103例药物性肝病患者临床特征分析
摘要
目的:分析诱导药物性肝病的药物分类、药物性肝病的临床特征及疾病转归,为进一步完善药物性肝病的临床研究提供依据。
方法:采用回顾性研究的方法对吉林大学中日联谊医院消化内科近10年因肝功能异常入院并最终确诊为药物性肝病的患者共103例,对服药史、临床表现、实验室检查、影像学检查及停药后效应进行综合评价,并对所有患者治疗前后肝功能(丙氨酸氨基转移酶ALT、天冬氨酸氨基转移酶AST、碱性磷酸酶ALP、γ-谷氨酰转肽酶GGT、总胆红素TBIL)进行比较,评价不同治疗方案对疾病预后的影响。血清生化学指标采用美国贝克曼公司全自动生化分析仪及配套试剂进行检测。
结果:103例药物性肝病患者中,男、女发病率之比为1:1.10,性别间无明显差异;发病年龄最小者8岁,最大者80岁,平均发病年龄43.68±15.40岁,服药至出现肝损害时间最短为5天,最长为120天,平均为5.73±24.04天;诱导肝损伤的药物以中药最为多见,尤其是治疗皮肤病、骨关节疾病及消化系统疾病的中药,西药主要为抗结核药、免疫抑制剂、非甾体类抗炎药;临床分型以急性肝炎型最常见,其肝功能恢复正常时间明显快于胆汁淤积型等其他类型药物性肝病(P<0.05);当药物性肝病患者与病毒性肝炎或酒精性肝病并存时肝功能恢复较慢(P<0.05);对ALT显著升高的药物性肝病患者大剂量甘草酸制剂治疗组明显优于常规甘草酸制剂剂量治疗组(P<0.05);对TBIL升高的药物性肝病患者采用UDCA治疗方案明显好于未应用UDCA者(P<0.05)。
结论:本组药物性肝病患者发病高峰年龄在40～49岁之间,性别间无明显差异,服药至出现肝损害时间以30～45天最常见;诱导本组患者出现肝损伤的药物以中药最为多见,尤其是治疗皮肤病、骨关节疾病及消化系统疾病的中药;西药主要为抗结核药、免疫抑制剂、非甾体类抗炎药、抗生素、抗甲状腺药及调脂药;本组药物性肝病患者的临床分型以急性肝炎型最常见,其肝功能恢复至正常时间明显快于胆汁淤积型等其他类型药物性肝病;当药物性肝病患者与病毒性肝炎、酒精性肝病等慢性肝病并存时,肝功能恢复较慢;针对药物性肝病的不同临床表现采用不同的个体化治疗方案至关重要。对ALT升高的药物性肝病患者应用大剂量甘草酸制剂治疗效果明显好于常规剂量治疗者;对TBIL升高的药物性肝病患者采用UDCA治疗方案明显好于未应用UDCA者。
Objective: To analyze drug classifications of revulsive drug-induced liver disease (DILD), clinical features and disease prognosis of DILD, hoping to provide a basis for further exploration of the DILD clinical investigation.
Methods: By means of retrospective research method, this essay was conducted a comprehensive evaluation on the medication history,clinical manifestation,lab -oratory tests, imaging examinations and the effects of drug withdrawal among 103 cases, which were hospitalized in the digestive division of China and Japan Union Hospital of Jilin University due to abnormal function of liver and final diagnoses of DILD in the recent decade. Meanwhile, this essay made a comparative study of liver function before and after medical treatment. (ALT, AST, ALP, GGT, TBIL). Lastly, this essay evaluated the effects of diverse therapeutic schedule on disease prognosis.
Results:Among 103 patients of DILD, incidence ratio of male and female was 1:1.10. There was no striking difference between genders. The age of onset ranged from minimum 8 to maximum 80, averaging 43.68±15.40. As for the length of time between medicine taking and hepatic lesion, the minimum day was 5, however, the maximum 120, averaging 5.73±24.04. Chinese Herbal Drugs was the most obvious medicine which could induce hepatic lesion, especially those medicine used to cure skin disease, bone and joint diseases and digestive diseases. Western medicine mainly includes anti-TB drugs, immunosuppressor and non-steroid anti-inflammatory drug. Acute hepatitis was the most common type of clinical classification and the recovery time of live function was much faster than that of cholestasis type or other types of DILD (P<0.05). The recovery was rather slow when the DILD combined with virus hepatitis or alcoholic liver disease (P<0.05). As for those patients whose ALT normalization degree were high, the effects after being used glycyrrhizin group was superior to that of S-adenosyl methi onine group (P<0.05), notably, on the part of those patients whose ALT normalization degree were extremely high, the treatment effect of megadose glycyrrhizin group was superior to that of normal glycyrrhizin group (P<0.05); As for the patients whose TBIL normalization degree were high, the therapeutic schedule of adopting UDCA was obviously better compared with those did not adopt UDCA therapeutic schedule (P<0.05).
