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Cited by 62Drug-Induced Hepatotoxicity and ProtectionPharmacovigilance and Adverse Drug ReactionsLiver Disease Diagnosis and Treatment

The DOI matches its Crossref record; 196 of the 198 references it cites were found in a registry or an index; 4 of the 239 sources its claims cite were checked for support.

Chinese guideline for the diagnosis and treatment of drug-induced liver injury: an update

Open access
Mao, Yimin, Ma, Shiwu, Liu, Chenghai, Liu, Xiaoyan, Su, Minghua, Li, Dongliang, Li, Yiling, Chen, Gongying, Chen, Jun, Chen, Jinjun, Zhao, Jingmin, Guo, Xiaoyan, Tang, Jieting, Zhuge, Yuzheng, Xie, Qing, Xie, Wen, Lai, Rongtao, Cai, Dachuan, Cai, Qingxian, Zhi, Yang, Li, Xiaoyun, the Technology Committee on DILI Prevention, Management, Chinese Medical Biotechnology Association; Study Group on Drug-Induced Liver Disease, Chinese Society of Hepatology, Chinese Medical Association·2024·Hepatology International
DOI 10.1007/s12072-023-10633-7
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Abstract

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, and antineoplastic drugs), and signal of DILI in clinical trials and its assessment.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This 2024 update from Chinese societies provides evidence-based guidance for diagnosing and managing drug-induced liver injury (DILI), emphasizing exclusion-based diagnosis, causality assessment, and management of special populations and common etiologies. It covers epidemiology, classification, risk factors, diagnosis, chronic DILI, HDS/anti-TB/antineoplastic DILI, HBV reactivation, biomarkers, clinical-trial signals, and treatment.

Key findings

  • In China, the estimated annual DILI incidence is at least 23.80/100,000, higher than other countries and increasing annually; hospitalized DILI incidence is approximately 1–6%, and DILI accounts for about 2–10% of patients with jaundice, 11.3% of patients hospitalized for severe acute liver injury, and 2.7% of hospitalized patients with liver diseases.
  • Common causes in China include TCM, HDS, anti-TB drugs, antineoplastic agents, and immunomodulators; HDS-DILI/HILI accounts for approximately 20–30% of DILI in China, anti-TB DILI incidence is 9.5–10.6% in China and accounts for 22–31.3% of investigated DILI cases, and antineoplastic agents account for approximately 10% of DILI cases in China.
  • Diagnosis uses R ratio classification: hepatocellular R ≥ 5, cholestatic R ≤ 2, mixed 2 < R < 5; acute DILI thresholds are ALT ≥ 5 × ULN, ALP ≥ 2 × ULN, or ALT ≥ 3 × ULN plus TBil ≥ 2 × ULN; RUCAM is recommended as the primary causality assessment method, with expert opinion in specific scenarios.
  • Approximately 7–13% of patients may not normalize liver biochemistry 6 months or 1 year after acute DILI; about 10% of cases fulfilling Hy’s law progress to ALF; liver transplantation can increase survival up to 66.2% in DI-ALF/ACLF; NAC is recommended for adult DI-ALF/SALF, and magnesium isoglycyrrhizinate and bicyclol are recommended for acute hepatocellular or mixed DILI with significant ALT elevation.

Methods

  • This is an updated clinical guideline developed according to the basic processes and procedures of guideline development promulgated by authoritative academic organizations; all expert writers signed a conflict-of-interest statement.
  • Evidence assessment used the 2011 Oxford Centre for Evidence-Based Medicine levels of evidence and grades of recommendation; evidence collection and assessment were performed by the Health Data Science Institute of Lanzhou University, an independent third party.
  • Recommendations are graded and cover diagnosis, differential diagnosis, causality assessment, severity/prognosis, chronic DILI and specific phenotypes, DILI with pre-existing liver disease, HBV reactivation, common etiologies, biomarkers, clinical-trial signals, treatment, prevention, and future research directions.

Limitations

  • Stated: the guideline cannot cover or address all issues of DILI diagnosis and treatment arising in clinical practice and is not mandatory standards; it will be updated in due course as research progresses.
  • Stated/evident: many recommendations rely on low-level evidence or expert consensus; the text notes no high-level evidence for conventional corticosteroid use in DILI, limited evidence for prophylactic liver-protective drugs, and that currently reported biomarkers have not been clinically validated for approval.
  • Evident from text: RUCAM has ambiguities and suboptimal reliability, with reduced reliability in TCM/HDS-DILI, multiple suspected drugs, pre-existing liver disease, and new-drug trials; RECAM requires external validation outside the US and Spain, and its reliability in herb-induced liver injury remains unknown.

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

Integrity signals

Registry

Crossref · 10.1007/s12072-023-10633-7

Cites

196 of 196 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

4 of 239 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Prolonged cholestasis with progressive reduction of the interlobular bile ducts can lead to vanishing bile duct syndrome with a poor prognosis.

    “Prolonged cholestasis with progressive reduction of the interlobular bile ducts can lead to vanishing bile duct syndrome with a poor prognosis [74].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [74] Bonkovsky HL, Kleiner DE, Gu J, et al. Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology. 2017;65:1267–1277 source
  • Premisecitation

    The overall prognosis of drug-induced acute liver failure or acute-on-chronic liver failure is poor, with 24% or 27.1% transplant-free survival.

