Overview of drug‐induced liver injury in China

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Abbreviations

ATLI

antituberculotics

drug‐induced liver injury; DILI

drug‐induced liver injury

NSAID

nonsteroidal anti‐inflammatory drug

TB

tuberculosis

ULN

upper limit of normal.

Introduction

Drug‐induced liver injury (DILI) can be dose‐dependent and predictable, or idiosyncratic and independent of the drug dose, host, or clinical factors.1, 2, 3, 4 The incidence of DILI appears to be increasing both in Western and Eastern countries, in part due to growing recognition of its variant presentation and clinical phenotype.1 DILI poses substantial challenges to both clinical physicians and regulatory agencies due to the absence of specific markers for diagnosis, the wide variety of medicines implicated, and the poorly understood pathogenesis of this adverse reaction. Although advanced age, preexisting liver pathology, chronic alcohol consumption, and obesity may increase susceptibility for DILI,2 risk factors for this disease are not definite. Due to differences in the underlying diseases and disorders in Eastern populations compared to Western populations, as well as the frequent use of traditional Chinese medicine, the epidemiology and etiologies of DILI may differ in China compared to other parts of the world. The aim of this review is to summarize the epidemiology, etiologies, and management of DILI in mainland China.

Epidemiology

DILI is a leading cause of death from acute liver failure in Western series.3, 4, 5 Recently Yao et al (6) summarized the clinical features and prognosis of 9335 DILI cases (50.6% male; mean age at onset of DILI: 42.3 +/− 13.1 years) reported in the Chinese literature from 2001 to 2011. Ninety five % of the cohort improved with supportive care. Another comprehensive article conducted by Zhou et al,7 has analyzed 279 Chinese studies, including 24,112 patients with DILI from 1994 to 2011, and concluded that the average age of the patients was more than 40 years old, with a male to female ratio of 1.2:1 and a mortality of 2.9%. In contrast, women have increased susceptibility to developing DILI and in the Western world are more likely to progress to acute liver failure.2, 8, 9 The two Chinese reviews also observed similar distributions of cases with an hepatocellular pattern (62.7%; 58.1%), cholestasic (23.8%; 22.5%) and mixed type (17.6%, 19.2%) of liver injury6, 7

Although older Western individuals tend to present with cholestatic or mixed patterns of DILI,9, 10 hepatocellular injury accounts for the largest proportion of elderly patients in China. Additionally, antibiotics, Chinese herbal medicine, and cardiovascular system drugs are the most common causes of DILI in the Chinese older patients compared to antibiotics in Western patients.11, 12

DILI Severity in China

According to the Hy's law, DILI with serum alanine aminotransferase (ALT) levels three or more times the upper limit of normal (ULN)—and serum bilirubin levels two or more times the ULN—is indicative of severe hepatotoxicity, resulting in a mortality of 10% to 50%.13 Patients in China meet the threshold of 'Severe DiLI' when their serum bilirubin reaches a level of 171 μmol/L (equal to 10 mg/dL) or when serum bilirubin is rising at a rate per day of 17 μmol/L (or 1 mg/dL) and prothrombin activity is less than 40% of expected. An investigation covering 41 medical centers from China showed that the mortality of severe DILI patients was up to 36.9% and 3.29% for patients who underwent liver transplantation.14 We recently searched 10 independent case series studies in the Chinese database ChianInfo, the Chinese Social Science Citation Index, VIP net, and China National Knowledge Internet during the period from 2005 to 2013 for various liver injury terms. The previously mentioned 10 studies (including 403 patients) published, in addition to an unpublished retrospective study (including 138 cases), were analyzed.40, 41, 42, 43, 44, 45, 46, 47, 48, 49 Of these, 10 studies comprising 476 subjects, of whom 212 (44.5%) were male. Occurrence of gastrointestinal bleeding, hepatic encephalopathy, and hepato‐renal syndrome were commonly reported, accounting for 16.15%, 43.08%, and 13.77% of 130 cases included in six studies, respectively. Mortality was 19.96%. The etiology and prognosis of severe DILI in China are shown in Tables 1 and 2.

