Causes, clinical features and outcomes of drug-induced liver injury in hospitalized patients in a Chinese tertiary care hospital
- Pengcheng Ou†1,
- Yi Chen†2,
- Baozhen Li1,
- Min Zhang1,
- Xingyu Liu1,
- Fangfang Li1,
- Yi Li1,
- Chengwei Chen†3,
- Yimin Mao4 and
- Jun Chen1Email author
© Ou et al. 2015
Received: 29 October 2015
Accepted: 8 December 2015
Published: 22 December 2015
Drug-induced liver injury (DILI) is an important liver disease in China, owing to the country’s huge population and the availability of a multitude of drugs. Consequently, DILI is becoming an increasingly serious health problem. However, there is not enough relevant epidemiological data, and the clinical features of these patients are not clear. We conducted this study to report the causes and clinical features of DILI in hospitalized patients, and identify the mortality and predictive factors. We retrospectively collected and analyzed the data of all hospitalized patients whose discharge diagnosis was DILI at the Second Xiangya Hospital between January 2011 and December 2014. The data analyses were performed using SAS version 9.2. Among the 469 patients who were diagnosed with DILI at discharge, 361 met the criteria for DILI on re-evaluation. The crude annual incidence rate of DILI was 92.95 cases per 100,000 patients. Chinese herbal medicine was identified as the primary cause of DILI in 36.01 % of the patients. The overall mortality was 8.59 %. Alcohol consumption, use of antituberculosis drugs, serum total bilirubin, direct bilirubin, total protein, albumin, thrombinogen time, international normalized ratio, and the model for end-stage liver disease (MELD) score were significantly correlated with DILI-associated mortality. Among them, the MELD score and albumin were found to be independent predictors of outcome in patients with DILI. Chinese herbal medicine was the primary cause of DILI in the identified patients. The MELD score and albumin were independent predictors of outcome in patients with DILI.
KeywordsDrug-induced liver injury Chinese herbal medicine Incidence Prognosis
Drug-induced liver injury (DILI) is a serious condition that is characterized by varying degrees of liver injury. A variety of drugs can lead to various types of acute and chronic liver injury, and even severe or acute liver failure. In recent years, DILI has become one of the major liver diseases in many countries, even in the West; it is the leading cause of acute liver failure, with a survival rate of only 20 % in the absence of liver transplantation (Ostapowicz et al. 2002; Lee 2003). Statistical data from Iceland has shown that the crude annual incidence rate of DILI was 19.1 cases per 100,000 inhabitants: 75 % of the DILI cases were caused by a single prescription medication, 16 % by dietary supplements, and 9 % by multiple agents (Björnsson et al. 2013). In Asia, herbal remedies are widely used and accepted as safe and effective medication, but they are often associated with high incidences of DILI. Data from Korea and Singapore show that herbs are the primary cause of DILI (Suk et al. 2012; Wai 2006). In China, because of the huge population and multitude of drugs available, especially, the vast number of Chinese herbal medicines, DILI is becoming an increasingly serious health problem. Although, a systematic analysis of the Chinese literature showed that tuberculostatics and complementary and alternative medicines are the most common etiologies of DILI in China (Zhou et al. 2013), but the relevant clinical features and outcomes of DILI are not mentioned. To further clarify the causes, clinical features, and outcomes of DILI in hospitalized patients; we conducted this study by retrospectively collecting the four-year data of hospitalized patients diagnosed with DILI.
Patients and methods
We performed a retrospective study and collected data from all the hospitalized patients whose diagnosis at discharge was DILI at the Second Xiangya Hospital (Hunan, China), who were hospitalized between January 1, 2011 and December 31, 2014. Informed consent was waived due to the retrospective nature of the study. Patients were included if their diagnosis at discharge was “DILI,” “drug-induced hepatitis,” “drug-induced liver disease,” “drug-induced liver failure,” or other diagnostic terminology that suggested some form of DILI. Patients were excluded (1) if their clinical information was incomplete, and therefore the diagnosis of DILI could not be confirmed, and (2) if DILI was ruled out after a re-evaluation.