    “The overall prognosis of DI-ALF/ACLF is poor, with 24% or 27.1% transplant-free survival.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [66] Hayashi PH, Rockey DC, Fontana RJ, et al. Death and liver transplantation within 2 years of onset of drug-induced liver injury. Hepatology. 2017;66:1275–1285 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [211] Reuben A, Koch DG, Lee WM. Drug-induced acute liver failure: results of a US multicenter, prospective study. Hepatology. 2010;52:2065–2076 source

      The Results (Outcomes; page not available) report 27.1% transplant-free survival for drug-induced acute liver failure, supporting the claim that its prognosis is poor. The paper does not report 24% transplant-free survival, and its Patients and Methods define the study population as having no apparent chronic liver disease, so its finding does not establish the prognosis of acute-on-chronic liver failure. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [212] Stravitz RT, Lee WM. Acute liver failure. Lancet. 2019;394:869–881 source

      The Drug-induced liver injury section describes a worse prognosis and says fewer than 25% recover after encephalopathy develops, but that is not an overall transplant-free survival rate. The Outcomes section gives 41% transplant-free survival for drug-induced liver injury, not 24% or 27.1%. The paper also distinguishes acute liver failure from acute-on-chronic liver failure rather than reporting an outcome for the latter. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    The most common drugs that cause liver injury in China include TCM, HDS, anti-TB drugs, antineoplastic agents, and immunomodulators.

    “The most common drugs that cause liver injury in China include TCM, HDS, anti-TB drugs, antineoplastic agents, and immunomodulators [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology. 2019;156:2230–2241 source
  • Premisecitation

    The drugs that cause liver injury vary across countries and regions owing to the epidemiology of the primary disease, variations in prescribing habits, and population heterogeneity.

    “The drugs that cause liver injury vary across countries and regions owing to the epidemiology of the primary disease, variations in prescribing habits, and population heterogeneity [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Low EXS, Zheng Q, Chan E, Lim SG. Drug induced liver injury: east versus west—a systematic review and meta-analysis. Clin Mol Hepatol. 2020;26:142–154 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Premisecitation

    Antibiotics and non-steroidal anti-inflammatory drugs such as APAP are still the commonest causing agents of DILI in most western countries.

    “Meanwhile, the importance of antibiotics, and non-steroidal anti-inflammatory drugs such as APAP should not be overlooked since these are still the commonest causing agents of DILI in most western countries [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148(7):1340–1352 source
  • It may state two separate claims as one. 38
  • Probably not a substantial claim. 28
  • The quote only partly states this claim. 1

  • It may state two separate claims as one.

    Premisecitation

    The cholestatic type of DILI is more prone to chronic injury and delayed recovery than other types and requires more time for recovery.

    “In addition, evidence shows that the cholestatic type is more prone to the development of chronic injury and delayed recovery than other types and requires more time for recovery [21,73].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [21] Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148(7):1340–1352 source
    • cites [73] Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147(1):96–108 source

      Checked before — its earlier verdict is held back until a new check runs.

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

    Study design and conductnone given

    The methodology of evidence assessment used in the production of the guideline was based on the 2011 Oxford centre for evidence-based medicine levels of evidence and grades of recommendation.

    “The methodology of evidence assessment used in the production of the guideline was based on the 2011 Oxford centre for evidence-based medicine levels of evidence and grades of recommendation (Tables 1, 2).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Hepatocellular injury accounts for 42-59% of DILI cases and is the most common clinical phenotype.

    “Hepatocellular injury accounts for 42-59% of DILI cases and is the most common clinical phenotype, which presents with an acute-hepatitislike significant elevation of ALT or AST level following administration of the suspected drug.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419–1425 source
    • cites [5] Andrade RJ, Lucena MI, Fernández MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129:512–521 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [21] Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148(7):1340–1352 source

  • It may state two separate claims as one.

    Premisecitation

    Cholestatic injury accounts for 20-32% of DILI cases and presents with ALP or GGT elevation.

    “Cholestatic injury is also a typical phenotype and accounts for 20-32% of DILI cases, which present with ALP or gamma-glutamyl transferase (GGT) elevation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419–1425 source
    • cites [5] Andrade RJ, Lucena MI, Fernández MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129:512–521 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [21] Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148(7):1340–1352 source

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

    Study design and conductnone given

    The guideline has been developed according to the basic processes and procedures of guideline development promulgated by authoritative academic organizations worldwide.

    “The guideline has been developed according to the basic processes and procedures of guideline development promulgated by authoritative academic organizations worldwide.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All evidence collection and assessment were performed by the Health Data Science Institute of Lanzhou University, an independent third party.

    “All evidence collection and assessment were performed by the Health Data Science Institute of Lanzhou University, an independent third party.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All experts who wrote the guideline signed a conflict-of-interest statement.

    “All experts who wrote the guideline signed a conflict-ofinterest statement.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    At least 1000 drugs have been reported to cause liver injury.

    “At least 1000 drugs have been reported to cause liver injury.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. https://www.ncbi.nlm.nih.gov/books/NBK547852/. Accessed 1 Apr 2023
    • cites [14] Mao Y. HepaTox: a professional website that promotes clincial and translational research of DILI in China. Gan Zang. 2014;8:575–576

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

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

    Premisecitation

    DILI can be classified as direct, idiosyncratic, or indirect based on its mechanisms.

    “DILI can be classified as direct, idiosyncratic, or indirect based on its mechanisms [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Hoofnagle JH, Björnsson ES. Drug-induced liver injury—types and phenotypes. N Engl J Med. 2019;381:264–273 source

  • It may state two separate claims as one.

    Premisecitation

    The absence of proper labeling on the medicine is a common phenomenon and has made it hard for physicians to pinpoint the exact culprit ingredient, creating obstacles to rigorous studies.

    “In addition, the absence of proper labeling on the medicine as a common phenomenon has made it hard for physicians to pinpoint the exact culprit ingredient [121], all of which have created obstacles to conduct rigorous studies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Philips CA, Augustine P, Rajesh S, Praveen Kumar Y, Madhu D. Complementary and alternative medicine-related drug-induced liver injury in Asia. J Clin Transl Hepatol. 2019;7:263–274 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    RECAM has similar diagnostic efficacy to RUCAM but better precision and reliability due to increased objectivity and clarity.

    “RECAM is a recently reported evidence-based update with similar diagnostic efficacy to RUCAM but better precision and reliability because of its increased objectivity and clarity since it is an electronic algorithm integrated with LiverTox likelihood category [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Hayashi PH, Lucena MI, Fontana RJ, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatology. 2022;76:18–31 source

  • It may state two separate claims as one.

