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Cited by 615Drug-Induced Hepatotoxicity and ProtectionPharmacovigilance and Adverse Drug ReactionsLiver physiology and pathology

The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index; none of the 57 sources its claims cite is checked for support yet.

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China

Open access
Shen, Tao, Liu, Yingxia, Shang, Jia, Xie, Qing, Li, Jun, Yan, Ming, Xu, Jianming, Niu, Junqi, Liu, Jiajun, Watkins, Paul B., Aithal, Guruprasad P., Andrade, Raúl J., Dou, Xiaoguang, Yao, Lvfeng, Lv, Fangfang, Wang, Qi, Li, Yongguo, Zhou, Xinmin, Zhang, Yuexin, Zong, Peilan, Wan, Bin, Zou, Zhengsheng, Yang, Dongliang, Nie, Yuqiang, Li, Dongliang, Wang, Yuya, Han, Xi’an, Zhuang, Hui, Mao, Yimin, Chen, Chengwei·2019·Gastroenterology
DOI 10.1053/j.gastro.2019.02.002
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Abstract

BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a nationwide retrospective study of 25,927 confirmed drug-induced liver injury (DILI) cases from 308 mainland China centers (2012–2014), the estimated annual incidence in the general population was 23.80 per 100,000 (95% CI 20.86–26.74), higher than several Western estimates. Traditional Chinese medicines/herbal and dietary supplements and anti-tuberculosis drugs were the leading implicated single drug classes.

Key findings

  • Most cases presented as hepatocellular injury (51.39%; 95% CI 50.76–52.03), followed by mixed (28.30%; 95% CI 27.73–28.87) and cholestatic (20.31%; 95% CI 19.80–20.82); chronic DILI occurred in 13.00%, and 44.40% of hepatocellular cases met Hy’s Law criteria.
  • Severe outcomes were uncommon: 280 cases (1.08%) progressed to hepatic failure, 2 (0.01%) underwent liver transplantation, and 102 (0.39%) died; among deaths, DILI was judged primary in 72 (70.59%), contributory in 21 (20.59%), and no role in 9 (8.82%).
  • Leading single implicated classes were TCM/HDS (26.81%) and anti-TB drugs (21.99%); other single classes >1% included antineoplastics/immunomodulators (8.34%), anti-infectious agents (6.08%), psychotropics (4.90%), non-sex hormones (3.04%), cardiovascular drugs (2.98%), digestive drugs (2.04%), respiratory drugs (1.47%), and musculoskeletal drugs (1.32%).
  • Among 66 centers with complete capture, 13,691 DILI cases occurred among 8,102,732 inpatients (mean proportion 1.69‰; 95% CI 1.66–1.72); annual estimated incidence was 21.37, 23.86, and 26.00 per 100,000 in 2012, 2013, and 2014, averaging 23.80 per 100,000 (95% CI 20.86–26.74).

Methods

  • Retrospective multicentric “DILI-R” study at 308 medical centers in mainland China, searching inpatient discharge diagnoses from January 1, 2012 to December 31, 2014; of 29,478 initial DILI discharge cases, 80 with admission date out of range and 2,153 with missing data were excluded, leaving 27,245 with eligible data.
  • Causality assessment used RUCAM: cases with scores ≥6 (n=13,555) entered directly; cases with scores <6 (n=13,690) were reviewed by a panel of 3 hepatologists, and those judged probable DILI by at least two (n=12,372) were enrolled, yielding 25,927 eligible DILI cases.
  • Clinical type was classified by R value (hepatocellular ≥5.0, cholestatic ≤2.0, mixed 2.0–5.0); incidence was estimated using only the 66 centers with complete event capture as (DILI inpatients in 66 centers annually ÷ total inpatients in 66 centers annually) × (nationwide inpatients annually ÷ general population in mainland China annually), with SAS 9.3 and standard nonparametric/categorical tests.

