Epidemiological Characteristics And Drug Use Analysis Of Drug-induced Liver Injury In Children In China

DILI is one of the most serious and common adverse drug reactions(ADR).The slightest ADR is only manifested by abnormal liver function,while the heaviest ADR can lead to liver failure or even death.Children’s liver is immature,their immune system is not perfect,their tolerance and metabolic ability to drug potential hepatotoxicity are insufficient,and they are more likely to suffer from liver injury.However,compared with a large number of studies on DILI in adult,the research on DILI in children is still very limited.The disease composition,types of medication,usage and dosage of drugs in children are different from adult patients,so there are also some differences in the pathogenic drugs leading to liver injury.It is urgent to study the epidemiological characteristics of DILI in children and their liver-damaging drugs in China.Part Ⅰ The study of Liver specific adverse drug reaction in children based on national ADR monitoring data.Objective:To explore the epidemiological characteristics and suspicious hepatotoxic drugs of liver-related adverse drug reaction(LSADR)in children in China,and to explore the potential risk signals of DILI in children,so as to provide reference for the prevention and management of DILI in children.Methods:A retrospective study was conducted to collate and analyze the clinical data of gender,age,suspicious hepatotoxic drugs,latency and adverse reactions of spontaneously reported LSADR cases in children aged 0-14years from January 1,2012 to December 31,2016 in the National Adverse Drug Reaction Monitoring Database.The LSADR cases in children were divided into western medicine-induced LSADR group(WM group),traditional Chinese medicine-induced LSADR group(TCM group)and LSADR group induced by combination of TCM and WM(combination of TCM and WM group)by the method of causality judgment of adverse reactions of WHO-UMC.To analyze the epidemiological characteristics of LSADR in children in recent five years and the characteristics of suspicious hepatotoxic drugs in children of different groups and ages.The potential risk factors of DILI in children are explored and the prevention and control countermeasures are put forward.Descriptive statistical analysis was carried out by SPSS 19.0 software.The measurement data conforming to normal distribution were expressed by (?)±s,the measurement data of skewed distribution were expressed by M(Q1~Q3),and the number of cases of counting data was expressed by rate(%).Results:1.1518 cases of LSADR in children were reported spontaneously in China from 2012 to 2016,and the number of reported cases increased year by year.The male-female ratio of LSADR in 1518 children was 1.39:1(884/634 cases).Children under one year old accounted for 37%of the total population of children.2.Injection was the main form of suspected hepatotoxic drugs in children(61%),and antibiotics accounted for 51%of the injections.The latency of suspected hepatotoxic drugs in children was mainly within two weeks,accounting for 84%.3.There were 1404 cases of liver injury caused by WM,accounting for92%.The main suspected hepatotoxic drugs were anti-infective drugs,anti-tumor drugs and antipyretic,analgesic and anti-inflammatory drugs.Anti-infective drugs rank first in all age groups of children,and the proportion of anti-infective drugs in neonatal period is as high as 83.2%,which is much higher than other age groups.The first suspected hepatotoxic drug in neonatal period is meropenem;the first hepatotoxic drug in infant and early childhood is azithromycin;the first hepatotoxic drug in pre-school and school age is methotrexate.In neonatal period,vancomycin-induced liver injury ranked second,accounting for 10.7%of neonatal period,while in other age groups,the proportion of vancomycin-induced liver injury was less than 3.1%.In school-age children,besides anti-infective drugs and anti-tumor drugs,the use of drugs in endocrine system,nervous system and psychotropic are also increasing.It is also noteworthy that vitamins,minerals and parenteral nutrition drugs(mainly fat emulsion)rank second in neonatal period.4.29 cases of liver injury caused by TCM accounted for 2%.The main suspected hepatotoxic TCM for children are dermatological medicines.The reported hepatotoxic TCM include Polygonum multiflorum,Psoralea corylifolia and Fresh Peel.5.85 cases(6%)of liver injury were caused by combination of TCM and WM.Which is more common due to combination of anti-infective drugs or(and)antipyretic,analgesic and anti-inflammatory drugs with TCM such as heat-clearing category,antitussive and phlegm-resolving category and relieving convulsion and spasm category.Conclusion:More children in males than in females of reported LSADR cases in China.The proportion of LSADR in children under 1 year old is relatively high.We should attach great importance to the risk of liver injury in children under 1 year old.In addition,we need to focus on preventing and controlling the risk of liver injury caused by anti-infectives,anti-cancer drugs,antipyretics,analgesics and anti-inflammatory drugs.In addition,attention should be paid to the risk of liver injury in neonates treated with vitamins,minerals,parenteral nutrition drugs and endocrine,nervous and psychotropic drugs in school-age children.The proportion of liver injury caused by traditional Chinese medicine is relatively