领跑者5000抗结核药物所致肝损伤相关危险因素及临床处置

中国防痨杂志2013，35（11）：858-864

抗结核药物所致肝损伤相关危险因素及临床处置对策

【摘要】背景抗结核治疗中药物性肝损伤是最常见的不良反应，是危害结核病人治疗中的生命安全和健康、影响国家结核病控制策略的常见难题。目前国内外尚缺乏抗结核治疗中防治抗结核药物性肝损伤的临床诊治指南和专家共识。解决这一难题既是临床工作者的迫切需要，也是业界亟需共同努力的问题。目的本文目的是探讨抗结核治疗中药物性肝损伤的临床防治对策。方法 通过复习1986至2013期间国内外抗结核药物性肝损伤相关文献和各类肝病肝损伤诊治相关指南，结合自己43年的临床和科研心得，分析抗结核治疗中引起肝损伤的的相关危险因素（药物因素、病人相关因素、医护及管理因素、防控策略上的缺陷）等。通过分析出的相关危险因素，找出相应的应对策略。结果 抗结核治疗中药物性肝损伤的危险因素：（1）与各种抗结核药的体内代谢过程和特点、药物剂量、药物过敏性肝损伤相关危险因素、药物的联合应用等因素密切相关。指出常规剂量INH几乎不引起肝损伤，目前的INH使用说明书最高用量不超过0.3 g/d是缺乏科学依据很不恰当的，是造成低剂量用药过程中诱导耐药产生的重要原因，必须修正。（2）与病人自身因素如先天性肝药酶因素、过敏体质、自身免疫病或潜在自身免疫缺陷、器官老化、不良生活习惯如嗜酒引起酒精中毒性慢性肝病、常见肝脏基础疾病（病毒性肝炎、酒精中毒、胆汁淤滞、循环障碍如慢性心脏疾病、免疫紊乱、代谢紊乱、工业毒物或药物、营养障碍、血吸虫病性肝纤维化、原因不明的隐源性肝硬化等）、严重结核病、合并其他严重的全身性疾病、低蛋白血症、内分泌疾病（如肾上腺皮质功能下降、女性内分泌改变期）等相关。（3）医护及管理因素（如部分医护人员的知识局限，对肝损伤相关危险因素、应检查项目、诊断和防范方法缺乏了解；部分医护人员不能正确地把握降低医疗费用和合理检查的尺度，放弃了必要的检测和监测；部分医护人员对规范化治疗的概念存在认识误区，不知道必须遵循一般化和个体化相结合的原则，片面地将一般原则当作规范化原则；未能及时发现和治疗肝脏基础疾病和全身性疾病；免疫调节剂的使用不合理）等相关。（4）防治策略在与时俱进上还存在差距（防治策略中缺乏控制抗结核药物不良反应的内容；对使用抗结核药物之前的检查项目和治疗中的应监测项目缺乏规范指导；对医务人员培训不足，以致许多医务人员、特别是基层医务人员对于结核病治疗中肝损伤的危险因素认识不足、对肝功能的判断及分级标准认识不够；对当前“规范化”的概念有必要重新认识，任何一个患者的治疗都存在“一般原则”和“个体化原则”相结合的规范化问题；组合药制剂不利于采取个体化治疗也不利于防止不良反应的发生，不应当强行推广。（5）认同Tostmann等提出的“除外病毒性肝炎、自身免疫性肝炎和其他原因所引起的肝损伤的前提下，抗结核药物性肝损伤的判断标准为：在抗结核治疗中，未出现肝炎症状，但ALT升高至正常上限值的5倍以上；或出现了肝炎症状，ALT升高至正常上限的3倍或者胆红素升高至正常上限的2倍以上”。其严重程度分为轻度：转氨酶升高但未出现肝炎的临床症状，重度：出现急性肝衰竭表现，中度：在轻度和重度之间。结论（1）在抗结核治疗之前必须查明肝脏和全身基础疾病，规范病史采集内容。包括（包括饮食习惯，饮酒史，各型肝炎史特别是乙型肝炎、丙型肝炎病史及其潜在感染史，胆管疾病史，营养不良有关病史，内分泌及代谢性疾病史，引发肝脏病变的寄生虫接触史及发病史，中毒史，用药不良反应史，过敏史及过敏性疾病家族史，是否有便秘，当前是否在服用治疗其他疾病的药物，等等）。（2）应规范抗结核治疗前和治疗中的检测和监测的实验室及相关辅助检查项目。对相关的检测项目应予补充完善，临床工作者要正确面对患者不合理的降低医疗费用要求的压力，坚持合理检查。（3）规范治疗中应监测的项目的检测时间间隔。当前要将针对抗结核治疗中肝损伤隐患的检测项目全面普及开展还不现实，但应逐步开展和完善。（4）制定针对已测知危险因素的应对及治疗措施（治疗合并的肝脏基础疾病，纠正低蛋白血症和营养不良，避免联合使用增强肝毒性的其他药物，选择对肝脏毒副反应较小的抗结核药物组成联合方案，酌情使用护肝药，加强治疗中肝功能的监测，指导患者注意治疗期间禁止饮酒，避免过度的疲劳并保证良好的生活习惯，避免不适当地使用免疫调节剂）。（5）制定出现肝损伤时的应对措施（加强肝肾功能和血常规的监测，调整抗结核药物联合方案，制定暂停抗结核治疗和恢复抗结核治疗的判断标准及肝损伤的治疗措施，人工肝和肝移植技术的应用）。建议如果ALT和总胆红素升高达到ALT≥6×ULN或（和）总胆红素≥3×ULN时，应根据患者的具体情况考虑是否暂时停用抗结核药物，可酌情选择对肝脏不良反应较小的抗结核药物联合方案在护肝、利胆等保护措施下继续抗结核治疗；当ALT≥8×ULN或（和）总胆红素≥5×ULN时应暂时停用抗结核药物，给予护肝及利胆药物治疗（6）必须进一步共同关注的事宜（加强结核病防治工作人员抗结核治疗肝损伤相关知识的培训教育，实现结核病防控策略的与时俱进，建立针对药物不良反应的补偿机制）。展望全体同道和全社会共同努力，提高和普及结核病治疗中肝损伤相关知识，熟悉相关危险因素，完善实验室检查发现手段，探讨合理的调整抗结核治疗、护肝治疗及停药措施，努力实现治疗和管理措施与时俱进。必然会减少抗结核治疗中肝损伤的发生，提高结核病的治疗质量，降低医疗风险，更好地造福人类。