Limitations

  • Paper-stated: only hospitalized patients were included, so the true incidence is likely higher; mild/moderate DILI patients who were unrecognized or managed as outpatients were not considered, and underdeveloped parts of the country not well covered by the survey have higher incidence of diseases requiring hepatotoxic drug treatment, so actual DILI incidence is very likely higher than 23.80 per 100,000.
  • Paper-stated: there were no entrance criteria based on liver chemistries, so the cohort may include more relatively mild cases than other registries; enrollment of children and teenagers (<18 years) was relatively low, possibly related to the limited number of pediatric hospitals participating; the panel did not evaluate why RUCAM scores were calculated as below 6 for enrolled cases.
  • Evident from design: retrospective discharge-diagnosis searching and incomplete capture at 242 centers may miss DILI cases; extrapolating incidence from 66 complete-capture centers to all mainland China assumes those centers are representative; no hospitals from Hong Kong, Macau, or Taiwan were included.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1053/j.gastro.2019.02.002

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Chronic DILI occurred in 13.00% of the DILI cases in mainland China.

    “Chronic DILI occurred in 13.00% of the cases”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among patients with DILI in mainland China, mixed injury occurred in 28.30% (95% CI 27.73-28.87).

    “Most cases of DILI presented with hepatocellular injury (51.39%; 95% CI, 50.76-52.03),followed by mixed injury (28.30%; 95% CI, 27.73-28.87)and cholestatic injury (20.31%; 95% CI, 19.80-20.82).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among DILI cases in mainland China, 2 cases (0.01%) underwent liver transplantation.

    “2 cases underwent liver transplantation (0.01%)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among DILI cases in mainland China, 280 cases (1.08%) progressed to hepatic failure.

    “only 280 cases (1.08%) progressed to hepatic failure”
    Quote in the paperSubstantial claim
  • Findingown data

    Among hepatocellular DILI cases in mainland China, 44.40% fulfilled Hy's Law criteria.

    “44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria”
    Quote in the paperNot a substantial claim
  • It may state two separate claims as one. 30
  • Probably not a substantial claim. 23

  • It may state two separate claims as one.

    Findingown data

    Traditional Chinese medicines, herbal and dietary supplements, and anti-tuberculosis drugs were the leading causes of DILI in mainland China.

    “Traditional Chinese medicines, herbal and dietary supplements, and anti-tuberculosis drugs were the leading causes of DILI in mainland China.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Among DILI cases in mainland China who died, DILI was judged to have a primary role in 70.59%, a contributory role in 20.59%, and no role in 8.82%.

    “Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingreasoning

    Children generally had higher ALP levels than adults.

    “As expected from continuing bone growth, children generally had higher ALP levels than adults (Figure 2).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Of the 308 involved centers, 66 centers provided all recorded hospitalized DILI cases during the 3-year period of observation, and the other 242 centers provided DILI cases from some but not all clinical departments.

    “Of the 308 involved centers, 66 centers provided all recorded hospitalized DILI cases during the 3-year period of observation, and the other 242 centers just provided DILI cases from some but not all clinical departments.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Latency period in DILI cases without jaundice was shorter than in cases with jaundice (P < .0001) and in fatal cases (P < .0001).

    “In this study, latency period in DILI cases without jaundice was shorter than in cases with jaundice (P < .0001)and in fatal cases (P < .0001)(Supplementary Figure 6).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Few cases progressed to life-threatening outcomes, which included 280 progressing to hepatic failure (1.08%), two undergoing liver transplantation (.01%) and 102 dying (.39%).

    “Of note, few cases progressed to life-threatening outcomes, which included 280 progressing to hepatic failure (1.08%), two undergoing liver transplantation (.01%) and 102 dying (.39%).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Latency period (P <.05) and duration of usage of implicated agents (P < .01) was significantly longer in ethnic minorities than in Han Chinese.

    “Interestingly, we found that the latency period (P <.05) and duration of usage of implicated agents (P < .01)was significantly longer in ethnic minorities than in Han Chinese.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Children had a shorter mean latency period (P <.0001) and duration of usage of implicated agents (P<.0001), and lower peak levels of TBil, DBil, TBA, ALT, AST and GGT than in adults (P<.0001).

