Cortisolism, also known as Cushing’s syndrome, is a syndrome in which the adrenal glucocorticoids (mainly cortisol) are overproduced. It is more common in middle-aged and young adults, and is more common in women than men.
Etiology and pathogenesis
1.Primary
(1) Adrenocortical adenoma accounts for about 15% of the adrenal gland, which is a proliferation of functionally autonomous cells, not affected by adrenocorticotropic hormone (ACTH). Most of them are unilateral, so that the adrenal cortex is atrophied except for the adenoma. Cortisol secretion from this adenoma is not inhibited by exogenous glucocorticoids.
(2) Adenocortical carcinoma accounts for about 2-5% of adenocortical carcinomas, which have a secretory function and are not affected by ACTH.
2.Secondary
(1) Somatic tumor or hypothalamic-pituitary dysfunction
Secondary to hypothalamic-pituitary disease can cause adrenal cortical hyperplasia, called hyperplastic cortisolism, or Cushing’s disease, accounting for about 70%. In this group of patients, there are anterior pituitary macroadenomas (>10 mm in diameter) with enlargement of the pterygoid saddle in about 10% of cases. Recent experience with microsurgery of the pituitary gland via the pterygoid sinus has confirmed the presence of pituitary microadenomas (<10 mm in diameter) in more than 80% of patients without enlargement of the pterygoid saddle. A significant proportion of patients are cured after removal of microadenoma, while another proportion of patients can recur, indicating that the onset of the latter is related to hypothalamic-pituitary dysfunction.
(2) Bite-sized ACTH-like tumors
Such as lung cancer (about 50%), thymic, pancreatic and prostate cancers can secrete ACTH-like active substances, and the pathology shows bilateral adrenal cortical hyperplasia. Due to poor differentiation of the primary carcinoma and short survival, the clinical manifestations of adrenocortical hormone increase are mostly atypical.
(3) Source glucocorticoid hyperplasia
Long-term high-dose corticosteroid therapy. Such as rheumatoid arthritis, disseminated lupus erythematosus and bronchial asthma can cause symptoms similar to Cushing’s disease, all accompanied by adrenal cortical atrophy and hyposecretory function, as well as reduced blood ACTH concentration.
Pathology
1. Cortical hyperplasia
Bilateral adrenal gland enlargement, cortical thickening and yellow-brown color are seen in the cut surface, and the adrenal cortical bundle band is widened and the cells are hyperplastic and enlarged under microscope. In a few cases, there is simultaneous hyperplasia of the fasciculus and reticular zone, and the globular zone is compressed, atrophied, or even disappeared.
2.Cortical adenoma
Adenomas are mostly round or elliptical in shape, with a diameter of 2 to 5 cm and an intact envelope, sometimes in a lobulated form. Microscopically, adenomas contain clear cells and granular cells, and some cells have heterogeneous and deep staining nuclei. Most of them are mainly granulosa cells.
3.Cortical adenocarcinoma
Fast-growing, large size, hemorrhage, necrosis, heterogeneous adenocarcinoma cells and nuclear division, infiltrating or crossing the envelope are common. It can metastasize to lymph nodes, liver and lung in late stage.
4.Other
Osteoporosis, muscle and fibrous tissue atrophy, arteriosclerosis, left ventricular hypertrophy, possible calcium salt deposition in the renal tubules, urinary stones, hepatic fatty infiltration, etc.
Clinical manifestations
The onset of disease is mostly slow, and typical clinical signs may appear within a few weeks in individual cases.
1. External appearance
The centripetal obesity of face and trunk is the characteristic body shape of the disease. It includes full-moon face, fat accumulation on the back of neck, bulge, and abdominal bulge. The limbs appear relatively small due to fat and muscle atrophy, the face is rosy and lustrous, and there is this fat overflow phenomenon. The skin is thin, prone to purpura and petechiae, and the capillary fragility test is mostly positive. Purple lines are also a specific sign of the disease, about 56% positive, often distributed in the lower abdomen, buttocks, shoulders, anterior axillae, etc. The purple lines are wide in the center and thin at both ends, with a purplish-red color. Acne frequently occurs on the skin of the face and back. Body hair increases, thickens, black color, some patients have hair loss phenomenon.
