Clinical Research Of Acute Drug-induced Liver Injury And Fundamental Study Of HSOS

Background Acute drug-induced liver injury is one of common drug adverse reactions in clinical practice,which can result in acute liver failure and even death.Clinicians need the ability to identify and diagnose early acute drug-induced liver injury.Because of lack of characteristic clinical symptoms,signs and serological markers,at present,the diagnosis of acute drug-induced liver injury depend on method of exclusion.On the basis of clinical symptoms,signs of liver injury and anomal liver function and excluding virus hepatitis and biliary obstruction,the diagnosis of acute drug-induced liver injury maybe convincing.At present,a variety of method used for diagnosis of acute drug-induced liver injury emerge internationally,among them,use of the RUCAM is the most wide.It is necessary to collect acute drug-induced liver injury and use RUCAM to evaluate the intension of association of suspicious drugs with acute liver injury to increase accuracy of clinical diagnosis.A lot of drugs can lead to acute drug-induced liver injury.I n addition to the common anti-tuberculosis drugs,antineoplastic drugs,etc,the number of acute drug-induced liver injury caused by Chinese herbal medicine is more and more in recent years.acute liver injury-hepatic sinusoidal obstruction syndrome caused by tusanqi has its particularity.clinically,manifestations of HSOS main include hepatomegaly,weight gain and jaundice,liver of HSOS is gore.hepatic sinusoid congestion expansion arise obviously in pathological histology.Now,the pathogenesis of HSOS is still not completely clear,so it is necessary to establish HSOS animal models to explore the HSOS pathogenesis.Aims 1.To survey hospitalized cases of acute drug-induced liver injury in recent five years our hospital,judge the type of liver injury and evaluate correlation intension intensity of suspected drug with acute liver injury.To calculate the proportion of Chinese herbal medicine in suspected drugs.To analyse clinical data and prognosis of tusanqi related and to provide reference for clinical doctors;2.To establish rat HSOS model and to observe dynamic histological change and ultrastructure change.To investigate the role of matrix metalloproteinase-9(MMP-9)and tissue inhibitor of metalloproteinase-1(TIMP-1)in the pathogenesis of HSOS.Methods 1.Collecte retrospectively cases of acute drug-induced liver injury in recent five years our hospital,record patients’ general clinical data,symptoms and signs,suspected drugs and laboratory examinations,adopte RUCAM to differentiate the type of liver injury and evaluate correlation intension intensity of suspected drug with acute liver injury and classify suspicious drugs,calculate percentage.Record medical reasons and methods of tusanqi related HSOS and analyze prognosis;2.32 SD male rats are randomly divided into 2 groups-normal control group and experimental group.Experimental group rats are single lavaged by monocrotaline(MCT)to preparate HSOS model.Rats are executed on 1,2,4 days after lavage.Control group rats are single lavaged by equivalent dimethyl sulfoxide(DMSO),rats are executed on 4 days after lavage,and then observe dynamicly HSOS pathological changes and ultrastructure changes.Immunohistochemical method and the real-time PCR are used to detecte expression of rats MMP-9 and TIMP-1 protein and m RNA expression on early HSOS.Results 1.Acute drug-induced liver injury are collected and include liver cell type 312 cases(68.9%),cholestasis type 59 patients(13.0%)and mixed 82 cases(18.1%).there are 53 cases(11.7%)RUCAM score greater than 8 points(very possible),6 ~ 8 points(probably)249 cases(55.0%),3 ~ 5 points(possibly)117 cases(25.8%),1 ~ 2 points(unlikely),30 cases(6.6%),less than 1 points(independent)4 cases(0.9%).Chinese herbal medicine is most(49.7%)in suspicious drugs of acute liver injury and includes 43 cases tusanqi related HSOS.In the 43 cases HSOS,there are 9 cases due to joints disease and trauma to eat tusanqi,there are 13 cases to eat tusanqi by bubble wine.72.1%(31/43)cases are cured or improved,cases fatality rate is 11.6%(5/43),no better or worse rate is 16.3%(7/43)in tusanqi related HSOS.It is worthy of special attention aboout tusanqi related HSOS.2.In HSOS rat experiment model induced by MCT,compared with normal control group,on day 1,liver sinusoidal endothelial linear structure is not completed in ultrastructure,on day 2,there are evidence of hepatic sinusoidal congestion expansion,central vein endothelial injury,on day 4,hepatic sinusoidal congestion is more severe.Compared with normal control group,day 1 after MCT lavage,MMP-9 liver protein and m RNA expression increased(P < 0.05),protein and m RNA of TIMP-1 have no obvious change,MMP-9 on 2 days protein and m RNA expression increased(P < 0.05),TIMP-1 protein and m RNA expression increased(P < 0.01).Conclusions 1.The most common type of liver injury is liver cell type in our hispital acute druginduced liver injury cases.RUCAM is helpful to evaluate correlation intension intensity of suspected drug with acute liver injury.The cases of casued by Chinese herbal medicine increase,we need pay attention to tusanqi related HSOS.2.MCT can build HSOS animals model.The first histological change of HSOS is hepatic sinusoid endothelial injury.extracellular matrix degradate,hepatic sinusoid endothelial cell damage,liver sinusoid integrity damage,and then lead to hepatic sinusoid congestion expansion and then progress clinical HSOS.MMP-9 and TIMP-1 piay a role in degradation of extracellular matrix in HSOS.