The following data were collected: (1) general information (gender, age, occupation, nationality, height, weight, etc.); (2) diagnosis at admission and discharge, disease history (including history of allergies), and drinking history; (3) information about the drug suspected to have caused the liver injury; (4) symptoms and signs; (5) results of biochemical examinations, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), globulin (GLO), thrombinogen time (PT), international normalized ratio (INR), alkaline phosphatase (ALP), and creatinine (Cr), and routine blood examination results the first time DILI was diagnosed and at later examinations; (7) results of laboratory tests for other liver diseases (including HAV, HBV, HCV, HDV, HEV, EBV, CMV, and herpes virus infection, Wilson’s disease, autoimmune hepatitis, etc.); (8) imaging and endoscopic results; (9) results of liver histological examination; (10) severity and prognosis of DILI.
Diagnosis and evaluation of DILI
After the data were collected, we re-diagnosed all the patients according to the ACG clinical guidelines for the diagnosis and management of idiosyncratic DILI (Chalasani et al. 2014). Briefly, the R value was calculated (R value = Serum [ALT/ALT upper limits of normal (ULN)] ÷ [ALP/ALP ULN]), and Roussel Uclaf Causality Assessment Method (RUCAM) was performed. Patients with RUCAM scores less than six were excluded, and those with RUCAM scores greater than or equal to six were retained for further analysis. The type of DILI was determined according to the R value: it was hepatocellular if the R value was >5.0, cholestatic if the R value was <2.0, and mixed if the R value was in the range of 2.0–5.0 (Chalasani et al. 2014). Acute liver failure is defined as evidence of coagulation abnormality, usually an INR >1.5, and any degree of mental alteration (encephalopathy) in a patient without pre-existing cirrhosis and with an illness of less than 26 weeks’ duration (Polson 2005). The MELD score was calculated using the following formula (Said et al. 2004): 3.78 (Ln serum bilirubin [mg/dl]) + 11.2 (Ln INR) + 9.57 (Ln serum creatinine [mg/dl]) + 6.43. Hy’s law cases have been defined as drug-induced liver injury resulting in increased alanine aminotransferase (ALT) levels greater than three times ULN and TBIL levels greater than two times ULN after excluding other potential causes. To exclude cholestatic or mixed cases, the guidance for clinical trials states that for a Hy’s law case the liver injury should not have a significant ALP increase reflecting a cholestatic component (Temple 2006). Cases in which the ALT and TBIL corresponded to these values were classified as Hy’s cases.
Categorical variables were expressed as frequencies and percentages. Continuous variables were presented as median (range). Variables were analyzed using univariate and multivariate logistic regression analysis for dichotomous outcomes. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated from the confidence and standard errors of the model. Statistical significance was defined as a two-sided p value less than 0.05. The data analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).
Incidence rate of DILI
The total number of 4-year hospitalized patients was 388,365, and 469 (120.76/100,000) of them were diagnosed with DILI. Based on the RUCAM causality assessment, 361 patients met the criteria for DILI, so the remaining 108 patients were excluded. The crude annual incidence rate of DILI in the hospitalized patients was 92.95 cases per 100,000 patients. According to the age distribution of all the DILI patients (range, 1–90 years), the DILI incidence in age group 0–10, 11–20, 21–30, 31–40, 41–50, 51–60,61–70,71–80 and 81–90 was 1.11, 2.49, 12.37, 14.96, 25.49, 20.22,14.13,7.75 and 1.39 %, respectively. The age group with the highest incidence rate (25.49 %) was found to be 41–50 years and the second highest incidence rate (20.22 %) was found to be 51–60 years.
Baseline characteristics of the 361 patients
Total (N = 361)
49 (37, 59)a
Gender (M/F), n (%)
195 (54 %)/166 (46 %)b
Alcohol consumption, n (%)
33 (9.14 %)b
Pre-existing liver disease, n (%)
91 (25.21 %)b
HBV, n (%)
32 (8.86 %)b
Autoimmune antibodies, n (%)
24 (6.65 %)b
Alcoholic liver disease, n (%)
22 (6.09 %)b
NAFLD, n (%)
13 (3.60 %)b
Days from drug use to symptom appearance
30 (9, 60)a
Days from drug discontinuation to symptom
20 (12, 30)a
225.7 (89.7, 541.3)a
125.8 (57.1, 325.1)a
135.1 (81.7, 203.9)a
53 (14.5, 237.1)a
38.1 (6.7, 182.9)a
13.3 (12, 16.6)a
1 (1, 1.4)a
53 (14.5, 237.1)a
33.4 (29.5, 36.8)a
56.1 (45.8, 69)a
6.9 (0.1, 13.3)a
Type of DILI
Hepatocellular, n (%)
228 (63.16 %)b
Cholestatic, n (%)
50 (13.85 %)b
Mixed, n (%)
48 (13.30 %)b
NA, n (%)
35 (9.70 %)b
Main clinical manifestations
The digestive symptoms, including nausea, anorexia, vomiting and abdominal distension, were observed in most patients (59.28 %). Jaundice was also one of the main clinical symptoms (52.63 %). Itching occurred in 13.30 % of the patients, fever in 15.51 %, and rash in 8.31 %. Severe liver damage symptoms including hemorrhage tendency and hepatic encephalopathy occurred in 3.05 % of the patients. In 21.61 % of the patients, the results of liver biochemical examination were abnormal, but there were no symptoms.