    “Also, children had a shorter mean latency period (P <.0001) and duration of usage of implicated agents (P<.0001), and lower peak levels of TBil, DBil, TBA, ALT, AST and GGT than in adults (P<.0001).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Compared to DILI cases without jaundice, female gender occupied higher frequencies than men in cases with jaundice (P < .0001) and in life-threatening DILI (P < .01).

    “Of note, compared to the DILI cases without jaundice, female gender occupied higher frequencies than that of men, either in cases with jaundice (P < .0001)or in life-threatening DILI (P < .01)(Supplementary Figure 6).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    DILI patients appeared most frequently in departments of internal medicine (41.74%; 95% CI 41.14-42.34) and infectious diseases (32.59%; 95% CI 32.02-33.16), while only 14.42% (95% CI 13.99-14.85) and 3.35% (95% CI 3.13-3.57) were diagnosed in departments of hepatology and oncology respectively.

    “In addition, our study showed that DILI patients appeared most frequently in departments of internal medicine (41.74%; 95% CI 41.14-42.34)and infectious diseases (32.59%; 95% CI 32.02-33.16),while only 14.42% (95% CI 13.99-14.85)and 3.35% (95% CI 3.13 -3.57) were diagnosed in departments of hepatology and oncology respectively (Table 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The highest proportion of DILI cases were in patients aged 40-59 years, followed by ages 18-39, ages ≥60, and ages <18 years, with children and teenagers representing the lowest proportion.

    “The highest proportion of DILI cases were in patients with ages between 40 and 59 years followed by ages 18-39, ages ≥ 60 and ages < 18 years old.”
    • Also stated in: § Demographic features · plain
      “Thus, DILI in children and teenagers represented the lowest proportion of the subjects enrolled.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The vast majority (25,113 cases, 96.93%) of DILI patients was Han Chinese and only 3.07% (795 cases) were minorities.

    “We found that the vast majority (25,113 cases, 96.93%) of DILI patients was Han Chinese and only 3.07% (795 cases) were minorities and this is consistent with the overall population composition.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    TCM or HDS (26.81%) and anti-TB drugs (21.99%) were the two leading classes of implicated agents.

    “TCM or HDS (26.81%) and anti-TB drugs (21.99%) were the two leading classes of implicated agents.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Men with DILI were found slightly more frequently than females.

    “As shown in Table 1, men with DILI were found slightly more frequently than females.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Female patients had higher serum TBil (P <.01), DBil (P < .01), TBA (P < .0001), ALT (P < .0001), AST (P < .0001) and ALP (P < .0001) than males.

    “Also, female patients had higher serum TBil (P <.01), DBil (P < .01),TBA (P < .0001),ALT (P < .0001),AST (P < .0001)and ALP (P < .0001)than males.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The highest proportion of pre-existing liver disease was among fatal cases (64.32%), followed by cases with jaundice (29.21%) and cases without jaundice (21.34%) (P < .0001).

    “The highest proportion of pre-existing liver disease was among the in fatal cases (64.32%), followed by cases with jaundice (29.21%) and cases without jaundice (21.34%) (P < .0001)(Supplementary Figure 6).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Cases with serum ALT≥3×ULN and <5×ULN and cases with serum ALT<3×ULN formed 16.73% (95% CI 16.27-17.17) and 33.81% (95% CI 33.23-34.39) of the cases respectively.

    “Cases with serum ALT≥ 3×ULN and <5× ULN and cases with serum ALT<3×ULN formed 16.73% (95% CI 16.27-17.17)and 33.81% (95% CI 33.23 -34.39) of the cases respectively (Table 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Most DILI cases were hepatocellular injuries (51.39%; 95% CI 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82).

    “Most DILI cases were hepatocellular injuries (51.39%; 95% CI 50.76 -52.03), following by mixed injury (28.30%; 95% CI 27.73 -28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82)(Table 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Of 102 death cases, DILI was judged to have had a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%).

    “Of 102 death cases, DILI was judged to have had a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%) (Table 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Higher proportions of hepatocellular DILI were found in fatal cases (65.67%, P<.0001) and in cases with jaundice (65.09%, P<.0001) than in non-fatal cases or in the absence of jaundice (48.53%).