【关键词】肝损伤；药物性；诊断标准；预防；危险因素

Risk factorsrelated to anti-tuberculosis drug-induced liver injuryand countermeasures of clinical managementLEI Jian-ping*, WU Xue-qiong, ZHANGWen-hong.*Chest Hospital of Jiangxi Province，Nanchang 330008，China.

【Abstract】Background：Drug-induced liver injury is the most common adverse reaction in anti-tuberculosis treatment, which is a common problem of endangering the life safety and health of tuberculosis patients and affecting national tuberculosis control strategy.At present, there is a lack of clinical diagnosis and treatment guidelines and expert consensus on the prevention and treatment of anti-tuberculosis drug-induced liver injury in China and abroad. It is imperative for clinical workers to solve this problem. Objective：The purpose of this paper is to explore the countermeasures on the clinical prevention and treatmentof drug-induced liver injury in anti-tuberculosis treatment. Methods:The relative risk factors (including drugs, patients, medical care and management, defects in prevention and control strategy etc.) of anti-tuberculosis drug-induced liver injury were analyzed through the review of literatures and related guidelines between 1986 and 2013, and then find out the corresponding strategies.Results: The risk factors of drug-induced liver injury in anti-tuberculosis treatment were as follows:(1) Closely related with the metabolic process and characteristics in vivo, drug dosage, drug allergic liver injury and combined use of various anti-tuberculosis drugs. It is pointed out that the comventional dose of Isoniazid (INH) can hardly cause liver injury. At present, the maximum dosage of INHuse should not be more than 0.3 g/d in the drug instruction manual, which lacks scientific evidence and is inappropriate. This is an important reason inducing drug resistance in the process of low dose of drug use, and must be corrected. (2) Closely related with the patient's own factors (for example, congenital liver drug enzymes, allergic constitution, autoimmune disease or potential autoimmune defect, organ aging, bad living habits such as being addicted to drink), common liver basic diseases (for example, viral hepatitis, alcoholism, cholestasis, chronic heart disease, immune disorders, metabolic disorders, industrial poisons or drug poisons, nutritional disorders, schistosomiasis liver fibrosis, unknown cryptogenic cirrhosis), severe tuberculosis, other severe systemic diseases, hypoproteinemia, endocrine diseases (for example, adrenal cortical dysfunction, female endocrine change phase) and so on. (3)Related with medical care and management factors (such as the limited knowledge of some medical staff, lack of understanding on the risk factors, examination items, diagnosis and prevention methods related to liver injury; some medical workers could not correctly grasp the scale of reducing medical costs and reasonable examination, and gave up the necessary testing and monitoring; some medical workers had some misunderstanding about the concept of standardized treatment, did not know to follow the principle of the combination of generalization and individualization, and regarded general principle as standardization principle one-sidedly; failure to diagnose and treat basic liver diseases and systemic diseases in time; irrational use of immunomodulators). (4) Related with imperfect the strategy of prevention and control (the content of controlling the adverse reaction of antituberculotic drug lacks in the prevention and cure strategy;lack of normative guidance on examination items before the use of anti-tuberculosis drugs and on monitoring projects in the treatment; the training of medical personnel was insufficient, so that many medical personnel, especially the primary medical workers, did not know enough about the risk factors of liver injury in tuberculosis treatment, the judgment of liver function and grading criteria of liver function). At present, it is necessary to re-understand the concept of "standardization". There is a problem of "general principle" and "individualized principle" in the treatment of any patient.Combined drug preparation are unfavourable for individualized treatment and for preventing adverse reactions, and should not be forcibly promoted.