoid replacement therapy is also required.

5. Primary pigmented nodular adrenal disease

Surgical removal of bilateral adrenal glands is the main treatment method. Adrenal corticosteroid replacement therapy is required for life after surgery.

6. ACTH independent nodular hyperplasia

One side of the adrenal gland can be removed for pathological diagnosis, followed by close observation after surgery, to decide whether to selectively remove the other side of the adrenal gland.