    “It was noteworthy that the higher proportions of hepatocellular DILI were found in fatal cases (65.67%,P<.0001) and in cases with jaundice (65.09%,P<.0001) than in non-fatal cases or in the absence of jaundice (48.53%) (Supplementary Figure 6).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Among DILI cases, there were 20,938 without jaundice, 4,605 with jaundice, and 384 life-threatening.

    “Comparison of demographic and clinical features among DILI cases without jaundice (W/O jaundice, n=20,938), DILI cases with jaundice (W/ jaundice, n=4,605) and life-threatening (”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    A total of 7,594 cases were diagnosed as tuberculosis in the study.

    “A total of 7, 594 cases were diagnosed as tuberculosis, in which gender information of 132 cases was missing or unknown.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Life-threatening DILI cases included 280 cases of progression to hepatic failure, 2 liver transplantations and 102 deaths.

    “Life-threatening DILI cases included 280 cases of progression to hepatic failure, 2 liver transplantations and 102 deaths.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The true incidence of DILI in China is likely higher than the estimated 23.80 per 100,000 because only hospitalized patients were included in the analysis.

    “Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Across various registries, the most common causative drugs for DILI were anti-infectious agents, anti-TB drugs, and natural herbal medicines.

    “Also, the most common causative drugs were anti-infectious agents, anti-TB drugs and natural herbal medicines across various registries.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Leise, 2014, Drug-induced liver injury, Mayo Clin Proc source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In the United States, the annual incidence of DILI in the general population has been estimated as 2.7 per 100,000 adults.

    “In the United States, the annual incidence of DILI in the general population has been recently estimated as 2.7 per 100,000 adults, through surveillance in the state of Delaware.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Vega, 2017, The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the State of Delaware, Drug Saf source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Two population-based studies in France and Iceland estimated annual incidences of DILI of approximately 13.9/100,000 and 19.1/100,000, respectively.

    “Two population-based studies conducted in France and Iceland estimated the annual incidences of DILI to be approximately 13.9/100,000 and 19.1/100,000 respectively.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Bjornsson, 2013, Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland, Gastroenterology source
    • cites [9] Sgro, 2002, Incidence of drug-induced hepatic injuries: a French population-based study, Hepatology source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In western countries, the annual incidence of DILI in the general population has been estimated to be 1/100,000-20/100,000.

    “In the west, the incidence of DILI has been estimated to be 1/100,000-20/100,000 in the general population.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 2,[4][5][6][7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationcitation

    The estimated DILI incidence in mainland China (23.80 per 100,000) was higher than that estimated in Iceland (19.1/100,000), France (13.9/100,000), the United States (2.7/100,000), Spain (3.42/100,000) and Sweden (2.4/100,000).

    “which was still higher than that estimated in Iceland (19.1/100,000) 7 , France (13.9/100,000), 9 the United states (2.7/100,000), 10 Spain (3.42/100,000) 21 and Sweden (2.4/100,000) 22 (Table 4).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Bjornsson, 2010, Review article: drug-induced liver injury in clinical practice, Aliment Pharmacol Ther source
    • cites [9] Sgro, 2002, Incidence of drug-induced hepatic injuries: a French population-based study, Hepatology source
    • cites [10] Vega, 2017, The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the State of Delaware, Drug Saf source

  • Probably not a substantial claim.

    Study design and conductown data

    Cases with RUCAM scores ≥6 were entered into the study directly.

    “Cases with scores greater than or equal to 6 (”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    DILI is a common adverse drug reaction that can lead to liver failure and even death.

    “Drug-induced liver injury (DILI) is a common adverse drug reaction (ADR), and it can lead to liver failure and even death.[1][2][3]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Kaplowitz, 2005, Idiosyncratic drug hepatotoxicity, Nat Rev Drug Discov source
    • cites [2] Navarro, 2006, Drug-related hepatotoxicity, N Engl J Med source
    • cites [3] Chalasani, 2014, ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury, Am J Gastroenterol source

  • Probably not a substantial claim.

    Study design and conductnone given

    Cases judged by at least two of the three hepatologists as probable DILI were enrolled in the study.