Table 1.

The Etiology of Severe DILI (n = 476)

Etiology of severe DILI	n(%)
Chinese herbal medicine	203(42.65)
Medicines for tuberculosis	83(17.44)
Antibiotics	42(8.82)
NSAIDs	24(5.04)
Antithyroid agents	22(4.6)
Psychotropic	15(3.15)

Information in this table was summarized from 10 independent case series studies including 403 patients and a published study containing 108 cases.40, 41, 42, 43, 44, 45, 46, 47, 48, 49

Table 2.

The Prognosis of Severe DILI (n = 501)

Prognosis	n(%)
Death	91(18.16)
Healing and improving	308(61.48)
Getting worse or being discharged from hospital without cure	99(19.76)

Information in this table is from the same source as Table 1.

Chronic DILI in China

Chronic DILI has been defined as liver test abnormalities associated with use of a medicinal agent which persist more than 6 months after stopping the implicated agent.3 A prospective analysis of a cohort of 300 cases of DILI from the US, showed that 13.6% developed chronic DILI, and there was no association between the chronicity of DILI and the severity of liver injury, implicated agents, and patterns of DILI.3 Hou et al. reported that 6% of 300 Chinese DILI patients had biochemical abnormalities that persisted for at least 6 months after withdrawal of the putative causative drug.15 Of 33 chronic DILI cases observed in another article by Hou et al.,16 27 presented a hepatocellular type of injury, two presented cholestatic type, and four presented mixed type. The authors also showed that herbal medicines (43.9%), antibiotics (31.7%), and cardiovascular drugs (12.2%) were the culprit.16

Etiologies of DILI in China

It is well‐known that acetaminophen is the most common cause of DIL and acute liver failure in the West.10, 17 However, the etiology of DILI is likely to be different in Asia.18 Chinese herbal medicine, medicines for tuberculosis, and antibiotics have been noted as the top three causes of DILI in China.6, 7, 19, 20 Based on an investigation of hospitalized patients with DILI from 2000 to 2005 in 16 medical units of China, Xu et al. revealed that Chinese herbal medicine and medicines for tuberculosis were responsible for 21.5% and 21.2% of acute hepatotoxicity related to drugs, respectively.21 A meta‐analysis of the etiology of DILI in China showed that antituberculotics (constituent ratio = 26.54%) was the leading cause from 1999 to 2005, but in the period from 2006 to 2012 it was replaced by herbal medicine (constituent ratio = 30.38%).19 Additionally, antineoplastic drugs, nonsteroidal anti‐inflammatory drugs (NSAID), antidiabetics, antithyroid agents, psychotropics, immunomodulators, cardiovascular system drugs and hypolipidemic agents were also the common medicines causing DILI in China.6, 7, 19

Chinese Herbal Medicine

With the frequent use of traditional Chinese medicine in China, the liver damage caused by Chinese herbal medicine in China will be doubtlessly higher than in other countries and regions. Although prospective studies from Korea and Singapore also reported a high prevalence of Chinese herbal hepatotoxicity, with 39.9% and 55% of all cases respectively,18, 22 the exact incidence of these two regions is still unknown because of the limited number of the patients (371 and 31) included. In a study from China including 300 patients with DILI,15 Chinese herbal medicines actually accounted for 40.3% of acute liver injury, and almost one‐half of all herbal medicines were prescribed for dermatological or orthopedic diseases. Furthermore, in two systematic analyses containing 9335 and 24,112 cases respectively, Chinese herbal medicine were responsible for 18.6% and 21.15% of DILI.6, 7 Among 279 investigations reviewed by Zhou et al.,7 only 17 (comprising 354 DILI patients) reported the specific names of the proprietary Chinese medicines. Of those, the top five were: Xiao Feng Pian, Common Three‐Wing‐Nut Root, Polygonum multiflorum, Tian Hua Fen, and Zhuang Gu Guan Jie Wan. Only five case series studies (comprising 383 cases) could be searched from 1994 to 2013 in the Chinese periodical database, with the goal of exclusively assessing Chinese herbal medicine‐induced liver injury23, 24, 25, 26, 27 (Table 3). In addition, the clinical study of DILI caused by Polygonum multiflorum recently has aroused great interest in physicians in China28, 29, 30, 31, 32 due to the high incidence. Zhang et al. found that R50 from Polygonum multiflorum extracts had different injurious effects on human liver L02 cells and liver cancer HepG2 cells.33