Discussion: With the wide application of drugs, the constant appearance of new drugs and multiplication of combination therapy. DILD had become the common and serious diseases both at home and abroad. According to the statistics of WHO, the DILD had increased to the fifth reason causing death in the world, at the same time, it became the serious social and public health problem around the globe. Both doctors and patients attached less importance to DILD, had insufficient recognition of the dangers of DILD in China. Doctors still could not observe the patients integrally and failed to make timely diagnose on DILD. Hence, the current reportage of disease rate was lower than that in the Occident. However, there still remained one assumption that actual DILD incidence rate in China was higher than that of the Occident. Currently, the reported drugs which could induce liver damage amount to about 1000 kinds. The regional difference was quite striking, acetaminophen application was the most common at abroad. However, in this essay, the subjects investigated were mainly liver damage patients who took traditional Chinese herbals. Due to the reason that Chinese herbals had been already widely applied in disease treatment and health care, the liver damages caused by Chinese herbals had become major problems in clinical applications. In this sense, much more priority had been given to the liver damages caused by Chinese herbals. Clinical classification was the significant description of the clinical features of DILD. The main subjects in this essay were acute hepatitis patients, the discovery was that the recovery time of liver function was obvious short for acute hepatitis patients compared with other types, because most acute hepatitis patients mainly suffered from hepatocellular necrosis and inflammatory infiltration. In other words, they could easily get well recovered compared with other pathology damage. In the research, when DILD co-exist with other liver diseases, the recovery time of liver function was obviously been prolonged than DILD. This effect was supposed to be the joint effects of hepatitis virus and alcohol, which aggravated liver damage. As for the DILD, the key to therapy was to stop and prevent of the use of the drugs that might cause liver damage. Meanwhile, to repair liver epicyte and bile duct injury was also the significant factor during the process of therapy. In the research, as for those patients whose ALT normalization degree were high, the effects after being used glycyrrhizin group was superior to that of S-adenosyl-methionine group, notably, on the part of those patients whose ALT normalization degree were extremely high, the treatment effect of megadose glycyrrhizin group was superior to that of normal glycyrrhizin group. As for the patients whose TBIL normalization degree were high, the therapeutic schedule of adopting UDCA was obviously better compared with those did not adopt UDCA therapeutic schedule. Glycyrrhizic acid could dissolve into glycyrrhetinic acid in one’s body, which had the similar function of steroid hormone. Meanwhile, the different isomer of glycyrrhizic acid cooperated together, glycyrrhizic acid could repair liver epicyte. UDCA belonged to water-soluble bile acid, which could effectively prevent the toxic bile acid from damaging liver cells and bile duct cells. Still, UDCA’s immune regulation function could stop prodrug-mediated liver immune pathology damage. UDCA could effectively cure DILD, especially suitable for those Cholestasis patients.
Conclusion: The boom of DILD in this research occurred between 40 to 49, there was no great difference between genders. As for the length of time between medicine taking and hepatic lesion, the minimum day was 5, however, the maximum 120, averaging 5.73±24.04. Chinese Herbal Drugs was the most obvious medicine which could induce hepatic lesion, especially those medicine used to cure skin disease, bone and joint diseases and digestive diseases. Western medicine mainly includes anti-TB drugs, immunosuppressor , non-steroid anti -inflammatory drug, antibiotics antithyroid drug and blood lipid-lowering drugs. Acute heaptitis was the most common type of clinical classification and the recovery time of live function was much faster than that of cholestasis type or other types of DILD. The recovery was rather slow when the DILD combined with virus hepatitis or alcoholic liver disease . As for different clinical feature of DILD, custom-tailored therapeutic schedule is of great importance. The ALT normalization degree after being used glycyrrhizin group was better than S-adenosyl-methionine group, and the TBIL normalization degree after being combined with UDCA was better than other groups.