    “Cases judged by at least two of the three hepatologists as probable DILI (n=12,372) were enrolled in the study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Females are suggested to have a higher risk of idiosyncratic DILI than males in many retrospective studies.

    “Though females are suggested to have a higher risk of idiosyncratic DILI than males in many retrospective studies, 8,[27][28][29][30]”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [8] Bjornsson, 2013, Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland, Gastroenterology source
    • cites [27] Chalasani, 2008, Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States, Gastroenterology source
    • cites [28] Suk, 2012, A prospective nationwide study of drug-induced liver injury in Korea, Am J Gastroenterol source
    • cites [29] De Valle, 2006, Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic, Aliment Pharmacol Ther source
    • cites [30] Hartleb, 2002, Drug-induced liver damage—a three-year study of patients from one gastroenterological department, Med Sci Monit

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No hospitals from Hong Kong, Macau or Taiwan were included in this study.

    “No hospitals from Hong Kong, Macau or Taiwan were included in this study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    The requirement to obtain informed patient consent was waived by the institutional review board because the analysis was retrospective of existing administrative and clinical data.

    “Owing to the retrospective analysis of existing administrative and clinical data, the requirement to obtain informed patient consent was waived by the institutional review board.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    Each patient was given a unique number to identify multiple visits to different centers or readmissions during the 3-year period, thereby avoiding duplication.

    “Each patient was given a unique number allowing identification of multiple visits to different centers or readmissions during the 3-year period and thereby avoiding duplication.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Females have been reported to have increased, unchanged, or even decreased incidence of DILI.

    “females have been reported to have increased, 8,26,27,31 unchanged, 9,30 or even decreased 12,21 incidence of DILI (Table 4).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [8] Bjornsson, 2013, Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland, Gastroenterology source
    • cites [26] Takikawa, 2009, Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006, Hepatol Res source
    • cites [27] Chalasani, 2008, Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States, Gastroenterology source
    • cites [31] Lucena, 2009, Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex, Hepatology source
    • cites [9] Sgro, 2002, Incidence of drug-induced hepatic injuries: a French population-based study, Hepatology source
    • cites [30] Hartleb, 2002, Drug-induced liver damage—a three-year study of patients from one gastroenterological department, Med Sci Monit
    • cites [12] Zhou, 2013, Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients, Eur J Gastroenterol Hepatol source
    • cites [21] Andrade, 2005, Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period, Gastroenterology source

  • It may state two separate claims as one.

    Interpretationown data

    Female and older DILI patients tended to have more severe DILI than male and younger individuals.

    “In summary, female and older DILI patients tended to have more severe DILI than male and younger individuals.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The study protocol was reviewed and approved by the institutional review board at Renji Hospital of Shanghai JiaoTong University (ClinicalTrials.gov Identifier: NCT02407964).

    “The protocol for the present study was reviewed and approved by the institutional review board at Renji Hospital of Shanghai JiaoTong University, Shanghai, China (ClinicalTrials.govIdentifier: NCT02407964).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    Causality assessment for each case was performed using the Roussel Uclaf Causality Assessment Method (RUCAM).

    “Investigators at each site were asked to complete causality assessment scoring for each case whose diagnosis at discharge was DILI (n=29,478) according to the Roussel Uclaf Causality Assessment Method (RUCAM).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Danan, 1993, Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries, J Clin Epidemiol source
    • cites [15] Benichou, 1993, Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge, J Clin Epidemiol source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    In our study, we had no entrance criteria based on liver chemistries, so may have included more relatively mild cases than in other registries.

    “In our study, we had no entrance criteria based on liver chemistries so may have included more relatively mild cases than in other registries.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductreasoning

    Of the 308 involved centers, only 66 centers provided all recorded hospitalized DILI cases during 3-year observation, and DILI cases from these 66 centers were used to assess the diagnostic rate of DILI in this study, since all inpatients were screened for the occurrence of DILI.

    “Of the 308 involved centers, only 66 centers provided all recorded hospitalized DILI cases during 3-year observation (red dots).Thus, DILI cases from these 66 centers were used to assess the diagnostic rate of DILI in this study, since all inpatients were screened for the occurrence of DILI.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    Our relatively low enrollment of children and teenagers (<18 years old) may be related to the relatively limited number of pediatric hospitals participating in the study.

