摘要
药物性肝损伤是患者抗结核治疗过程中最常见的药物不良反应之一,为提高临床医师及结核病防控工作者对抗结核药所致药物性肝损伤(anti-tuberculosis drug-induced liver injury,ATB-DILI)的正确诊断和处理能力,中华医学会结核病学分会于2013年组织相关专家制定了《抗结核药所致药物性肝损伤诊断与处理专家建议》,2019年对该建议进行了更新,形成了《抗结核药所致药物性肝损伤诊治指南(2019年版)》,上述建议和指南的出台对规范我国ATB-DILI的诊治以及提升临床处理能力起到了重要的指导作用。根据全球近年来的相关领域研究进展,更新现有的文献证据,中华医学会结核病学分会对指南进行修订和更新,形成了《抗结核药所致药物性肝损伤诊治指南(2024年版)》。本次指南更新内容主要包括以下几个方面:(1)流行病学:ATB-DILI发生率全球呈现明显的上升趋势,我国为9.5%~14.1%。(2)危险因素:强调减少或避免其他损害肝脏药物的合并应用,中药的合并应用需评估获益与风险。(3)发生机制:可分为固有型、特异质型和间接型。ATB-DILI的发生与多种机制相关。(4)ATB-DILI的诊断:提出肝脏生化诊断阈值标准仅适用于急性DILI的诊断,不适用于慢性和特殊表型DILI的诊断。伴基础肝病患者,当转氨酶较基线水平升高1倍或肝脏生化指标显著恶化无法用基础肝病解释时,应怀疑DILI的可能性。在RUCAM量表的应用基础上,建议结合专家意见进行因果关系评估,避免误诊及漏诊。(5)ATB-DILI的严重程度分级:调整为4级。(6)保肝药物:推荐根据ATB-DILI的肝损伤类型应用保肝药物。(7)抗结核药物:环丝氨酸和利奈唑胺可在不能组成有效抗结核治疗方案时应用;对于合并基础肝病或其他疾病的患者,可进行多学科会诊,在专业药师的参与下制定个体化方案。本指南共形成23条推荐意见,为ATB-DILI的规范诊治提供了临床证据和决策依据。
Drug-induced liver injury (DILI) is one of the most common adverse reactions of anti-tuberculosis treatment. To improve the diagnosis and management of anti-tuberculosis drug-induced liver injury (ATB-DILI) for clinicians and tuberculosis control workers, the Chinese Medical Association Tuberculosis Branch has developed guidelines for the diagnosis and treatment of ATB-DILI. These guidelines summarized recent research progress in relevant fields and provide detailed explanations, recommendations, and quality assessments related to ATB-DILI, covering aspects such as definition, risk factors, mechanisms, pathological manifestations, clinical classification, diagnosis, and management. The key recommendations are as follows. Recommendation 1: Risk factors: NAT2 slow acetylation genotype, GSTM1 gene variation, advanced age, hepatitis virus infection or concurrent acute/chronic liver disease, HIV infection, malnutrition, and alcohol (ethanol) intake are risk factors for ATB-DILI (2, B). Recommendation 2: R-value calculation: Calculate the R-value for suspected ATB-DILI patients at different time points during the course of the disease. ALT and ALP values should be obtained on the same day, with a maximum interval of no more than 48 hours. This helps to accurately determine the clinical type and prognosis of DILI (2, C). Recommendation 3: Comprehensive medical history collection: Collect information on past medication history, clinical features, dynamic changes in liver biochemical markers, drug rechallenge reactions, comorbidities, and underlying liver diseases (4, B). Recommendation 4: Liver biochemical tests: Include at least ALT, AST, ALP, GGT, TBil, DBil, and albumin. If necessary, measure prothrombin time or international normalized ratio (INR) (3, B). Recommendation 5: Abdominal imaging: Routine abdominal imaging should be performed for suspected ATB-DILI patients (3, B). Recommendation 6: Liver histopathological examination: Histology of liver biopsies aids in the diagnosis and differential diagnosis of DILI (4, B). Recommendation 7: Biochemical diagnostic criteria for acute ATB-DILI: Liver biochemical tests should meet one of the following criteria: ALT≥3×ULN and/or TBil≥2×ULN;simultaneous elevation of AST, ALP, and TBil, with at least one parameter≥2×ULN (4, C). Recommendation 8: Diagnostic criteria for ATB-DILI: Diagnosis requires:(1) A history of exposure to anti-tuberculosis drugs that can cause liver injury;(2)Rapid normalization of abnormal liver biochemical markers after drug discontinuation: For patients with hepatocellular injury, a decrease in the peak serum ALT level of at least 50% within 8 days is highly suggestive, while a decrease of at least 50% within 30 days is considered important. For patients with cholestatic injury, a serum ALP or TBil peak level that decreases by at least 50% within 180 days is also considered important;(3) Exclusion of other causes of liver injury;(4) Positive rechallenge reaction. Meeting three of the above criteria confirms ATB-DILI, whereas meeting (1) and (2) criteria indicates a suspected case. In practice, the vast majority of ATB-DILI are suspected cases (3, B). Recommendation 9: Avoid re-exposure: Minimize re-exposure to the same suspected drug, especially if the initial exposure caused severe liver injury (4, B). Recommendation 10: Causality assessment: Use the RUCAM scale as the primary