方法:采用回顾性研究的方法对吉林大学中日联谊医院消化内科近10年因肝功能异常入院并最终确诊为药物性肝病的患者共103例,对服药史、临床表现、实验室检查、影像学检查及停药后效应进行综合评价,并对所有患者治疗前后肝功能(丙氨酸氨基转移酶ALT、天冬氨酸氨基转移酶AST、碱性磷酸酶ALP、γ-谷氨酰转肽酶GGT、总胆红素TBIL)进行比较,评价不同治疗方案对疾病预后的影响。血清生化学指标采用美国贝克曼公司全自动生化分析仪及配套试剂进行检测。
结果:103例药物性肝病患者中,男、女发病率之比为1:1.10,性别间无明显差异;发病年龄最小者8岁,最大者80岁,平均发病年龄43.68±15.40岁,服药至出现肝损害时间最短为5天,最长为120天,平均为5.73±24.04天;诱导肝损伤的药物以中药最为多见,尤其是治疗皮肤病、骨关节疾病及消化系统疾病的中药,西药主要为抗结核药、免疫抑制剂、非甾体类抗炎药;临床分型以急性肝炎型最常见,其肝功能恢复正常时间明显快于胆汁淤积型等其他类型药物性肝病(P<0.05);当药物性肝病患者与病毒性肝炎或酒精性肝病并存时肝功能恢复较慢(P<0.05);对ALT显著升高的药物性肝病患者大剂量甘草酸制剂治疗组明显优于常规甘草酸制剂剂量治疗组(P<0.05);对TBIL升高的药物性肝病患者采用UDCA治疗方案明显好于未应用UDCA者(P<0.05)。
结论:本组药物性肝病患者发病高峰年龄在40～49岁之间,性别间无明显差异,服药至出现肝损害时间以30～45天最常见;诱导本组患者出现肝损伤的药物以中药最为多见,尤其是治疗皮肤病、骨关节疾病及消化系统疾病的中药;西药主要为抗结核药、免疫抑制剂、非甾体类抗炎药、抗生素、抗甲状腺药及调脂药;本组药物性肝病患者的临床分型以急性肝炎型最常见,其肝功能恢复至正常时间明显快于胆汁淤积型等其他类型药物性肝病;当药物性肝病患者与病毒性肝炎、酒精性肝病等慢性肝病并存时,肝功能恢复较慢;针对药物性肝病的不同临床表现采用不同的个体化治疗方案至关重要。对ALT升高的药物性肝病患者应用大剂量甘草酸制剂治疗效果明显好于常规剂量治疗者;对TBIL升高的药物性肝病患者采用UDCA治疗方案明显好于未应用UDCA者。
Objective: To analyze drug classifications of revulsive drug-induced liver disease (DILD), clinical features and disease prognosis of DILD, hoping to provide a basis for further exploration of the DILD clinical investigation.
Methods: By means of retrospective research method, this essay was conducted a comprehensive evaluation on the medication history,clinical manifestation,lab -oratory tests, imaging examinations and the effects of drug withdrawal among 103 cases, which were hospitalized in the digestive division of China and Japan Union Hospital of Jilin University due to abnormal function of liver and final diagnoses of DILD in the recent decade. Meanwhile, this essay made a comparative study of liver function before and after medical treatment. (ALT, AST, ALP, GGT, TBIL). Lastly, this essay evaluated the effects of diverse therapeutic schedule on disease prognosis.
Results:Among 103 patients of DILD, incidence ratio of male and female was 1:1.10. There was no striking difference between genders. The age of onset ranged from minimum 8 to maximum 80, averaging 43.68±15.40. As for the length of time between medicine taking and hepatic lesion, the minimum day was 5, however, the maximum 120, averaging 5.73±24.04. Chinese Herbal Drugs was the most obvious medicine which could induce hepatic lesion, especially those medicine used to cure skin disease, bone and joint diseases and digestive diseases. Western medicine mainly includes anti-TB drugs, immunosuppressor and non-steroid anti-inflammatory drug. Acute hepatitis was the most common type of clinical classification and the recovery time of live function was much faster than that of cholestasis type or other types of DILD (P<0.05). The recovery was rather slow when the DILD combined with virus hepatitis or alcoholic liver disease (P<0.05). As for those patients whose ALT normalization degree were high, the effects after being used glycyrrhizin group was superior to that of S-adenosyl methi onine group (P<0.05), notably, on the part of those patients whose ALT normalization degree were extremely high, the treatment effect of megadose glycyrrhizin group was superior to that of normal glycyrrhizin group (P<0.05); As for the patients whose TBIL normalization degree were high, the therapeutic schedule of adopting UDCA was obviously better compared with those did not adopt UDCA therapeutic schedule (P<0.05).