    “Additionally, our relatively low enrollment of children and teenagers (<18 years old) may be related to the relatively limited number of pediatric hospitals participating in the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In western studies, acute liver failure was most associated with use of non-steroidal anti-inflammatory drugs (NSAIDs), anti-infective drugs, and herbs and dietary supplements (HDS).

    “As reported by the western studies, acute liver failure was most associated with use of non-steroidal anti-inflammatory drugs (NSAIDs), anti-infective drugs, and herbs and dietary supplements (HDS).13,33,34”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Yu, 2017, CSH guidelines for the diagnosis and treatment of drug-induced liver injury, Hepatol Int source
    • cites [33] Russo, 2004, Liver transplantation for acute liver failure from drug induced liver injury in the United States, Liver Transpl source
    • cites [34] Bjornsson, 2005, Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden, Scand J Gastroenterol source

  • It may state two separate claims as one.

    Premisecitation

    All anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) have hepatotoxicity potential and could lead to DILI during anti-tuberculosis treatment, which commonly leads to interruption of anti-TB treatment and may promote antibiotic resistance.

    “All these anti-TB drugs have hepatotoxicity potential and could lead to DILI during M A N U S C R I P T ## A C C E P T E D ACCEPTED MANUSCRIPT anti-tuberculosis treatment, which commonly leads to interruption of anti-TB treatment and may promote antibiotic resistance.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Frieden, 2003, Tuberculosis. Lancet source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Among TB patients, male to female ratio was 2.1:1.

    “Among TB patients, male to female ratio was 2.1:1.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationnone given

    This study is the largest registry of its kind and provides a complete characterization of DILI in mainland China.

    “In summary, in the largest registry of its kind, we have provided a complete characterization of DILI in mainland China.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Liver injury caused by antineoplastic or immunomodulators includes hepatocyte necrosis, hepatic steatosis, hepatic mitochondrial injury, cholestasis and vascular injury.

    “Liver injury caused by antineoplastic or immunomodulators includes hepatocyte necrosis, hepatic steatosis, hepatic mitochondrial injury, cholestasis and vascular injury.[42][43][44][45]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Wang, 2012, Non-genetic risk factors and predicting efficacy for docetaxel—drug-induced liver injury among metastatic breast cancer patients, J Gastroenterol Hepatol source
    • cites [43] Ridruejo, 2007, Imatinib-induced fatal acute liver failure, World J Gastroenterol source
    • cites [44] Ma, 2002, Acute toxicity of adjuvant doxorubicin and cyclophosphamide for early breast cancer—a retrospective review of Chinese patients and comparison with an historic Western series, Radiother Oncol source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In China, it was estimated that 918,000 individuals suffered from tuberculosis (TB) (including TB co-infected with HIV) with overall incidence of 67/100,000 population, which accounted for 8.65% of the world's reported cases of TB in 2015.

    “In China, it was estimated that 918,000 individuals suffered from tuberculosis (TB) (including TB co-infected with HIV) with overall incidence of 67/100,000 population, which accounted for 8.65% of the world's reported cases of TB in 2015 (WHO Global tuberculosis report 2016).32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

49 of 49

  • The authors state this as an assumption.

    The proportion of DILI in the entire hospitalized population of China is represented by that observed in the 66 centers where DILI capture was complete.

    “Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete”

  • The paper relies on this without support.

    The ratio of DILI inpatients to total inpatients in the 66 centers with complete event capture is representative of the ratio in all hospitals in mainland China.

    “The incidence of DILI in the general population was evaluated as (number of DILI inpatients in 66 centers annually ÷ total number of inpatients in 66 centers annually) × (number of inpatients nationwide annually ÷ the general population in mainland China annually).”

  • The paper relies on this without support.

    The 25,927 DILI cases collected from 308 medical centers are representative of hospitalized DILI patients in mainland China.