method for assessing causality. In cases involving multiple hepatotoxic drugs, concurrent liver disease, or new drug clinical trials, combine expert opinions for reliable assessment (3, B). Recommendation 11: Baseline testing: All patients are recommended to undergo baseline liver biochemistry, HBsAg (if HBsAg is positive, further HBV DNA testing), anti-HCV testing, and abdominal imaging before starting anti-TB treatment (3, B). Recommendation 12: Monitoring frequency: Patients without high-risk factors should have monthly liver biochemical monitoring (4, C);high-risk patients or those using hepatotoxic drugs should be monitored every 2 weeks during the first 2 months of anti-tuberculosis treatment, then monthly (2, B). Recommendation 13: Avoid concurrent hepatotoxic drugs: Evaluate the benefit-risk ratio of using other hepatotoxic drugs or traditional Chinese medicine (4, C). Recommendation 14: Antiviral treatment: In ATB-DILI patients with viral hepatitis, consider prompt antiviral therapy if indicated (3, B). Recommendation 15: NAT2 genotyping: Guide isoniazid dosing based on NAT2 gene polymorphism (4, C). Recommendation 16: Application of preventive hepatoprotective drugs: People with high risk factors for liver damage may consider it (4, C);however, routine use in the general population is not recommended (2, B). Recommendation 17: Immediate discontinuation: In the case of ATB-DILI, suspected drugs should be discontinued immediately (4, A). Recommendation 18: N-acetylcysteine (NAC): Early intravenous administration of NAC is beneficial for acute liver failure and subacute liver failure induced by drugs in adults (4, D). Recommendation 19: Glucocorticoids: Use with caution;not recommended as routine treatment for ATB-DILI(4, C);may be considered for immune-mediated DILI with hypersensitivity and autoimmune features (3, B). Recommendation 20: For acute hepatocellular injury or mixed DILI with significantly elevated ALT/AST, bicyclol and/or magnesium isoglycyrrhizinate are recommended (2, B). Recommendation 21: For mild to moderate hepatocellular injury type DILI with elevated ALT/AST, reasonable choices include ammonium glycyrrhizinate, compound glycyrrhizin, and other glycyrrhizic acid derivatives, glutathione, silymarin, polyenylphosphatidylcholine, and other drugs (4, C);For cholestatic DILI with elevated ALP/GGT/TBil, ursodeoxycholic acid or S-adenosylmethionine may be selected (4, C);the combined use of two or more drugs that mainly reduce ALT is not recommended (4, B). Recommendation 22: Treatment of severe patients: For severe patients such as those with drug-induced liver failure, liver transplantation is recommended (2, B);artificial liver (high-volume plasma exchange, dual plasma molecular adsorption system, etc.) may be a beneficial option (4, C);ornithine aspartate may help reduce blood ammonia levels in patients with severe disease or liver failure (4, C). Recommendation 23: Rational drug use during the recovery period: During or after liver function recovery, clinicians should comprehensively assess the patient′s liver injury severity, presence of liver injury-related risk factors, and tuberculosis severity. Based on this assessment, anti-tuberculosis drugs should be selected rationally (4, C). These recommendations provide clinical evidence and decision-making guidance for the standardized diagnosis and treatment of ATB-DILI.
作者
中华医学会结核病学分会
顾瑾
林明贵
唐神结
Chinese Medical Association Tuberculosis Branch;Gu Jin;Lin Minggui;Tang Shenjie(不详;Shanghai Pulmonary Hospital,Tongji University School of Medicine,Shanghai 200433,China;Center for Infectious Diseases,Beijing Tsinghua Chang Gung Hospital,Tsinghua University,Beijing 102218,China;Institute of Tuberculosis and Thoracic Tumor,Beijing Chest Hospital,Capital Medical University,Beijing 101149,China)
出处
《中华结核和呼吸杂志》
CAS
CSCD
北大核心
2024年第11期1069-1090,共22页
Chinese Journal of Tuberculosis and Respiratory Diseases
基金
国家重点研发计划(2023ZX10003001)
上海市加强公共卫生体系建设三年行动计划(2023-2025)
重点学科项目(GWVI-11.1-05)。
作者简介
通信作者:顾瑾,同济大学附属上海市肺科医院上海市结核病临床研究中心,上海200433,Email:gujin51250@163.com;通信作者:林明贵,清华大学附属北京清华长庚医院感染疾病中心,北京102218,Email:linminggui309301@126.com;通信作者:唐神结,首都医科大学附属北京胸科医院北京市结核病胸部肿瘤研究所,北京101149,Email:tangsj1106@vip.sina.com。