Chinese herbal medicine
Antipyretics and analgesics
Specific drug of causing DILI
Chinese herbal medicine
Herbal medicine ingredients
Radix polygoni multiflori
And shenbao mixture
Isoniazid + rifampicin + pyrazinamide
Isoniazid + rifampicin
Isoniazid + pyrazinamide
Docetaxel + platinum
Antipyretics and analgesics
Severity and prognosis of DILI
Severity and prognosis of DILI
Cause of death
Died from anti-TB
Mortality in Hy’s cases
Logistic regression analysis
Logistic regression analysis
95 % CI
95 % CI
Pre-existing liver disease
Chinese herbal medicine
Antipyretics and analgesics
Days from drug use to symptom appearance
Days from drug discontinuation to symptom disappearance
Type of DILI
Our statistical data indicated that the crude annual DILI incidence in hospitalized patients was 92.95/100,000. This is higher than the incidence rate reported in Iceland (19.1/100,000 inhabitants) (Björnsson et al. 2013). Certainly, the study population is different and may be the reason for the difference, especially as the drug use in hospitalized patients may be higher. As there is a lack of epidemiological data for it, the DILI incidence in the general population of China is not known.
In hospitalized patients, misdiagnosis and missed diagnosis are common, and there is still no standard diagnostic criteria for DILI in China. Most of the diagnoses are based on the physicians’ individual ability and experience, and the RUCAM causality assessment is seldom used. Sometimes, because of conflicts with the hospital administration, physicians often refuse to diagnose DILI, which leads to a missed diagnosis. Therefore, there is a clear need to establish standard diagnostic criteria and reporting guidelines for DILI.
It is generally believed that the incidence of DILI is higher in patients aged over 50 years and that the incidence of DILI increases with age (Björnsson et al. 2013; Chalasani et al. 2014). However, in our group of hospitalized patients, the incidence was the highest in the 41- to 50-year age group. However, it should be noted that this does not reflect its incidence in the general population.
In China, Chinese herbal medicine is broadly accepted as safe and effective medication for the treatment of various ailments. The diagnosis and treatment strategies of traditional Chinese medicine are completely different from those of Western medicine. In traditional Chinese medicine, the practice is experienced-based rather than evidence-based. Therefore, very often, there is not enough evidence to prove the treatment and side effects of a drug. Our data suggest that the use of Chinese herbal medicine was associated with more than one-third of the DILI cases (36.01 %) in all the hospitalized patients diagnosed with DILI. In Korea and Singapore too, herbal medicine has been reported to be the leading cause of DILI (Suk et al. 2012; Wai 2006). Another group of data from Shanghai (China) also confirmed that Chinese herbal medicine accounted for 53.62 % of DILI cases in hospitalized patients diagnosed with DILI (Lai et al. 2012). Thus, it is important to monitor the hepatotoxicity of Chinese herbal medicine. This is especially important as the dosage of herbal drugs and their compositions vary between these traditional practitioners, and it is therefore very difficult to determine which component or, rather, components is the cause of the liver injury. Currently, only a few components of Chinese herbal medicine are known to cause DILI. There seems to be an urgent need to standardize the compositions of herbal medication and provide guidelines for the dosage.
The incidence of hyperthyroidism and tuberculosis is fairly high in China, which is reflected in our results: antithyroid and antituberculosis drugs were found to be the second and third most hepatotoxic drugs. Recently, a nationwide retrospective epidemiological investigation on DILI has been undertaken by a study group, with more than 300 hospitals participating; the results of this study will be highly useful for clarifying the DILI situation in the general population of China.