Discussion: With the wide application of drugs, the constant appearance of new drugs and multiplication of combination therapy. DILD had become the common and serious diseases both at home and abroad. According to the statistics of WHO, the DILD had increased to the fifth reason causing death in the world, at the same time, it became the serious social and public health problem around the globe. Both doctors and patients attached less importance to DILD, had insufficient recognition of the dangers of DILD in China. Doctors still could not observe the patients integrally and failed to make timely diagnose on DILD. Hence, the current reportage of disease rate was lower than that in the Occident. However, there still remained one assumption that actual DILD incidence rate in China was higher than that of the Occident. Currently, the reported drugs which could induce liver damage amount to about 1000 kinds. The regional difference was quite striking, acetaminophen application was the most common at abroad. However, in this essay, the subjects investigated were mainly liver damage patients who took traditional Chinese herbals. Due to the reason that Chinese herbals had been already widely applied in disease treatment and health care, the liver damages caused by Chinese herbals had become major problems in clinical applications. In this sense, much more priority had been given to the liver damages caused by Chinese herbals. Clinical classification was the significant description of the clinical features of DILD. The main subjects in this essay were acute hepatitis patients, the discovery was that the recovery time of liver function was obvious short for acute hepatitis patients compared with other types, because most acute hepatitis patients mainly suffered from hepatocellular necrosis and inflammatory infiltration. In other words, they could easily get well recovered compared with other pathology damage. In the research, when DILD co-exist with other liver diseases, the recovery time of liver function was obviously been prolonged than DILD. This effect was supposed to be the joint effects of hepatitis virus and alcohol, which aggravated liver damage. As for the DILD, the key to therapy was to stop and prevent of the use of the drugs that might cause liver damage. Meanwhile, to repair liver epicyte and bile duct injury was also the significant factor during the process of therapy. In the research, as for those patients whose ALT normalization degree were high, the effects after being used glycyrrhizin group was superior to that of S-adenosyl-methionine group, notably, on the part of those patients whose ALT normalization degree were extremely high, the treatment effect of megadose glycyrrhizin group was superior to that of normal glycyrrhizin group. As for the patients whose TBIL normalization degree were high, the therapeutic schedule of adopting UDCA was obviously better compared with those did not adopt UDCA therapeutic schedule. Glycyrrhizic acid could dissolve into glycyrrhetinic acid in one’s body, which had the similar function of steroid hormone. Meanwhile, the different isomer of glycyrrhizic acid cooperated together, glycyrrhizic acid could repair liver epicyte. UDCA belonged to water-soluble bile acid, which could effectively prevent the toxic bile acid from damaging liver cells and bile duct cells. Still, UDCA’s immune regulation function could stop prodrug-mediated liver immune pathology damage. UDCA could effectively cure DILD, especially suitable for those Cholestasis patients.
Conclusion: The boom of DILD in this research occurred between 40 to 49, there was no great difference between genders. As for the length of time between medicine taking and hepatic lesion, the minimum day was 5, however, the maximum 120, averaging 5.73±24.04. Chinese Herbal Drugs was the most obvious medicine which could induce hepatic lesion, especially those medicine used to cure skin disease, bone and joint diseases and digestive diseases. Western medicine mainly includes anti-TB drugs, immunosuppressor , non-steroid anti -inflammatory drug, antibiotics antithyroid drug and blood lipid-lowering drugs. Acute heaptitis was the most common type of clinical classification and the recovery time of live function was much faster than that of cholestasis type or other types of DILD. The recovery was rather slow when the DILD combined with virus hepatitis or alcoholic liver disease . As for different clinical feature of DILD, custom-tailored therapeutic schedule is of great importance. The ALT normalization degree after being used glycyrrhizin group was better than S-adenosyl-methionine group, and the TBIL normalization degree after being combined with UDCA was better than other groups.
引文
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[2]Ostapowi cz Fontana R J,Schiodt FV,et al.Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States [J].Ann Intern Med,2002,137(12):947-949.
[3]谢志萍.药物性肝病378例病因和临床分析[J].传染病信息,2006,19(4):212-214.
[4]王文,于红.药物性肝病临床特点与转归分析[J].实用肝脏病学杂志,2008,11(3):191-192.
[5]HARTLEB M,BOERNATL,KOCHEL A.Drug-induced liver damage a three-year study of patients from one gastroen terological department [J].Med SciMonit,2002,8:CR 292-296.
[6]Critchley JA,Nimmo GR,Gregson CA,Woolhouse NM,Prescott LF.Inter-subject and ethnic differences in paracetamol metabolism[J] .Br J Clin Pharmacol 1986, 22:649-657.
[7]贾继东,崔儒涛.非甾体类抗炎药的肝脏毒性[J].肝脏,2001,6(1):50.
[8]Lukasic GM,Klimaszy KD Alcohol-paracetamol syndrome:clinical issues [J] .Przegl Lek,2002,59(4-5):381.
[9]Norris W,Paredes AH,Lewis JH.Drug-induced liver injury in 2007[J] .Curr Opin Gastroenterol.2008,24(3):287-297.
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