(5) Agree to the following suggestion ofTostmannet al.:With the exception of viral hepatitis, autoimmune hepatitis and other causes of liver injury, the diagnostic criteria for liver injury induced by anti-tuberculous drugs are as follows:during anti-tuberculosis treatment, the patients without hepatitis symptoms increased ALTmore than 5 times of the normal upper limit;or the patients with hepatitis symptoms increased the ALT to 3 times of the normal upper limit or the bilirubin to more than 2 times of the normal upper limitThe criteria for severity of liver injury are as follows: mild, be asymptomatic and elevation of hepatic aminotransferase; severe: acute hepatic failure; moderate: between mild and severe liver injury.Conclusion：(1) The basic diseases of liver and whole body must be clear before anti-tuberculosis treatment,and the collection of disease history should be standardized, including eating habits, drinking history, the history of hepatitis (especially hepatitis B, hepatitis C) and the history of potential infection, the history of bile duct disease, malnutrition-related disease, endocrine and metabolic diseases, contact with parasites and developing disease, poisoning, drug adverse reactions, allergies, family history of allergic diseases, constipation, current medication for other diseases, etc. (2)Laboratory and related accessory examination should be standardized before and in the anti-tuberculosis treatment. The relevant examination items should be supplemented and improved.Clinical workers should correctly face the pressure of unreasonable reduction of medical costs and insist on reasonable examination. (3)Detection interval for monitoring items in the treatment should be standardized. At present, it is not realistic to popularize the examination items for the hidden dangers of liver injury in anti-tuberculosis treatment, but it should be carried out and perfected step by step. (4) Develop response and treatment measures for perceived risk factors: treating liver basic diseases, correcting hypoproteinemia and malnutrition, avoiding combined use of other drugs that enhance liver toxicity,selecting a joint regimen of anti-tuberculosis drugs that have less adverse effects on the liver, appropriately using hepatinica, strengthening the monitor of liver function during the treatment, instructing the patients to refrain from drinking alcohol during the treatment, avoiding excessive fatigue and ensuring good living habits, avoiding improper use of immunomodulators. (5) Set down the countermeasures in the event of liver injury：strengthening the monitoring of liver function, kidney function and blood routine, adjusting the combined programme of anti-tuberculosis drugs, developing the criteria for temporary cessation of anti-tuberculosis treatment and resumption of anti-tuberculosis treatment and the treatment methods of liver injury, the application of artificial liver and liver transplantation techniques.It is suggested that ifthe patients’ ALT and total bilirubin increase to ALT ≥ 6 × ULN or/and total bilirubin ≥ 3 × ULN, it should be considered whether to suspend anti-tuberculosis drugs according to the specific situation of patients,the combination of anti-tuberculosis drugs with less adverse effects on liver may be selected to continue anti-tuberculosis treatment under the protective measures such as liver protection and cholagogue; when the patients’ ALT ≥ 8 × ULN or/and total bilirubin ≥ 5 × ULN, the patients should suspend anti-tuberculous drugs, and give liver protection and cholagogue treatment.(6) Matters requiring further common concern: strengthening the training and education of tuberculosis prevention and control workers about liver injury of anti-tuberculosis treatment, realizing the strategy of tuberculosis prevention and control with the times, and establishing a compensation mechanism for drug adverse reactions. Look ahead:Thewhole anti-tuberculosis workers and the whole society will make further efforts to improve and popularize the liver injury-related knowledge in tuberculosis treatment,to be familiar with the relevant risk factors, to improve the methods of laboratory examination and discovery, and to explore the reasonable measures of anti-tuberculosis treatment, liver protection and drug stop,make great efforts to achieve the treatment and management measures with the times.It will reduce the incidence of liver injury induced by anti-tuberculosis drugs, improve the quality of tuberculosis treatment, reduce the medical risk and better benefit the human.

【Key words】Liver injury；Drug-induced；Diagnostic standard； Prevention；Risk factors