According to our data, the prognosis of most DILI patients was good, and the survival rate was 91.41 %. The manifestation was mild in most of the patients, and some patients were even asymptomatic. Further, the liver function of the patients rapidly improved after the hepatotoxic drugs were discontinued. These findings suggest that early detection of abnormal liver function and timely discontinuation of the drugs are very necessary. Generally, the mortality rate of DILI has been reported to be 8–17 % (Larrey and Pageaux 2005; Andrade et al. 2005; Chalasani et al. 2008; Devarbhavi et al. 2010). In our study, the mortality rate was 8.59 %. According to Hy’s law, if hepatocellular injury causes jaundice in a patient during a phase three trial, have at least a 10 % mortality rate (Temple 2006). In our investigation, the mortality rate in Hy’s cases was 12.69 %, these findings confirmed Hy’s theory is an important indicator of the potential of a drug to cause serious liver injury. This observation was also confirmed in some large studies on DILI in Spain (Andrade et al. 2005) and in Sweden (Björnsson et al. 2005) in which 10 % of the subjects with hyperbilirubinemia or jaundice died or needed liver transplants.
The risk factors for mortality were baseline alcohol consumption, the use of antituberculosis drugs, TBIL, DBIL, PT, INR MELD score, TP and ALB. Among these risk factors, alcohol consumption was associated with poor outcome. However, there is not enough evidence to indicate that chronic alcohol consumption is a risk factor for all-cause DILI. It has been reported that heavy alcohol consumption is a risk factor for DILI owing to the presence of compounds such as APAP, methotrexate, and isoniazid (Chalasani et al. 2014).
The other risk factor for mortality is antituberculosis drugs, as it is well known that antituberculosis drugs such as rifampicin, isoniazid and pyrazinamide have strong hepatotoxicity. A study from India revealed acute liver failure occurred in a quarter of DILI patients receipted antituberculosis treatment and the overall motality was 22.7 % (Devarbhavi et al. 2013). Our data also indicate that antituberculosis drugs caused 32.26 % of the mortalities, which suggested that the hepatoxicity of antituberculosis medication is a serious problem among patients undergoing antituberculosis treatment. A survey from Taiwan followed 926 patients for 4122.9 person-months (pm) and found that 111 (12.0 %) developed hepatotoxicity after a median of 38.0 days from the start of treatment; moreover, the severe hepatotoxicity rate was 3.5 %. The independent risk factors for hepatotoxicity were old age, female sex, autoimmune disease, human immunodeficiency virus infection, higher pyrazinamide dosage in the last 8–14 days, and lower rifampicin dosage in the last 15–21 days (Shu et al. 2013).
The other risk factors for mortality were TBIL, DBIL, TP, ALB, PT, INR and the MELD score, which reflect the state of the liver parenchyma. Compared to ALT, AST or ALP, these risk factors can more objectively and accurately reflect the degree of damage to the liver parenchyma. Increase in TBIL, DBIL, PT, INR and the MELD score was accompanied by an increase in mortality; this is expected, as increase in these biochemical indices is one of the criteria for diagnosis of liver dysfunction. On the other hand, increase in the level of some indicators such as ALB was accompanied with a decrease in mortality. Our results also show that sex, age, latencies and DILI type are not correlated with DILI-associated mortality. This finding is consistent with studies from the USA (Chalasani et al. 2015) and Korea (Jeong et al. 2015). The data from the US study showed that the DILI-associated mortality was significantly higher in individuals with pre-existing liver disease (Chalasani et al. 2015). Although our results showed that pre-existing disease is not a risk factor for DILI-associated mortality (p = 0.073), the results did indicate that pre-existing liver disease could enhance the mortality. This needs to be examined in a larger population in order to confirm the results.
Our study found that the MELD score and ALB were independently associated with poor outcome. Thus, the MELD score and ALB are key risk factors for DILI-associated mortality. The MELD score is widely accepted as an accurate predictor of mortality across a broad spectrum of liver diseases (Said et al. 2004; Martin et al. 2014). The study from Korea also confirmed that the c-statistic for the MELD score alone was 0.93 and that the MELD score had strong discriminatory power and may be a reliable predictor of the prognosis in patients with DILI (Jeong et al. 2015).
One of the main limitations of our study is its nature, this study being a single-center retrospective study. Another limitation was that some important examinations such as liver biopsy were not performed in most of the patients, and the data for some important biochemical indexes were missing from the first time the patients were diagnosed with DILI. Moreover, we did not consider the effects of drug interaction in cases where multiple drugs were used, as these interactions are quite complicated and unclear. In China, several drugs for liver protection are used in cases of DILI, usually at least two different liver protection drugs for one patient. This makes it difficult to compare the therapeutic effects of these drugs, so we did not analyze the treatment data in our study.