    Premisecitation

    Patients comorbid with HBV and HCV infection are at greater risk of developing DILI during anti-TB therapy and highly active antiretroviral therapy for HIV infection, while active HBV infection may be associated with fatal cases.

    “Several studies have shown that patients comorbid with HBV, and hepatitis C virus (HCV) infection are at greater risk of developing DILI during anti-TB therapy and highly active antiretroviral therapy for human immunodeficiency virus (HIV) infection while active HBV infection may be associated with fatal cases [19,[96][97][98][99][100].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19,[96][97][98][99][100]

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

  • It may state two separate claims as one.

    Premisecitation

    HILI-specific risk factors include quality of products, identical names but different substances, counterfeit drug misuse, mixing or adulteration, environmental contaminants, unreasonable or incompatible formulation, and irrational use of HDS.

    “However, the following HILI-specific risk factors may cause liver injury [126-133]: (1) quality of products: different places of origin and improper preparation may cause differences in components, thereby increasing the risk of hepatotoxicity; (2) identical names but different substances, counterfeit drug misuse, mixing, or adulteration; (3) environmental contaminants, such as pesticide residues,”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [126] Lin L, Li H, Lin H, et al. A new perspective on liver injury by traditional chinese herbs such as : the geographical area of harvest as an important contributory factor. Front Pharmacol. 2017;8:349 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [127] Cui H-R, Bai Z-F, Song H-B, Jia T-Z, Wang J-B, Xiao X-H. Investigation of potential toxic factors for fleece-flower root: from perspective of processing methods evolution. Zhong Guo Zhong Yao Za Zhi. 2016;41:333–339

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

    • cites [128] Teschke R. Traditional Chinese medicine induced liver injury. J Clin Transl Hepatol. 2014;2:80–94

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

    • cites [129] Fasinu PS, Bouic PJ, Rosenkranz B. An overview of the evidence and mechanisms of herb-drug interactions. Front Pharmacol. 2012;3:69 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [130] Wu S-X, Sun H-F, Yang X-H, et al. “Re-evaluation upon suspected event” is an approach for post-marketing clinical study: lessons from adverse drug events related to Bupleuri Radix preparations. Zhong Guo Zhong Yao Za Zhi. 2014;39:2983–2988

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

    • cites [131] Tian D. Huang Di Nei Jing Su Wen. Beijing: People’s Medical Publishing House; 2005. p. 189–190
    • cites [132] Key technical issues of herbal medicines with reference to interaction with other medicines. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240019140.
    • cites [133] Song H-B, Han L. Epidemiologic characteristics, risk factors and safety evaluation of traditional Chinese medicine induced liver injury. Zhong Guo Yao Li Xue Yu Du Li Xue Za Zhi. 2016;30:291–305

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

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Stepwise therapy with anticoagulants (low-molecular-weight heparin and/or warfarin) and transjugular intrahepatic portosystemic shunt (TIPS) is currently the recommended standard therapy for PA-HSOS, confirmed in multiple retrospective studies.

    “Stepwise therapy with anticoagulants (low-molecular-weight heparin and/or warfarin) and transjugular intrahepatic portosystemic shunt (TIPS) is currently the recommended standard therapy, which has been confirmed in multiple retrospective studies [89].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Zhuge Y, Liu Y, Xie W, Zou X, Xu J, Wang J. Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome. J Gastroenterol Hepatol. 2019;34:634–642 source

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

    Premisecitation

    In RECAM, competing medications are removed to encourage assessment of each culprit drug.

    “The original criteria of risk factors in RUCAM is removed in RECAM for lack of diagnostic value, so is competing medications to encourage assessment of each culprit drug.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Hayashi PH, Lucena MI, Fontana RJ, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatology. 2022;76:18–31 source

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

    Premisecitation

    HMs are the leading cause of DILI in many Asian countries such as Korea, Thailand, and Singapore, accounting for 27.5%, 41.5%, and 61.4% respectively.

    “HMs are the leading cause of DILI in many Asian countries such as Korea [7], Thailand [17], and Singapore [18], and accounts for 27.5%, 41.5%, and 61.4% respectively.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Suk KT, Kim DJ, Kim CH, et al. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol. 2012;107:1380–1387 source
    • cites [17] Chirapongsathorn S, Sukeepaisarnjaroen W, Treeprasertsuk S, et al. Characteristics of drug-induced liver injury in chronic liver disease: results from the Thai Association for the Study of the Liver (THASL) DILI Registry. J Clin Transl Hepatol. 2023;11:88–96 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [18] Teo DCH, Ng PSL, Tan SH, et al. Drug-induced liver injury associated with complementary and alternative medicine: a review of adverse event reports in an Asian community from 2009 to 2014. BMC Complement Altern Med. 2016;16:192 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    RECAM demonstrated better overall agreement with expert opinion and greater sensitivity for detecting patients in extreme DILI diagnostic categories.

    “It demonstrated a better overall agreement with expert opinion and greater sensitivity for detecting patients in extreme DILI diagnostic categories (e.g., highly likely/probable; unlikely/excluded).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Hayashi PH, Lucena MI, Fontana RJ, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatology. 2022;76:18–31 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Quality control and safety assessment significantly differ across regulatory categories of HMs, which has brought great challenges to the prevention, clinical evaluation, and management of HILI and is one reason why HDS-DILI, including HILI, is rapidly increasing worldwide.

    “Quality control and safety assessment significantly differ across regulatory categories of HMs, which has brought great challenges to the prevention, clinical evaluation, and management of HILI; this is also one of the reasons why HDS-DILI, including HILI, is rapidly increasing worldwide.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationcitation

    The likelihood of DI-ALH increases in the absence of relapse after discontinuation of corticosteroid or immunosuppressive therapy.

