Cholestasis refers to the obstruction of bile formation, secretion and excretion caused by various reasons inside and outside the liver, and the bile flow cannot flow into the duodenum normally And into the pathological state of the blood. The Autoimmune Hepatology Group of the Chinese Medical Association Hepatology Branch organized an expert group to evaluate the literature and evidence in recent years, and formulated the “Guidelines for the Management of Cholestatic Liver Diseases (2021)”, and put forward 22 recommendations. The purpose is to provide clinical bile Provide reference and guidance for the diagnosis and treatment of stasis liver disease.
Diagnostics
1. Liver biochemical examination found that ALP exceeding 1.5×ULN and GGT exceeding 3×ULN can be diagnosed as cholestatic liver disease (B1). Some familial intrahepatic cholestasis manifests as elevated conjugated bilirubin and/or bile acids, but GGT may not be elevated (B2).
2. Imaging examination is the main clinical method to distinguish intrahepatic and extrahepatic cholestasis. Abdominal ultrasound, CT and MRCP can be selected according to the situation. . (C1)
3. ERCP or ultrasonography is recommended when routine imaging examinations cannot confirm the diagnosis, and extrahepatic biliary obstruction or cholangitis is highly suspected clinically Endoscopy. (B1)
4. For unexplained intrahepatic cholestasis and negative for AMA/AMA2 and/or SP100 and/or GP210 Other antibody tests to rule out systemic or other organ autoimmune diseases, and liver biopsy may be performed when they are still uncertain (C1). In patients with suspected hereditary cholestasis who cannot be diagnosed, the related gene can be tested (B1).
5. Jaundice may not appear in the early stage of cholestatic liver disease, and it is necessary to distinguish hereditary hyperbilirubinemia and hemolytic diseases in patients with jaundice. (B1)
Treatment
6. Cholestasis The principle of treatment of liver disease is to remove the cause and treat cholestasis. The main therapeutic drugs are ursodeoxycholic acid (A1), S-adenosylmethionine (B1), cholestyramine (B1), fibrates (B1) and obeticholic acid (B1), etc., which can be used alone or in combination. use.
7. Hormones and/or immunosuppressive agents, ultraviolet radiation, extracorporeal albumin dialysis and nasobiliary duct can be used as appropriate for those who are ineffective after the above drug treatment Drainage, etc. (C2)
8. Patients with cholestatic liver disease are ineffective after active medical treatment and may die within 6-12 months or have MELD≥15 points Liver transplantation should be evaluated. (B1)
Hereditary cholestatic liver disease
9. The diagnosis of cystic fibrosis-related liver disease (CFLD) is based on cystic fibrosis, enlargement, abnormal biochemical parameters, and cystic lesions of different numbers and sizes in the liver detected by imaging (C2). Ursodeoxycholic acid (20-30 mg·kg-1·d-1) can improve liver biochemical and histological indexes (C1) in CFLD. Patients with severely restricted daily life or end-stage patients should be evaluated for liver transplantation (B1).
10. Familial intrahepatic cholestasis (FIC) is a group of autosomal recessive genetic diseases with pruritus and jaundice as the main manifestations , which can be expressed as pedigrees of varying severity (B1). Genetic testing is the gold standard for diagnosis (B1). FIC types 1, 2, 4, 5, and 6 are characterized by low GGT, severe pruritus, and may be associated with different extrahepatic manifestations. FIC type 3 is characterized by high GGT. There is no effective treatment for FIC (C2). Ursodeoxycholic acid can improve liver function indexes (C2) in some patients with FIC type 3. Bile shunt is beneficial to liver biochemical parameters in some FIC patients (C2). Liver transplantation evaluation is recommended for advanced patients (B1).