In summary, Chinese herbal medicine was the main cause of DILI in hospitalized patients in China, followed by antithyroid and antituberculosis drugs. The survival rate was 91.41 %. The major cause of mortality was severe liver diseases, and primary diseases were the other cause. DILI associated with the use of antituberculosis drugs was the cause in 32.26 % of the patients. Further, alcohol consumption, the use of antituberculosis drugs, serum TBIL, DBIL, TP, ALB, PT, INR and the MELD score were significantly correlated with DILI-associated mortality. Among them, the MELD score and ALB were independent predictors of outcome in patients with DILI.
The local ethics committee, which acts as the institutional review board of the Second Xiangya Hospital of Central South University.
All authors made contributions to the article. PO contributed on data acquisition and work reporting. YC contributed on data analysis and interpretation. He also contributed on conducting and reporting of the work. CC and YM contributed on the planning and design. BL, MZ, XL, FL, YL contributed on data acquisition. All authors read and approved the final manuscript.
Financial supported by Chinese Ministry of Science and Technology (Grant number: 2012ZX09303-001).
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E et al (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129:512–521View ArticleGoogle Scholar
- Björnsson E, Olsson R (2005) Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 42(2):481–489View ArticleGoogle Scholar
- Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S (2013) Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 144(7):1419–1425View ArticleGoogle Scholar
- Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J et al (2008) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924–1934View ArticleGoogle Scholar
- Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ (2014) Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 109(7):950–966View ArticleGoogle Scholar
- Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J et al (2015) United States drug induced liver injury network. features and outcomes of 889 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 148(7):1340–1352View ArticleGoogle Scholar
- Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK (2010) Single-center experience with drug induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 105:2396–2404View ArticleGoogle Scholar
- Devarbhavi H, Singh R, Patil M et al (2013) Outcome and determinants of mortality in 269 patients with combination anti-tuberculosis drug-induced liver injury. J Gastroenterol Hepatol 28(1):161–167View ArticleGoogle Scholar
- Jeong R, Lee YS, Sohn C, Jeon J, Ahn S, Lim KS (2015) Model for end-stage liver disease score as a predictor of short-term outcome in patients with drug-induced liver injury. Scand J Gastroenterol 50(4):439–446View ArticleGoogle Scholar
- Lai RT, Wang H, Gui HL, Ye MZ, Dai WJ, Xiang XG et al (2012) Clinical and pathological features in 138 cases of drug-induced liver injury. Zhonghua Gan Zang Bing Za Zhi 20(3):185–189. doi:https://doi.org/10.3760/cma.j.issn.1007-3418.2012.03.009 Article in Chinese Google Scholar
- Larrey D, Pageaux GP (2005) Drug-induced acute liver failure. Eur J Gastroenterol Hepatol 17(2):141–143View ArticleGoogle Scholar
- Lee WM (2003) Acute liver failure in the United States. Semin Liver Dis 23(3):217–226View ArticleGoogle Scholar
- Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M (2014) Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 59(3):1144–1165View ArticleGoogle Scholar
- Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH et al (2002) Results of a preospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137(12):947–954View ArticleGoogle Scholar
- Polson J, Lee WM (2005) American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 41(5):1179–1197View ArticleGoogle Scholar
- Said A, Williams J, Holden J, Remington P, Gangnon R, Musat A et al (2004) Model for end stage liver disease score predicts mortality across a broad spectrum of liver disease. J Hepatol 40(6):897–903View ArticleGoogle Scholar
- Shu CC, Lee CH, Lee MC, Wang JY, Yu CJ, Lee LN (2013) Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre. Int J Tuberc Lung Dis 17(7):934–939. doi:https://doi.org/10.5588/ijtld.12.0782 View ArticleGoogle Scholar
- Suk KT, Kim DJ, Kim CH, Park SH, Yoon JH, Kim YS et al (2012) A prospective nationwide study of drug induced liver injury in Korea. Am J Gastroenterol 107:1380–1387View ArticleGoogle Scholar
- Temple R (2006) Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 15:241–243View ArticleGoogle Scholar
- Wai CT (2006) Presentation of drug-induced liver injury in Singapore. Singapore Med J 47:116–120Google Scholar
- Zhou Y, Yang L, Liao Z, He X, Zhou Y, Guo H (2013) Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients. Eur J Gastroenterol Hepatol 25(7):825–829View ArticleGoogle Scholar