    “The likelihood of DI-ALH increases in the absence of relapse.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The proportion of HMs as cause of DILI is reported to be 13.9% and 6% in India and Japan, respectively.

    “The proportion are reported to be 13.9% and 6% in India and Japan, respectively [20,117].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Devarbhavi H, Joseph T, Sunil Kumar N, et al. The Indian network of drug-induced liver injury: etiology, clinical features, outcome and prognostic markers in 1288 patients. J Clin Exp Hepatol. 2021;11:288–298 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [117] Aiso M, Takikawa H, Tsuji K, et al. Analysis of 307 cases with drug-induced liver injury between 2010 and 2018 in Japan. Hepatol Res. 2019;49:105–110 source

  • It may state two separate claims as one.

    Premisecitation

    High TBil and ALP levels in the second month after an acute DILI episode and the biochemical nonresolution-6 model may help predict the risk of chronic injury and delayed recovery.

    “High TBil and ALP levels in the second month after an acute DILI episode and the biochemical nonresolution-6 model may help predict the risk of chronic injury and delayed recovery [26,72].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] EASL Clinical Practice Guidelines. Drug-induced liver injury. J Hepatol. 2019;70:1222–1261 source
    • cites [72] Wang C-Y, Deng Y, Li P, et al. Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: a large multicenter study. Hepatology. 2022;75:1373–1385 source

  • It may state two separate claims as one.

    Interpretationreasoning

    The increased risk of hepatotoxicity of certain drugs in patients with pre-existing liver disease may be associated with specific drugs or impaired liver function due to underlying liver diseases, particularly the latter.

    “The increased risk of hepatotoxicity of certain drugs in this population may be associated with specific drugs or impaired liver function due to underlying liver diseases, particularly the latter.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Some cases of chronic DILI develop from the chronicity of acute DILI, while others may be a specific phenotype caused by drugs.

    “Clinically, some cases with chronic DILI develop from the chronicity of acute DILI, however, some might be a specific phenotype caused by drugs (e.g., drug-associated fatty liver disease [75], druginduced fibrosis/cirrhosis, nodular regenerative hyperplasia [76], drug-induced autoimmune-like hepatitis [DI-ALH], and peliosis hepatis [77]).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [75] Amacher DE, Chalasani N. Drug-induced hepatic steatosis. Semin Liver Dis. 2014;34:205–214 source
    • cites [76] Ghabril M, Vuppalanchi R. Drug-induced nodular regenerative hyperplasia. Semin Liver Dis. 2014;34:240–245 source
    • cites [77] Tsokos M, Erbersdobler A. Pathology of peliosis. Forensic Sci Int. 2005;149:25–33 source

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

    Premisecitation

    The RUCAM causality assessment score includes seven distinct domains.

    “RUCAM: The RUCAM causality assessment score includes seven distinct domains [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Danan G, Benichou C. 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. 1993;46:1323–1330 source

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

    Premisecitation

    In China, the proportion of HMs as cause of DILI has been reported to be approximately 20-30%.

    “In China, this proportion has been reported to be approximately 20-30% [118-120].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [118] Zhu C, Wang H, Yuan J. Clinical features of drug-induced liver injury: an analysis of 445 cases. Lin Chuang Gan Dan Bing Za Zhi. 2018;34:354–358

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

    • cites [119] Zhou Y, Yang L, Liao Z, He X, Zhou Y, Guo H. Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients. Eur J Gastroenterol Hepatol. 2013;25:825–829 source
    • cites [120] Huang Y-S, Chang T-T, Peng C-Y, et al. Herbal and dietary supplement-induced liver injury in Taiwan: comparison with conventional drug-induced liver injury. Hepatol Int. 2021;15:1456–1465 source

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

    Premisecitation

    Withania somnifera, Curcuma longa, Psoralea corylifolia, and etc. are associated with hepatotoxicity in traditional Indian Ayurvedic herbs.

    “Withania somnifera, Curcuma longa, Psoralea corylifolia, and etc. are associated with hepatotoxicity in traditional Indian Ayurvedic herbs [122].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Philips CA, Ahamed R, Rajesh S, George T, Mohanan M, Augustine P. Comprehensive review of hepatotoxicity associated with traditional Indian Ayurvedic herbs. World J Hepatol. 2020;12:574–595 source

      Checked before — its earlier verdict is held back until a new check runs.

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

    Premisecitation

    The updated RUCAM score was published in 2016.

    “The updated score was published in 2016 [58], but remains to be validated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2015;17(1):14 source

  • It may state two separate claims as one.

    Premisecitation

    The Nanjing criteria have been clinically validated in a retrospective cohort and demonstrated excellent performance with a sensitivity of 95.35% and specificity of 100% for PA-HSOS.

    “The Nanjing criteria have recently been clinically validated in a retrospective cohort and demonstrated excellent performance with a sensitivity and specificity of 95.35% and 100%, in which the study also highlighted the importance of differential diagnosis from Budd-Chiari syndrome due to similar imaging features [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Zhang W, Liu L, Zhang M, et al. Validation of the Nanjing criteria for diagnosing pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome. J Clin Transl Hepatol. 2021;9:345–352 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim.

    Premisecitation

    The likelihood of DILI can be divided into five probability groups: definite >95%, highly likely 75-95%, probable 50-74%, possible 25-49%, unlikely <25%.

    “The likelihood of DILI can be divided into five probability groups: definite, > 95% likelihood; highly likely, 75-95% likelihood; probable, 50-74% likelihood; possible, 25-49% likelihood; and unlikely, < 25% likelihood [62].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel–Uclaf causality assessment method. Hepatology. 2010;51:2117–2126 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    Interactions between TCM, chemical drugs, and dietary supplements are complex and may cause systematic pharmacokinetic changes by altering absorption, distribution, metabolism, and excretion of medicinal components, resulting in adverse effects including hepatotoxicity and nephrotoxicity.