11. Alagille syndrome mainly occurs in children and adolescents. Mutations in JAG1 or NOTCH2 lead to decreased interlobular bile ducts, resulting in cholestasis with Itching, and abnormalities of the cardiovascular system, eyes, bones, and face are characterized by multi-system damage, and symptomatic and supportive treatment is the mainstay. (C2)
Intrahepatic cholestasis of pregnancy (ICP)
12. The diagnosis of intrahepatic cholestasis of pregnancy is based on: (1) pruritus during pregnancy; (2) elevated serum ALT and fasting bile acid and glycocholic acid levels; (3) abnormal liver function or pruritus except for other reasons . The diagnosis can be made after the postpartum liver biochemical indicators are completely normal. (B2)
13. Ursodeoxycholic acid and S-adenosylmethionine can be used for cholestasis in the second or third trimester of pregnancy and In symptomatic patients, pruritus can be relieved and liver biochemical indicators (B1) can be improved, but there are no methods to protect the fetus and reduce complications. (C2)
Extrahepatic manifestations and management
14. Cholestyramine is the first-line drug for the treatment of pruritus. The recommended dose is 4 g/d, and the maximum dose does not exceed 16 g/d. Note that it should be taken at an interval of 4-6 hours with other drugs (especially ursodeoxycholic acid) to avoid affecting the absorption of other drugs (B2).
15. Rifampicin is a second-line drug for the treatment of pruritus. It is usually taken as a single oral dose of 150 mg/d at first, and continues to be taken after it is effective. If ineffective, the dose can be increased stepwise to 300 mg/d every other week. Rifampicin has potential liver damage, and liver biochemical indicators (C2) must be closely monitored during treatment.
16. The oral opioid receptor antagonist naltrexone is the third-line drug for the treatment of pruritus. Gradually increase the dose to 50 mg/day to avoid anesthetic-like withdrawal effects (C1).
17. The selective serotonin (5-HT) reuptake inhibitor sertraline is a fourth-line drug for pruritus treatment, with an initial dose of 50 mg/d, which can be increased to 100 mg/d (C2) after several weeks.
18. For patients with pruritus that are ineffective after the above drug treatment, methods such as ultraviolet irradiation, extracorporeal albumin dialysis and nasobiliary drainage can be considered (C2). Liver transplantation should be considered in patients with severe pruritus not responding to medication and other methods. (C2)
19. Cholestatic fatigue should be excluded from anemia, glucoseDiabetes, hypothyroidism, renal and adrenal insufficiency, and depression. It is recommended to ensure adequate sleep, regular exercise, abstain from alcohol and coffee at night (C2). Selective 5-HT3 receptor antagonists such as ondansetron, opioid receptor antagonists and central nervous system stimulant modafinil (100-200 mg/d) have certain curative effects (C2). Antidepressants can partially reduce fatigue in depressed patients (C2). Liver transplantation had no significant effect on fatigue improvement (C2).
20. Xanthoma does not require special treatment (B2). Statins and fibrates can be used in patients with lipid metabolism disorders, and cholestyramine can improve dyslipidemia (B2).
21. It is recommended that patients supplement calcium and vitamin D to prevent osteoporosis. The daily calcium intake for adults is 800 mg; the recommended daily calcium intake for postmenopausal women and the elderly is 1000 mg. The recommended dose of vitamin D for adults is 200 IU/d; the recommended dose for the elderly is 400-800 IU/d (C1). Bisphosphonates (eg, alendronate 70 mg/week or ibandronate 150 mg/month or other similar drugs) treat and prevent osteoporosis (C2). Annual BMD measurements can be used for osteoporosis treatment and follow-up (C2).
22. Pay attention to the monitoring and supplementation of fat-soluble vitamins. Prothrombin time was prolonged, and vitamin K1 10 mg/d (B1) was injected. Night blindness caused by vitamin A, oral vitamin A 25000~50000 IU/d (C1). Vitamin E deficiency is rare and can be supplemented orally at 10-100 mg/d (C2).
The above content is excerpted from: Chinese Society of Hepatology. Guidelines for the management of cholestatic liver disease (2021)[ J]. Journal of Clinical Hepatobiliary Diseases, 2022, 38(1): 62-69.
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