2.High blood pressure
About 80% of the patients have elevated systolic and diastolic blood pressure. After reasonable treatment, the blood pressure can drop or return to normal.
3.Musculoskeletal system
Due to negative nitrogen balance, muscle atrophy, especially transverse muscle is obvious. There is osteoporosis and decalcification, which is obvious with branch weight bone, such as spine and pelvis may occur pathological fracture. Patients mostly feel low back pain, weakness of limbs, and difficulty in wound healing. After proper treatment, the symptoms can be improved to different degrees.
4.Gonads and reproductive system
Female patients have decreased menstruation or amenorrhea, breast atrophy, and enlarged clitoris. If there is obvious masculinization, it is mostly adrenal cancer. Male patients have impotence and testicular atrophy.
5.Mental symptoms
Emotional instability, impulsiveness, insomnia and disorientation. Severe cases may be depressed, and individual cases may have hallucinations and fantasies. After treatment, general psychiatric symptoms can disappear quickly, while depressive symptoms can last for several months to two years, and individual patients may last longer.
6.Disorders of glucose substitution
About 70% of patients can have glucose metabolism disorder, steroidal diabetes, insensitive to insulin. Treatment can normalize glucose metabolism. However, if the disease is too long and the pancreatic beta cells degenerate, it will lead to permanent diabetes.
7.Electrolytes
Blood sodium is normal or high, blood potassium is mostly low, if the change is significant, adenocarcinoma should be considered. Blood calcium and phosphorus are mostly within the normal range, and may have mild alkalosis.
8. Skin pigmentation
Patients with ectopic ACTH syndrome mostly have obvious pigmentation, which has diagnostic significance. Patients with severe adrenocortical hyperplasia also have darker skin pigmentation.
Laboratory and other tests
1. General tests
Red blood cell count and hemoglobin content are high. The total white blood cell count and neutrophils are increased, and the absolute value of lymphocytes and eosinophils is decreased.
2. Urinary 17 hydroxycorticosteroid 24-hour level is significantly elevated
The urinary 17-hydroxycorticosteroid 24-hour level exceeded 38.4 μmol/24h (13.9 mg/24h) (male) and 30.9 μmol/24h (11.2 mg/24h) (female). 17-hydroxycorticosteroid combined amount also frequently exceeded 40.3 μmol/24h (11.6 mg/24h) (male) and 37.3 μmol/24h (8.5 mg/24h) (female).
3. Elevated blood cortisol concentration
It exceeded 0.28μmol/L (10.1mg/dl) at midnight and 0.69μmol/L (24.9mg/dl) at 8am in the quiet state.
4.The circadian pattern of blood cortisol disappeared
That is, the cortisol concentration at midnight exceeds the level at 8:00 am. The disappearance of circadian rhythm can occur at the early stage of disease onset.
5.Small dose dexamethasone suppression test
Cortisolism is not inhibited, other reactive or functional cortisolism can make blood cortisol concentration or 24-hour urinary 17 hydroxycorticosteroid content drop more than 50% of the basic value, mainly used to identify with simple obesity. Method: simplified method; blood cortisol concentration was measured at 8 am on the first day as the basal value. Dexamethasone was taken at midnight: 1.5 mg, and blood cortisol was retested at 8 am the next day. Orthodox method: The first day to measure the blood cortisol concentration at 8 a.m. or 24-hour urinary 17 hydroxycorticosteroid content, the next day to start taking dexamethasone 0.75mg three times a day for 4 days, and then recheck the blood cortisol concentration or urinary 17 hydroxycorticosteroid content, and compare with the pre-dose.