    “These interactions between TCM, chemical drugs, and dietary supplements are complex and may cause systematic pharmacokinetic changes by altering the absorption, distribution, metabolism, and excretion of medicinal components, resulting in adverse effects including hepatotoxicity and nephrotoxicity [132].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Key technical issues of herbal medicines with reference to interaction with other medicines. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240019140.

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

    Premisecitation

    Therapies are classified into high, intermediate, low, and uncertain risk groups according to the risk level for HBVr.

    “Therapies are classified into high, intermediate, low, and uncertain risk groups according to the risk level for HBVr [112] (Table 7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Lau G, Yu M-L, Wong G, et al. APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int. 2021;15:1031–1048 source

      Checked before — its earlier verdict is held back until a new check runs.

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

    Premisecitation

    In the US, HDS accounts for approximately 20% of DILI cases, ranking second, and 8-16% in Europe and Latin America.

    “In the US, HDS accounts for approximately 20% of DILI cases, ranking second [123], and 8-16% in Europe and Latin America [3,124,125].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [123] Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the US drug-induced liver injury network. Hepatology. 2014;60:1399–1408 source
    • cites [3] Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419–1425 source
    • cites [124] Bessone F, García-Cortés M, Medina-Caliz I, et al. Herbal and dietary supplements-induced liver injury in latin America: experience from the LATINDILI network. Clin Gastroenterol Hepatol. 2022;20:e548–e563 source
    • cites [125] Robles-Diaz M, Gonzalez-Jimenez A, Medina-Caliz I, et al. Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids. Aliment Pharmacol Ther. 2015;41:116–125 source

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

    Premisecitation

    The proportion of patients with fatal adverse clinical outcomes varies from country to country owing to differences in study design, methods, and populations.

    “The proportion of patients with fatal adverse clinical outcomes varies from country to country owing to differences in study design, methods, and populations [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology. 2019;156:2230–2241 source

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

    Premisecitation

    Patients with specific phenotypes such as eosinophilia and systemic symptoms (DRESS syndrome) may present with various symptoms such as fever, rash, and other extrahepatic symptoms.

    “Patients with specific phenotypes such as eosinophilia and systemic symptoms (DRESS syndrome) may present with various symptoms such as fever, rash, and other extrahepatic symptoms [49,50].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Devarbhavi H, Kurien SS, Raj S, et al. Idiosyncratic drug-induced liver injury associated with and without drug reaction with eosinophilia and systemic symptoms. Am J Gastroenterol. 2022;117:1709–1713 source
    • cites [50] Huang Y-S, Wu C-Y, Chang T-T, et al. Drug-induced liver injury associated with severe cutaneous adverse drug reactions: a nationwide study in Taiwan. Liver Int. 2021;41:2671–2680 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 the United States and China, 10% and 23% of patients with DILI have underlying liver disease, respectively.

    “In the United States and China, 10% and 23% of patients with DILI have underlying liver disease, respectively [8,21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology. 2019;156:2230–2241 source
    • cites [21] Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148(7):1340–1352 source

  • It may state two separate claims as one.

    Premisecitation

    Multiple studies from Asia, Europe, and Latin-America have shown that liver injury caused by HMs/HDS is more severe than that caused by other drugs, with a higher risk of death or requirement of liver transplantation.

    “Multiple studies from Asia, Europe, and Latin-America have shown that liver injury caused by HMs/HDS is more severe than that caused by other drugs, with a higher risk of death or requirement of liver transplantation [120,124,134].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [120] Huang Y-S, Chang T-T, Peng C-Y, et al. Herbal and dietary supplement-induced liver injury in Taiwan: comparison with conventional drug-induced liver injury. Hepatol Int. 2021;15:1456–1465 source
    • cites [124] Bessone F, García-Cortés M, Medina-Caliz I, et al. Herbal and dietary supplements-induced liver injury in latin America: experience from the LATINDILI network. Clin Gastroenterol Hepatol. 2022;20:e548–e563 source
    • cites [134] Medina-Caliz I, Garcia-Cortes M, Gonzalez-Jimenez A, et al. Herbal and dietary supplement-induced liver injuries in the Spanish DILI Registry. Clin Gastroenterol Hepatol. 2018;16:1495–1502 source

  • Probably not a substantial claim.

    Premisecitation

    Analysis of biomarkers and clinical validation are necessary steps for biomarker evaluation by regulatory agencies.

    “the analysis of biomarkers and clinical validation are necessary steps for biomarker evaluation by regulatory agencies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Roth SE, Avigan MI, Bourdet D, et al. Next-generation DILI biomarkers: prioritization of biomarkers for qualification and best practices for biospecimen collection in drug development. Clin Pharmacol Ther. 2020;107:333–346 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationcitation

    Currently reported biomarkers have yet to be clinically validated for approval, and studies using large DILI cohorts are required for biomarker validation.

    “currently reported biomarkers have yet to be clinically validated for approval, and studies using large DILI cohorts are required for biomarker validation, highlighting the importance of collaborative DILI registry studies [181,182].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [181] Roth SE, Avigan MI, Bourdet D, et al. Next-generation DILI biomarkers: prioritization of biomarkers for qualification and best practices for biospecimen collection in drug development. Clin Pharmacol Ther. 2020;107:333–346 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [182] US Department of Health and Human Services FDA, Center for Drug Evaluation and Research. Letter of Support for Drug-Induced Liver Injury (DILI) Biomarker(s). 2016. https://fda.report/media/99532/Letter-of-Support-for-Drug-Induced-Liver-Injury-%28DILI%29-Biomarker%28s%29-7-25-16.pdf.

  • It may state two separate claims as one.