Table 3.

Medical Information Related to Herbal Medicine‐Induced Liver Injury (n = 383)

Herbal Medicines	n(%)
Prescribed for dermatologic diseases	84(21.93)
Prescribed for cardiovascular system	54(14.10)
Prescribed for orthopedic diseases	40(10.44)
Prescribed for gynecological diseases	40(10.44)
Prescribed for digestive system	43(11.23)
Health care medicine and weight‐reducing aid	19(4.96)

Information in Table 3 was summarized from 5 case series studies including 383 cases in China.23, 24, 25, 26, 27

Anti‐tuberculosis Medications

Antituberculotics‐induced liver injury (ATLI) in China contributes much to treatment failure, even life‐threatening events of tuberculosis (TB) in patients.34 In a prospective study from China, Shang et al. monitored 4304 TB patients receiving directly observed treatment strategies and found that 106 patients developed ATLI, with a cumulative incidence of 2.55%.35 Zhou et al. reported that 31.3% of 24,112 patients with DILI resulted from antituberculotics.7

Antibiotics

Antibiotics‐induced hepatotoxicity is responsible for 9.7% to 21.13% of DILI cases6, 7, 19 in China, which also is one of the most common causes of DILI in Western countries other than acetaminophen.10 However, the implicated antibiotics are different in the West and in China. Beta‐lactams such as penicillin, flucloxacillin, and cephalosporin are commonly associated with DILI in the West,2, 36 which are replaced by the macrolides and quinolones in China.7

Diagnosis and Management of DILI in China

The diagnosis of DILI remains a challenge worldwide due to the absence of “a gold standard.” Wang et al. reviewed the diagnostic criteria of DILI published in Chinese literatures from 2005 to 2012 and found 15 diagnostic tests used, among which “Chinese common standard,” “Maria Score in 1997,” and “diagnostic standard based on features and laboratory tests” were commonly utilized, but without perfect diagnostic sensitivity and specificity.37 Hence, causality should be established based on the clinical history, chronology of exposure and injury, clinical features, and laboratory parameters—while excluding other factors such as viral hepatitis, passive congestion of the liver from heart failure, fatty liver disease secondary to diabetes or obesity, alcoholic liver disease, and autoimmune liver disease by serological markers, and even liver biopsy.

Discontinuation of the potentially offending agents is the most important step in the treatment of DILI. No other specific therapies are suggested other than the use of N‐acetylcysteine for acetaminophen hepatotoxicity.38 Liver‐protective drugs are frequently used in the clinic to prevent further damage of the liver; therefore, inadequate evidence was available to judge the effectiveness and safety of them. With regard to corticosteroid therapy for severe DILI, no proven benefits were reported.

Conclusion

It is noteworthy that the epidemiology and etiology of DILI in China are different from those in the West. In China, acute hepatocellular injury is still the most common pattern of DILI, and Chinese herbal medicine is responsible for nearly one‐half of DILI patients. In addition, clinical data from China highlights herbal medicine, antibiotics, and medicines for tuberculosis as the top three causes, among which herbal medicines prescribed for dermatologic, gynecologic, orthopedic, and cardiovascular diseases such as Polygonum multiflorum—as well as the antibiotics macrolides and quinolones— account for a considerably large proportion of DILI patients. However, no diagnostic criteria and beneficial therapies for DILI were suggested.