Study Of Clinical Characteristics Of Drug-induced Liver Injury

Study of Clinical characteristics of drug-induced liver injuryThe liver is an important organ not only in the vivo processing of metabolites but also in detoxificating of most drugs.Drug induced liver injury(DILI) refers to the liver damage caused by the intake of drugs and/Or chemicals through respiratory tract, digestive tract and vein approach etc.With the wide application of drugs,the emergence of new drugs and the increase in drug combination,DILI has become a common and more serious medicine source liver disease.Many drugs have been reported to be DILI related at home and abroad,but the overall clinical significance is so limited since the spectrum is so diverse.Thus it is becoming a problem needing to be solved that how to make a fast judgment for the diagnosis of DILI as well as its type and degree.It is noteworthy that there is significant difference between DILI and alcoholic liver disease(ALD) in therapeutic and prognostic aspects though confusions can always be found for their resemblance in clinical manifestations as well as laboratory findings.System research of the clinical characteristics of DILI has great guiding significance for its prevention,therapy and prognosis.Materials and Methods1,Login National Knowledge Infrastructure(CNKI),select Chinese Journal Full-text Database(CJFD),choose "drug-induced liver injury" as keywords and time limited from 2003 to 2008,download all the literature and titles in detail related to liver damage caused by drug.Then the original texts will be divided into case analysis and case reports,for each of which the reported drug and the number of cases will be analyzed statistically.2,We collect 145 DILI patients hospitalized in the department of Gastroenterology of the First Affiliated Hospital of China Medical University from July 2004 to January 2009.Except the cases not fitting the diagnostic criteria,a total of 105 cases aging from 19 to 79 years(average age 49.16±15.92) were obtained,including 38 cases of male,67 cases of female.For all of them,the medication history,clinical symptoms and signs,blood biochemistry and therapy were recorded.3,Among the hospitalized patients we collected from January 2000 to December 2004,152 cases were in line with the diagnostic criteria for DILI with age from 18 to 85 years old(the average age of 45.84±15.73 years);181 cases meet the diagnostic criteria for ALD aging from 25 to 78 years old(the average age of 47.88±10.98 years old).For each of them,age,gender,body height and weight,onset age,admission date, underlying disease,medication history and history of drinking,pre-treatment symptoms and main laboratory indicators were recorded respectively.4,Statistical analysis All the data were analyzed statistically with SPSS 11.5 software,setting P＜0.05 as statistically significant difference.Results1,Analysis of common drugs causing drug-induced liver injury(1)A total of 197 literatures were collected,including 96 case analysis and 101 case reports,involving 11,643 patients.Reports related to traditional Chinese medicine-induced liver injury were 22 cases and those for antithyroid drug-induced liver injury were 12.The anti-tuberculosis drug-induced liver injury was the most frequent according to the case reports(28 cases).(2)Among the common drugs related to DILI,anti-tuberculosis drugs occupied the highest proportion,followed by traditional Chinese medicine and antibiotics.All the three elements amount to 69.75%totally.The proportions of antipyretic analgesics, anti-thyroid drugs and anti-cancer drugs are more than 5%respectively,up to 16.75% in sum.According to case analysis,the anti-tuberculosis drugs,traditional Chinese medicine and antibiotics account for 63.33%totally.However,DILI simply caused by anti-Tuberculosis(TB) drugs amounts to 67.8%as to case reports.In both case reports and case analysis,traditional Chinese medicine and health products take a stable proportion around 20%respectively.(3)For the 8 literatures involving 70 cases of severe liver injury,there are 4 case analysis and 4 cases reports.In the common drugs which cause severe DILI,nearly 2/ 3 are Chinese herbal medicine,anti-TB drugs and antibiotics,with Chinese herbal medicine holding for almost 1/3.These herbal medicine include Tripterygium wilfordii and those for the treatment virus hepatitis,rheumatoid arthritis,psoriasis, obesity and prescriptions;antineoplastic agents,immunosuppressants and anti-thyroid drug are also unneglectable causes of severe DILI.2,Blood biochemical characteristics of DILI(1) The first onset clinical symptoms of DILI include fatigue(18.10%), abdominal pain(18.10%),jaundice(10.48%),abdominal distension(10.48%),fever (9.57%),elevated liver enzymes(9.52%),yellow urine(8.57%),anorexia(5.71%), nausea(5.71%),pruritus(2.86%),diarrhea(1.90%) and so on.Except for jaundice, most of the clinical symptoms were thought to be caused by primary disease and the patients didn't seek treatment until the jaundice turned out.When administrated,more than 71.43%(75/105) of patients in this group have abnormal level of total bilirubin; only slightly more than half of the patients(56/105) have obvious jaundice while there are still 28.57%of patients administrated for the elevated liver enzyme.Therefore, DILI has a longer course than the liver diseases caused by other factors.(2) According to the experimental results of liver function with reference to the international standard classification,DILI can be divided into 3 types:Liver cell type, intrahepatic cholestasis and mixed type,with ratio of 34.29%,25.71%and 40% respectively.The incidence of cholestasis type liver injury was significantly higher than that of liver cell type(x~2=54.11,P＜0.001).