    Premisecitation

    Possible risk factors for immune checkpoint inhibitor-related hepatotoxicity include organ transplantation, comorbidity with autoimmune disease, history of immune checkpoint inhibitor-induced immune-related adverse events, high doses of immune checkpoint inhibitors (particularly cytotoxic T-lymphocyte antigen 4 inhibitors), combination therapy with multiple immune checkpoint inhibitors, or a组合 of

    “Possible risk factors for ICI-related hepatotoxicity include organ transplantation, comorbidity with autoimmune disease, history of ICI-induced irAEs, high doses of ICIs (particularly cytotoxic T-lymphocyte antigen 4 inhibitors), combination therapy with multiple ICIs, or a combination of an ICI with targeted therapy [165][166][167].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [165] Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2:234–240 source
    • cites [166] Menzies AM, Johnson DB, Ramanujam S, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28:368–376 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [167] Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review. Ann Intern Med. 2018;168:121–130 source

  • It may state two separate claims as one.

    Interpretationreasoning

    The reliability of the RUCAM score for causality assessment in clinical trials of new drugs may be lowered, and a combination with expert opinions may be a better option.

    “Therefore, the reliability of the RUCAM score for causality assessment in clinical trials of new drugs may be lowered, and a combination with expert opinions may be a better option [51,183].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [51] Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting. A consensus by a CIOMS Working Group. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS). 2020. https://cioms.ch/wp-content/uploads/2020/06/CIOMS_DILI_Web_16Jun2020.pdf. Accessed 1 Apr 2023 source
    • cites [183] U.S. Department of Health and Human Services FDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009. https://www.fda.gov/media/116737/download.
    • Rests on an assumption: In most cases, the risk of DILI and associated risk factors for new drugs in clinical development are unknown and information and literature on previous liver injury caused by these drugs are limited.
    • Rests on an assumption: Once participants in clinical trials develop liver injury, they are usually not rechallenged.

  • It may state two separate claims as one.

    Interpretationcitation

    The Common Terminology Criteria for Adverse Events-based severity grading is different from the DILIN or international DILI severity grading and may not truly reflect the clinical severity of liver-related adverse events.

    “which is different from the DILIN or international DILI severity grading and may not truly reflect the clinical severity of liver-related adverse events [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology. 2020;72:315–329 source

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

    Premisecitation

    Sunitinib, lapatinib, pazopanib, regorafenib, ponatinib, pexidartinib, and idelalisib are targeted drugs assigned box warnings for hepatotoxicity by the United States Food and Drug Administration.

    “Sunitinib, lapatinib, pazopanib, regorafenib, ponatinib, pexidartinib, and idelalisib are targeted drugs that have been assigned box warnings for hepatotoxicity by the United States Food and Drug Administration (FDA) [150,151].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Zhao Q, Wu ZE, Li B, Li F. Recent advances in metabolism and toxicity of tyrosine kinase inhibitors. Pharmacol Ther. 2022;237: 108256 source
    • cites [151] Coutré SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56:2779–2786 source

      Checked before — its earlier verdict is held back until a new check runs.

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

    Premisecitation

    The FDA is at present rigorously applying Hy's law to screen for potentially hepatotoxic drugs.

    “The FDA is at present rigorously applying Hy's law to screen for potentially hepatotoxic drugs [183].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] U.S. Department of Health and Human Services FDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009. https://www.fda.gov/media/116737/download.

  • It may state two separate claims as one.

    Premisecitation

    Some studies have suggested that corticosteroids ameliorate liver injury, while others have suggested that they increase adverse events without significant benefits.

    “While some studies have suggested that corticosteroids ameliorate liver injury [187][188][189][190][191], others have suggested that they increase adverse events without significant benefits [192,193].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [187] Hu PF, Wang PQ, Chen H, et al. Beneficial effect of corticosteroids for patients with severe drug-induced liver injury. J Dig Dis. 2016;17:618–627 source
    • cites [188] Sundaram S, Vuppalanchi R, Saxena R, Chalasani N. Treatment of idiosyncratic drug-induced liver injury using steroids. ACG Case Rep J. 2020;7: e00319 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [189] Wree A, Dechêne A, Herzer K, et al. Steroid and ursodesoxycholic acid combination therapy in severe drug-induced liver injury. Digestion. 2011;84:54–59 source
    • cites [190] Wang J-B, Huang A, Wang Y, et al. Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial. Aliment Pharmacol Ther. 2022;55:1297–1310 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [191] Niu H, Ma J, Medina-Caliz I, et al. Potential benefit and lack of serious risk from corticosteroids in drug-induced liver injury: an international, multicentre, propensity score-matched analysis. Aliment Pharmacol Ther. 2023;57:886–896 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [192] Ma J, Gu J, Lammert C. Characterization of steroid therapy for drug-induced liver injury. Gastroenterology. 2020;158:S-1304 source
    • cites [193] Wan Y-M, Wu J-F, Li Y-H, Wu H-M, Wu X-N, Xu Y. Prednisone is not beneficial for the treatment of severe drug-induced liver injury: an observational study (STROBE compliant). Medicine (Baltimore). 2019;98: e15886 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    In randomized controlled trials, an imbalance in liver enzyme levels between the trial and placebo (or positive control) groups or the presence of severe DILI cases in the trial group, characterized by elevated bilirubin, jaundice, and/or coagulation dysfunction accompanied by obvious symptoms of liver disease, are the two major signals that the trial drug has potential hepatotoxicity.

    “In randomized controlled trials (RCT), an imbalance in liver enzyme levels between the trial and placebo (or positive control) groups or the presence of severe DILI cases in the trial group, characterized by elevated bilirubin, jaundice, and/or coagulation dysfunction accompanied by obvious symptoms of liver disease, are the two major signals that the trial drug has potential hepatotoxicity [51].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting. A consensus by a CIOMS Working Group. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS). 2020. https://cioms.ch/wp-content/uploads/2020/06/CIOMS_DILI_Web_16Jun2020.pdf. Accessed 1 Apr 2023 source

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

    Premisecitation

    In Western countries, antineoplastic agent-induced liver injury accounts for 5-8% of DILI.