6.High dose dexamethasone suppression test
Adrenocortical hyperplasia is inhibited by more than 50%, while adrenal adenoma or adenocarcinoma is not significantly inhibited. The method is to measure blood cortisol or urinary 17 hydroxycorticosteroid content one day before the test, and then take dexamethasone 2mg every 6 hours for 5 days, and then recheck blood cortisol concentration or urinary 17 hydroxycorticosteroid content and compare with that before taking the drug.
7.ACTH excitation test
In normal people, simple obesity and adrenocortical hyperplasia can increase the blood cortisol concentration or urinary 17 hydroxycorticosteroid content by more than 2 times after ACTH injection, while adrenal adenoma or adenocarcinoma has no significant increase. Method: Simplified method: 25 mg of ACTH was injected intramuscularly or intravenously immediately after the blood was drawn at 8:00 am for cortisol measurement, and blood was drawn at 8:30 am and 9:00 am for cortisol measurement. Orthodox method. On days 1 and 2, 24-hour urine was kept to measure 17 hydroxycorticosteroid content, and on days 3 and 4, 24 mg of ACTH (plus 5% glucose solution in 500 ml) was administered intravenously starting at 8:00 a.m. for 8 hours, while 24-hour urine 17 hydroxycorticosteroid content was measured daily.
8.Imaging examination
These are localized examinations, including B-type ultrasound, CT scan, adrenal angiography, magnetic resonance examination, and segmental blood collection by intravenous catheter to determine cortisol. When available, 131 iodine-labeled cholesterol isotope scan or γ-imaging can also be performed to assist in diagnosis.
Diagnosis and differential diagnosis
The diagnosis is not difficult when laboratory results and other tests are carefully analyzed. It should be differentiated mainly from simple obesity, ectopic ACTH-like tumors, diabetes mellitus, and other secondary lesions of the adrenal cortex.
Treatment
1.General treatment
(1) Correct hypokalemia, take 3-9g of potassium chloride or potassium constructate orally every day, and if necessary, add anisodone.
(2) Correction of glucose metabolism disorder, can be treated with insulin injection, patients are often insensitive to insulin, so the dose needs to be gradually increased according to the condition.
(3) Correction of negative nitrogen balance, because protein catabolism is greater than synthesis, testosterone propionate or nandrolone phenylpropionate can be given as appropriate.
2.Adrenocortical adenoma or adenocarcinoma
After correcting electrolyte disorder and acid-base imbalance, maintaining normal blood pressure and controlling glucose metabolism disorder, surgery should be performed to remove the tumor. Corticosteroids should be given intraoperatively to maintain stress energy. Postoperatively, 60-80 U of long-acting ACTH should be injected intramuscularly daily along with hormone replacement therapy to restore the function of the atrophied adrenal cortex more quickly. The dosage should be tapered after two weeks, with longer-term cortisone replacement supplementation required for those who respond poorly. Most patients can gradually discontinue replacement therapy within 3 months to 1 year.
3.Adrenal cortical hyperplasia
In the past, the adrenalectomy was mostly performed on both sides, but the postoperative remission was poor and the recurrence rate was high. Some people advocate total adrenalectomy on both sides, which provides better remission, but requires lifelong corticosteroid replacement therapy, and after a few years some patients (about 10%) develop pituitary ACTH-secreting adenomas, i.e. Nelson syndrome, which requires surgery. If the diagnosis of pituitary microadenoma can be confirmed by CT scan and MRI, microscopic excision of pituitary adenoma can be performed via the pterygoid sinus. After surgery, alternative therapy should also be given.
4.For adrenal cortical hyperplasia or adenocarcinoma that cannot be treated surgically, oral aminoglutethimide 0.4g can be used.
It can be taken orally three times a day with minor side effects, mainly gastrointestinal reactions, skin rash, drowsiness and so on. It can also be used as a pre-surgical preparation. Mepyrone can also be tried 2-6g per day orally in divided doses. O,P-DDD can also be tried 2-10g per day, divided into oral doses, but the side effects are large and interruption of treatment will affect the efficacy. Those who are effective can get clinical remission, but cannot be cured.