low.It is necessary to focus on the prevention and control of the risk of liver injury caused by dermatological drugs.Multidrug combination may be one of the risk factors of liver injury associated with combination of TCM and WM in children..Whether the TCM in the combination of TCM and WM group has hepatotoxicity needs to be further clarified,and the benefit and risk assessment of the combination of TCM and WM need to be further studied.Part Ⅱ Clinical reevaluation of drug-induced liver injury in children based on hospitalized casesObjective:To explore the liver-damaging drugs and related risk factors leading to DILI in children,and to provide references for safe drug use in children.Methods:A retrospective study was conducted to collect and collate clinical records of children discharged from our hospital from January 2008 to December 2017 diagnosed as DILI.The DILI cases of children who met the diagnostic criteria of the Guidelines for the“Diagnosis and Treatment of Drug-induced Liver Injury”were included in the study.According to the criteria of the Integrated Evidence Chain(IEC)method in the Guidelines for the“Clinical Diagnosis and Treatment of Herbal-induced Liver Injury”,the clinical reassessment of DILI cases in children was carried out.The case screening was assisted by two liver specialists.The DILI cases in children were divided into three groups by the method of IEC:DILI caused by western medicine(WM group),DILI caused by traditional Chinese medicine(TCM group)and DILI caused by combination of TCM and WM(combined of TCM and WM group).To analyze the clinical characteristics of children with DILI,including sex,age,biochemical indicators,symptoms and signs,severity,clinical classification,clinical outcome,etc.To screen and evaluate the risk factors of DILI in children by analyzing the medication characteristics of different groups of children with different medication reasons,suspicious hepatotoxic drugs varieties and classifications,medication time and latency.The measurement data of skewed distribution were expressed by M(Q1~Q3),Kruskal-Wallis H test was used for comparison among groups,and the number of counting data was expressed by rate(%)andχ~2 test was used for comparison between groups,P<0.05was statistically significant.Results:1.Clinical features:187 children with DILI were included in this study.The ratio of male to female was 1.63:1(116/71)..The main clinical types were hepatocyte injury(144 cases,77%),and there were 19 cases(10%)of cholestasis and 24 cases(13%)of mixed cholestasis.The main clinical manifestations were jaundice.144 children(77%)had jaundice symptoms,86 children(46%)had digestive tract symptoms(such as anorexia,nausea and vomiting),67 children(36%)had signs of hepatosplenomegaly,45children(24%)had signs of fatigue,21 children(11%)had symptoms of fever,19 children(10%)had rash signs,32 children(17%)had no clinical symptoms and signs,which were only indicated by biochemical examination.Liver dysfunction.There were 116 children with DILI whose severity was severe or above,accounting for 62%of all cases.45 cases(24%)had chronic disease,4 cases(2%)died or underwent liver transplantation.2.Characteristic of suspected liver damage drugs:127 cases(68%)of children with DILI can obtain medication information,among which,Suspicious hepatotoxic drugs in the combination of TCM and WM group(n=37,20%)were mainly anti-infective drugs and/or antipyretic,analgesic and anti-inflammatory drugs combined with TCM such as antipyretic drugs and/or antipyretic drugs.The suspicious liver-damaging western medicine in WM group(n=75,40%)and combination of TCM and WM group were mainly antibiotics,antipyretics,analgesics and anti-inflammatory drugs,accounting for 42%and 30%,56%and 31%respectively.The suspected liver-damaging drugs in the TCM group(n=15,8%)were mainly TCM for dermatosis,accounting for 47%of the TCM group,and the main reason was the preparation of Polygonum multiflorum(33%).There were significant differences in the time of medication(H=11.658,P=0.003)and latency(H=10.945,P=0.004)among the three groups.After pairwise comparison,the time and latency of medication in the TCM group were longer than those in the other two groups,and the difference was statistically significant(P<0.05).3.Combination of multiple drugs at risk of hepatotoxicity,combination of drugs containing the same ingredients and drug use in violation of instructions are important risk factors for DILI in children.Conclusion:Children with DILI are more male than female.Most children with DILI are serious and the chronic rate is higher than that of adults.Great attention should be paid to the risk of liver injury caused by drug use in children.Especially,the risk of liver injury caused by anti-infectives,antipyretics,analgesics and anti-inflammatory drugs should be focused on prevention and control.The actual proportion of children with HILI is lower than that reported in the past.In the prevention and control of HILI,it is necessary to focus on the prevention and control of the risk of liver injury caused by long-term medication for dermatosis.The causal relationship evaluation,benefit and risk assessment of DILI related to combination of TCM and WM need to be further developed.In addition,we should be alert to the risk of liver injury caused by the combination of drugs with hepatotoxicity risk or drugs with the same composition,and drugs used in violation of the instructions.