    “In Western countries, antineoplastic agent-induced liver injury accounts for 5-8% of DILI.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Li X, Tang J, Mao Y. Incidence and risk factors of drug-induced liver injury. Liver Int. 2022;42:1999–2014 source

  • It may state two separate claims as one.

    Premisecitation

    Genetic polymorphisms may be associated with an increased risk of AT-DILI in people carrying the HLA-B*52:01 allele and in ultraslow metabolizers carrying NAT2*6 or NAT2*7 variants.

    “Genetic polymorphisms may be associated with an increased risk of AT-DILI in people carrying the HLA-B*52:01 allele and in ultraslow metabolizers carrying NAT2*6 or NAT2*7 variants [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Nicoletti P, Devarbhavi H, Goel A, et al. Genetic risk factors in drug-induced liver injury due to isoniazid-containing antituberculosis drug regimens. Clin Pharmacol Ther. 2021;109:1125–1135 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    In a phase II trial, bicyclol effectively reduced aminotransferase levels in patients with acute DILI and promoted recovery from liver injury when given 25 or 50 mg 3 times a day.

    “In a phase II trial, bicyclol effectively reduced level of aminotransferase in patients with acute DILI and promoted recovery from liver injury when given 25 or 50 mg 3 times a day [195].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [195] Tang J, Gu J, Chu N, et al. Efficacy and safety of bicyclol for treating patients with idiosyncratic acute drug-induced liver injury: a multicenter, randomized, phase II trial. Liver Int. 2022;42:1803–1813 source

  • It may state two separate claims as one.

    Interpretationnone given

    The magnitude of elevation in transaminase levels after drug administration may be a better indicator of severe DILI than the frequency of elevation, with higher peaks (10-15 × ULN) indicating specificity.

    “The magnitude of elevation in transaminase levels after drug administration may be a better indicator of severe DILI than the frequency of elevation, with higher peaks (10-15 × ULN) indicating specificity.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    The currently reported risk factors for AT-DILI include old age; female sex; Asian ethnicity; HBV, HCV, or HIV infection; and concomitant use of multiple hepatotoxic anti-TB treatments.

    “The currently reported risk factors for AT-DILI include old age; female sex; Asian ethnicity; HBV, HCV, or HIV infection; and concomitant use of multiple hepatotoxic anti-TB treatments (ATT) [51,59]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting. A consensus by a CIOMS Working Group. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS). 2020. https://cioms.ch/wp-content/uploads/2020/06/CIOMS_DILI_Web_16Jun2020.pdf. Accessed 1 Apr 2023 source
    • cites [59] Devarbhavi H, Aithal G, Treeprasertsuk S, et al. Drug-induced liver injury: Asia Pacific Association of Study of liver consensus guidelines. Hepatol Int. 2021;15:258–282 source

  • It may state two separate claims as one.

    Interpretationreasoning

    There is no definite evidence suggesting that corticosteroids can improve the survival of patients with drug-induced acute liver failure or the prognosis of cholestatic DILI or vanishing bile duct syndrome.

    “Similarly, we have no definite evidence suggesting that corticosteroids can improve the survival of patients with DI-ALF or the prognosis of cholestatic DILI or vanishing bile duct syndrome.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Usually, AT-DILI occurs within the first 2 months of ATT, but the risk of liver injury persists throughout the course of treatment.

    “Usually, AT-DILI occurs within the first 2 months of ATT, but the risk of liver injury persists throughout the course of treatment [141,142].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [141] Devarbhavi H, Singh R, Patil M, Sheth K, Adarsh CK, Balaraju G. Outcome and determinants of mortality in 269 patients with combination anti-tuberculosis drug-induced liver injury. J Gastroenterol Hepatol. 2013;28:161–167 source
    • cites [142] Abbara A, Chitty S, Roe JK, et al. Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK. BMC Infect Dis. 2017;17:231 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    MicroRNA-122 is a hepatocyte-specific miRNA that is elevated in the plasma of patients with APAP overdose before the ALT level is elevated and is considered able to predict the onset of liver injury at an early time point.

    “MicroRNA-122 is a hepatocyte-specific miRNA that is elevated in the plasma of patients with APAP overdose before the ALT level is elevated and is considered able to predict the onset of liver injury at an early time point [174].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Dear JW, Clarke JI, Francis B, et al. Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies. Lancet Gastroenterol Hepatol. 2018;3:104–113 source

      Checked before — its earlier verdict is held back until a new check runs.

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

    Premisecitation

    Approximately 10% of DILI cases in China and 8.34% in Japan are caused by antineoplastic agents.

    “Approximately 10% and 8.34% of DILI cases in China and Japan, respectively, are caused by antineoplastic agents [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Li X, Tang J, Mao Y. Incidence and risk factors of drug-induced liver injury. Liver Int. 2022;42:1999–2014 source

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

    Premisecitation

    The incidence of AT-DILI is 9.5-10.6% in China and 3.8-10.0% in India.

    “The incidence of AT-DILI is 9.5-10.6% in China and 3.8-10.0%in India [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Chinese society for tuberculosis. Guidelines for anti-tuberculosis drug-induced liver injury (2019 version). Zhong Hua Jie He He Hu Xi Za Zhi. 2019;42:343–56

  • It may state two separate claims as one.

    Interpretationcitation

    AT-DILI is the most common cause of DILI and a common cause of ALF and acute-on-chronic liver failure (ACLF) in Asian countries.

    “Therefore, AT-DILI is the most common cause of DILI and a common cause of ALF and acute-on-chronic liver failure (ACLF) in Asian countries [138,139].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [138] Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol. 2010;105:2396–2404 source
    • cites [139] Devarbhavi H, Choudhury AK, Sharma MK, et al. Drug-induced acute-on-chronic liver failure in Asian Patients. Am J Gastroenterol. 2019;114:929–937 source

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

    Premisecitation

    The DDInter covers approximately 240,000 DDI drugs reviewed and revised by clinical pharmacists, providing practical information on mechanisms of action, severity, potential risks, and drug-switching options.