(3) The result of biochemical examination in DILI is significantly different from other liver diseases,mainly manifested in the enzymatic changes and disorder of bilirubin excretion.Further,DILI and liver enzymes and bilirubin are positively correlated,while negatively correlated with the renal function.The synthesis of protein was mostly not affected in the early stage of DILI,but obvious changes in protein synthesis can be observed when a large quantity of drugs(such as high-dose paracetamol or a large number of single herbs) with more toxicity were took,and late or severe hepatic necrosis happened.(4) When the ratio of enzymes≥1,the positive rate of diagnosis for DILI is high either in the cytosolic enzyme or enzymes of biliary tract,especially Aspartate Transaminase(AST) followed by Alkaline phosphatase(ALP),for both of which the positive rate are more than 60%.Further chi-square test reflected that the ratio between the liver cell injury enzymes AST and Alanine aminotransferase(ALT) and responsive enzymes of biliary tractγ-glutamyltranspeptidase enzyme(GGT) and ALP is helpful for the diagnosis of DILI while the ratio simply between liver cell enzymes or the biliary tract enzymes was meaningless.3,Clinical differences between DILI and ALD(1)The incidence of ordinary clinical symptoms Clinically,the incidence of nausea,anorexia,fatigue,abdominal pain,diarrhea,abdominal distension,bleeding, jaundice,itching appears high.In addition,the incidence of abdominal pain,diarrhea, abdominal distension and bleeding is higher in DILI than in ALD,with significant difference of abdominal distension between the two groups(p＜0.05) while nausea, anorexia,fatigue,jaundice and itching are more frequent in alcoholic liver diseases, weakness and jaundice are more prominent in patients with alcoholic liver disease especially(p＜0.01).(2) The differences in laboratory tests between the two groups The levels of ALT,ALP,Total bilirubin(TBIL),Albumin(ALB),Platelet(PLT),etc are higher in DILI group compared with ALD while White blood cell(WBC) are significantly higher in ALD.There was no significant difference in AST,GGT,Red blood cells (RBC) or mean corpuscular volume(MCV) between the two groups.(3) The differences in treatment results After two weeks' treatment,the majority of the clinical symptoms of ALD group showed apparent recovery after abstinence,adequate nutritional support and application of drugs improving liver metabolism,besides that chemical indicators returned to normal in 4 to 6 weeks. Compared to that,a slow resumption of the symptoms and signs was observed in DILI group,especially obstinate jaundice;jaundice in some cases continued to increase (although in the treatment) until 4 weeks later;the time of ALP,GGT normalization is 4 to 8 weeks while that of TBIL can prolong to 3 to 6 months.DiscussionAll the anti-tuberculosis drugs can cause liver damage and the risk was further increased by the combination of many anti-TB drugs.With the increase of multi-drug resistant tuberculosis,the drug dose and type increased;liver damage is more likely to happen to the population with low immunity who often use a combination of other drugs.According to our study,anti-tuberculosis drugs induced liver injury had the highest proportion in our country,which should be paid great attention to since the incidence of tuberculosis has an upward trend in the whole world.In Europe and the United States,the most common drugs related to DILI are antipyretic analgesics such as acetaminophen and antibiotics,which are different from our country and other Asian countries due to the wider use of Chinese medicine.A Japanese study found a rising proportion of DILI due to the use of health care products,civil remedies and traditional herbal medicine.As to our study,traditional Chinese medicine-induced severe liver damage accounts for30%,which is much higher than the other drugs.As a result,enough attention should be paid to its potential to cause damage at the same time of promoting traditional medicine.Their drug-related risk of liver damage should also be emphasized with an increasing type of antibiotics and the deeper understanding of the mechanism of rheumatic diseases as well as the increasing incidence of cancer and other diseasesThe occurrence of DILI is not only due to the application of special drugs for certain diseases(tumor,skin diseases,rheumatic fever,etc) but also to the non-specificity of its clinical symptoms.Except for jaundice,most of the clinical symptoms were thought to be caused by primary disease and the patients didn't seek treatment until the jaundice turned out. When administrated,more than 71.43%(75/105) of patients in this group have abnormal level of total bilirubin;only slightly more than half of the patients(56/105) have obvious jaundice while there are still 28.57%of patients administrated for the elevated liver enzyme.Therefore,DILI has a longer course than the liver diseases caused by other factors.The general standard for classification of DILI mainly depends on blood biochemistry.Generally,ALT and AST are sensitive to reflecting liver mitochondria injury and acinar lesions,while GGT,ALP and bilirubin are sensitive to disturbance of formation and excretion of bile;the mixed type may cover all possible abnormalities.In our study,both the total protein and albumin were within normal range when admitted, which is important basis for the differential diagnosis for other liver diseases.Our study had an attempt to find relationship of the various index of DILI which has rarely been investigated.From