    “In this study, a total of 25,927 DILI cases among hospitalized patients were collected from 308 medical centers between January 1, 2012 and December 31, 2014 (Figure 1A).”

  • The paper relies on this without support.

    In mainland China, health care of Chinese inhabitants has been covered by the public medical service system, medical insurance system and the rural cooperative medical system since 2003.

    “In mainland China, health care of Chinese inhabitants has been covered by the public medical service system, medical insurance system and the rural cooperative medical system since 2003.”

  • The paper relies on this without support.

    In mainland China, hepatoprotective agents are generally administered to hospitalized patients with DILI.

    “In addition, in mainland China, hepatoprotective agents are generally administered to hospitalized patients with DILI.”

  • The paper relies on this without support.

    The 66 centers that provided all recorded hospitalized DILI cases are representative of all hospitals in mainland China for estimating the proportion of DILI among inpatients.

    “Of the 308 medical centers that participated in this study, only 66 centers provided all recorded hospitalized DILI cases during the three-year observation period and could therefore be used to estimate the proportion of DILI patients among all inpatients.”

  • The paper relies on this without support.

    The gender distribution ratio among TB patients is the expected ratio among DILI patients due to TB treatments if susceptibility to DILI is not affected by gender.

    “Among TB patients, male to female ratio was 2.1:1.32”

  • The paper relies on this without support.

    The 66 centers that provided complete enrollment are representative of all 308 centers and of mainland China for estimating DILI incidence.

    “Of the 308 involved centers, only 66 centers provided all recorded hospitalized DILI cases during 3-year observation (red dots).Thus, DILI cases from these 66 centers were used to assess the diagnostic rate of DILI in this study, since all inpatients were screened for the occurrence of DILI.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Herbal drugs and dietary supplements are a major growing concern for liver injury, liver failure, and death or liver transplantation globally.

    “Herbal drugs and dietary supplements are a major growing concern for liver injury, liver failure, and death or liver transplantation globally.3–6”

    From Ashwagandha-induced liver injury—A case series from India and literature review (2023) · cites this paper as [5]

    The discussion (accepted manuscript; page unavailable) identifies herbal drugs and dietary supplements as major causes of drug-induced liver injury in mainland China, links them to acute liver failure in Western studies, and says their use has increased worldwide. The results report deaths and liver transplants among Chinese drug-induced liver injury cases, and the supplementary death table includes herbal-medicine cases. The copy does not establish that herbal products are a major cause of death or liver transplantation globally. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The problems can well be solved in a new, promised prospective study, whereby the use of RUCAM may again be helpful, now applying its updated version.

    “but it seems that the problems can well be solved in a new, promised prospective study, whereby the use of RUCAM may again be helpful, now applying its updated version.36,102–105”

    From Herb-induced Liver Injury in Asia and Current Role of RUCAM for Causality Assessment in 11,160 Published Cases (2020) · cites this paper as [36]

    The causality-assessment methods section (page not available) says investigators used RUCAM to score cases, supporting the reference to its use in this research. The study-design section describes a retrospective study; our copy does not substantiate a promised prospective study or a plan to use updated RUCAM in one. (LLM, conf=0.80)

    Experimental — accuracy not yet measured

  • In that Chinese study, DILI was the main reason for death in 52 (70.59%) of the patients.

    “In this study, ALF was defined as INR ≥2, the presence of HE, total bilirubin ≥10 times upper limit of normal or daily elevations ≥1 mg/dL, and the disease duration of <26 weeks, and DILI was the main reason for death in 52 (70.59%) of the patients.”

    From Drug-induced liver injury: Diagnosis, management and the role of liver transplantation (2025) · cites this paper as [10]

    The Abstract reports that DILI had a primary role in 72 deaths (70.59%), not 52. The percentage and the characterization of DILI as the main reason for death are supported, but the count is not. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • In that Chinese study, of those with ALF, 102 (0.30%) died.

    “In an observational retrospective study from China conducted between 2012–2014, out of 25,927 patients, 280 (1.08%) patients developed ALF, and of those with ALF, 2 patients (0.01%) underwent LT and 102 (0.30%) died (10).”