the research about the relevance of liver enzyme, bilirubin excretion and renal function,it can be seen that the level of liver enzymes was positively correlated with bilirubin,while negatively correlated with renal function when the patients were admitted.It is suggested that only the liver was impacted instead of other systems(urinary,blood,etc) in the early stage of drug metabolism. Timely detection and early withdraw of drug are of great significance for the prevention of fulminant hepatic failure(secondary to multiple organ dysfunction).In order to simplify the diagnostic procedures,our study explored the inter-relationship of various biochemical indexes.We compared positive rate(%) of the ratio between enzymes≥1 obtained in patients diagnosed as DILI and looked for their inner contact.The results reflect that the ratio between enzymes in response of liver cell injury(AST,ALT) and enzymes in response of biliary tract injury(GGT,ALP) shows significant differences for the majority of the positive rate of DILI,particularly the ratio between AST and other enzymes.This provides further evidence for the relationship between the occurrence of DILI and mitochondrial damage.Meanwhile,the ratio simply between the liver cell enzymes or the biliary tract enzymes is not valuable for the diagnosis of DILI which also requires further clinical study with larger sample.Lots of clinical similarities can be found in the ALD and DILI,since alcohol is also a special kind of drug.In this study,nausea,anorexia,fatigue,abdominal pain, diarrhea,abdominal distension,bleeding,jaundice and itching all have high incidence, while the incidence of abdominal pain,diarrhea,abdominal distension and bleeding are higher in DILI than ALD,with significant difference in distention between the two groups(p＜0.05);However,the incidence of nausea,anorexia,fatigue,jaundice and pruritus is higher in ALD than DILI,with fatigue and jaundice more prominent(p＜0.01)in patients with ALD in particular.Mechanism for this difference is still not very clear,which may be related to the directly or indirectly gastrointestinal mucosal injury caused by drugs,while bleeding is usually due to the impact on coagulation system; The occurrence of nausea,anorexia,fatigue,jaundice and itching in ALD may be explained by the impact of protein synthesis,bile acid formation and excretion in the liver as well as the metabolic disorders of inflammatory cytokines generated by oxidative stress.If the two factors exist simultaneously,there will be superposition of clinical symptoms. The increases of GGT and MCV have been viewed as the indicators of drinking. In this study,GGT increased obviously and half of the patients showed increasing trend of MCV,which is in line with the clinical features of ALD.In ALD,serum transaminase is usually less than 5 times the upper limit with AST increased dominantly(AST/ALT＞2) and ALT within normal range,as a result of the mitochondrial toxicity and inhibition of pyridoxal activity ~[9]caused by alcohol. Although the AST and ALT have also increased to varying degrees,but found no predominance of the AST increase has been found in this group.In ALD,there is frequently a marked increase in blood leukocyte due to the aseptic inflammatory response(mainly arising from increased TNF-α),which has been confirmed in this study.Conclusion(1) Common causes of drug-induced liver injury in China are consequently anti-tuberculosis drug,traditional Chinese medicine and antibiotics,with a total of the three and up to 69.75%.(2) As to the common causes of severe DILI,Chinese herbal medicine hold for almost 1/3,followed by anti-TB drugs and antibiotics,while antineoplastic agents, immunosuppressants and anti-thyroid drugs are also unneglectable.(3) Fatigue,abdominal pain are frequently the early symptoms of DILI,while mucocutaneous stained yellow(or elevated bilirubin)is probably the main reason for visit.(4) Simple biochemical examinations DILI can be used to roughly estimate the type of cell injury:increased ALT indicates the type of liver cell injury while increased ALP and GGT reflect the damage of biliary system.(5) The ratio between enzymes in response of liver cell injury(AST,ALT) and enzymes in response of biliary tract injury(GGT,ALP) shows significant differences for the majority of the positive rate of DILI.Meanwhile,the ratio simply between the liver cell enzymes or the biliary tract enzymes is not valuable for the diagnosis of DILI.(6) Although many symptoms are overlapping in DILI and ALD,the incidence of abdominal pain,abdominal distension and diarrhea are higher in DILI than ALD with significant difference in distention between the two groups(p＜0.05);However, the incidence of nausea,anorexia,fatigue,jaundice and pruritus is higher in ALD than DILI,with fatigue and jaundice more prominent(p＜0.01) in patients with ALD in particular.(7) As a clinically acute process,DILI showed higher level of hepatocytoplasmic enzymes(ALT,AST) and enzymes(ALP,TBIL) reflecting the function of bile secretion and excretion than those of ALD.Except for the changes in GGT(specific enzyme for alcoholic damage),the function of protein synthesis is often decreased,as well as much higher impact on the components of the blood(WBC,MCV,PLT) than DILI since ALD is caused by chronic alcoholism.(8) The restoration of clinical symptoms and laboratory indicators is relatively fast in ALD group,after abstinence,adequate nutritional support and application of drugs improving liver metabolism;while most of symptoms and signs in DILI group recovered more slowly than ALD group,especially the resumption of jaundice which can extend to 3 to 6 months.