    From Drug-induced liver injury: Diagnosis, management and the role of liver transplantation (2025) · cites this paper as [10]

    The Results (accepted manuscript; page not provided) report 102 deaths, but give the rate as 0.39% of DILI cases, not 0.30%. They list 280 cases progressing to hepatic failure separately from the deaths; the source does not say that all 102 deaths occurred among those 280 patients. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Some studies included HILI cases not only with highly probable or probable causality gradings but also with a possible causality level based on RUCAM scores ≥3.

    “Some studies included HILI cases not only with highly probable or probable causality gradings but also with a possible causality level based on RUCAM scores ≥3 (Table 1).24,25,27,28,30,36,38”

    From Herb-induced Liver Injury in Asia and Current Role of RUCAM for Causality Assessment in 11,160 Published Cases (2020) · cites this paper as [36]

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Metadata

Authors
Shen, T., Liu, Y., Shang, J., Xie, Q., Li, J., Yan, M., Xu, J., Niu, J., Liu, J., Watkins, P. B., Aithal, G. P., Andrade, R. J., Dou, X., Yao, L., Lv, F., Wang, Q., Li, Y., Zhou, X., Zhang, Y., Zong, P., Wan, B., Zou, Z., Yang, D., Nie, Y., Li, D., Wang, Y., Han, X., Zhuang, H., Mao, Y., & Chen, C.
Affiliations
  • Peking University (CN)
  • Shenzhen Third People’s Hospital (CN)
  • Henan Provincial People's Hospital (CN)
  • Shanghai Jiao Tong University (CN)
  • Jiangsu Province Hospital (CN)
  • Qilu Hospital of Shandong University (CN)
  • First Affiliated Hospital of Anhui Medical University (CN)
  • First Hospital of Jilin University (CN)
  • First Affiliated Hospital of Xiamen University (CN)
  • University of North Carolina at Chapel Hill (US)
  • Nottingham University Hospitals NHS Trust (GB)
  • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
  • China Medical University (CN)
  • Fujian Medical University (CN)
  • Sir Run Run Shaw Hospital (CN)
  • Shanxi Medical University (CN)
  • Harbin Medical University (CN)
  • Xijing Hospital (CN)
  • Xinjiang Medical University (CN)
  • Jiangxi Chest Hospital (CN)
  • Public Health Clinical Center of Chengdu (CN)
  • 302 Military Hospital of China (CN)
  • Wuhan Union Hospital (CN)
  • Guangzhou First People's Hospital (CN)
  • Fuzhou General Hospital of Nanjing Military Command (CN)
Corresponding author
  • Mao, Yimin
  • Chen, Chengwei
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2019-06
Volume
156
Issue
8
Pages
2230-2241.e11
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2019.02.002
OpenAlex
W2914750127
Cited by
615
References
43
Citations by year
2026: 66 · 2025: 89 · 2024: 95 · 2023: 84 · 2022: 91 · 2021: 82 · 2020: 67 · 2019: 41
FWCI
45.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Repository@Nottingham (University of Nottingham) (acceptedVersion, cc-by-nc-nd)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by-nc-nd)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by-nc-nd)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by-nc-nd)
  • UNC Libraries
Funders
  • Shanghai Shenkang Hospital Development Center (16CR2009A)
  • School of Medicine, Shanghai Jiao Tong University (DLY201607)
  • National Natural Science Foundation of China (81670524)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
drug-induced liver injury, incidence, etiology, hepatocyte injury, cholestatic liver injury, traditional Chinese medicine, herbal and dietary supplements, antitubercular agents, liver failure, liver transplantation, Hy's law, RUCAM, hospitalized patients, China, pharmacovigilance, incidence estimation
MeSH terms
Acute Disease, Adult, Aged, Cause of Death, China, Chronic Disease, Female, Humans, Liver Function Tests, Male, Middle Aged, Registries, Retrospective Studies, Severity of Illness Index, Cohort Studies, Incidence, Survival Rate, Confidence Intervals, Liver Failure, Acute, Age Distribution, Sex Distribution, Risk Assessment, Young Adult, Chemical and Drug Induced Liver Injury, End Stage Liver Disease

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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