    “The DDInter covers approximately 240,000 DDI drugs reviewed and revised by clinical pharmacists, providing practical information on mechanisms of action, severity, potential risks, and drug-switching options [219].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Xiong G, Yang Z, Yi J, et al. DDInter: an online drug-drug interaction database towards improving clinical decision-making and patient safety. Nucleic Acids Res. 2022;50:D1200–D1207 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationcitation

    In clinical trials, the severity of liver-related adverse events, including DILI, is usually assessed using the Common Terminology Criteria for Adverse Events, which may not accurately reflect the clinical severity of DILI.

    “in clinical trials, the severity of liver-related adverse events, including DILI, is usually assessed using the Common Terminology Criteria for Adverse Events, which may not accurately reflect the clinical severity of DILI [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting. A consensus by a CIOMS Working Group. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS). 2020. https://cioms.ch/wp-content/uploads/2020/06/CIOMS_DILI_Web_16Jun2020.pdf. Accessed 1 Apr 2023 source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    Significant improvement and recovery from liver injury after discontinuation of a single agent in combination regimens (dechallenge) may help clarify the suspected agent.

    “Significant improvement and recovery from liver injury after discontinuation of a single agent in the combination regimens (dechallenge) may help clarify the suspected agent.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    The incidence of any grade of immune checkpoint inhibitor-related hepatitis in combination therapy is higher than that in monotherapy, for both the combination of two immune checkpoint inhibitors and a combination of an immune checkpoint inhibitor with targeted therapy.

    “The incidence of any grade of ICI-related hepatitis in combination therapy is higher than that in monotherapy, for both the combination of two ICIs and a combination of an ICI with targeted therapy [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology. 2020;72:315–329 source
60 of 60

  • The paper relies on this without support.

    Currently, the diagnosis of DILI still follows the strategy of exclusion.

    “Currently, the diagnosis of DILI still follows the strategy of exclusion.”

  • The paper relies on this without support.

    Early detection, diagnosis, prognosis, management, and prevention of DILI is challenging owing to complex drug classes, differences in prescribing habits, limitations in understanding of population heterogeneity, mechanisms of injury, risk factors, and phenotypes, and lack of specific diagnostic biomarkers and effective interventions.

    “The early detection, diagnosis, prognosis, management, and prevention of DILI is challenging owing to the following factors: complex drug classes causing liver injury; differences in prescribing habits; limitations in the understanding of population heterogeneity, mechanisms of injury, risk factors, and phenotypes; and lack of specific diagnostic biomarkers and effective interventions.”

  • The paper relies on this without support.

    DILI is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases.

    “Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases.”

  • The paper relies on this without support.

    Liver injury caused by the use of herbal and dietary supplements (HDS) and herbal medicines (HMs) has been a global concern, especially in Asian and African countries where such complementary and alternative medicine (CAM) are frequently used and recently in western countries where HDS-DILI has also increased.

    “Liver injury caused by the use of herbal and dietary supplements (HDS) and herbal medicines (HMs) has been a global concern, especially in Asian and African countries where such complementary and alternative medicine (CAM) are frequently used and recently in western countries where HDS-DILI has also increased.”

  • The paper relies on this without support.

    With the recent approval of targeted therapies and immune checkpoint inhibitors (ICIs), new challenges such as immune-mediated ICI-related hepatotoxicity have been posed in the field of DILI.

    “Moreover, with the recent approval of targeted therapies and immune checkpoint inhibitors (ICIs), new challenges such as immune-mediated ICIrelated hepatotoxicity have been posed in the field of DILI.”

  • The paper relies on this without support.

    In direct DILI, the risk of liver injury is dose dependent.

    “In direct DILI, the risk of liver injury is dose dependent.”

  • The paper relies on this without support.

    iDILI is largely dose-independent.

    “Idiosyncratic DILI (iDILI) is largely doseindependent, although some studies have suggested that a dose threshold is usually required [28,29].”

  • The paper relies on this without support.

    Drugs that affect both ATP-dependent BSEP and mitochondrial function are associated with an increased risk of DILI.

    “Drugs that affect both adenosine triphosphate-dependent BSEP and mitochondrial function are associated with an increased risk of DILI.”

  • The paper relies on this without support.

    Concomitant use of certain drugs may increase the risk of hepatotoxicity.

    “Drug interactions: Concomitant use of certain drugs may increase the risk of hepatotoxicity.”

  • The paper relies on this without support.

    Age is not a general risk factor for DILI.

    “Age is not a general risk factor for DILI.”

  • The paper relies on this without support.

    There is insufficient evidence suggesting that female are at a higher risk of DILI than men.

    “There is insufficient evidence suggesting that female are at a higher risk of DILI than men.”

  • The paper relies on this without support.

    High alcohol consumption increases the risk of liver injury induced by certain drugs such as APAP, isoniazid, methotrexate, and halothane.

    “However, high alcohol consumption increases the risk of liver injury induced by certain drugs such as APAP, isoniazid, methotrexate, and halothane.”

  • The paper relies on this without support.

    DILI during pregnancy is rare because of conservative drug use.

    “DILI during pregnancy is rare because of conservative drug use.”

  • The paper relies on this without support.

    Limited evidence suggests that comorbidities increase the risk of developing DILI.

    “Limited evidence suggests that comorbidities increase the risk of developing DILI.”

  • The paper relies on this without support.

    Polymorphisms in drug-metabolizing enzymes, transporters, and human leukocyte antigen (HLA) may be important determinants of DILI.

    “Polymorphisms in drug-metabolizing enzymes, transporters, and human leukocyte antigen (HLA) may be important determinants of DILI.”

  • The paper relies on this without support.

    The clinical presentation of DILI is usually nonspecific, similar to that of other acute and chronic liver diseases.

    “The clinical presentation of DILI is usually nonspecific, similar to that of other acute and chronic liver diseases.”

  • The paper relies on this without support.

    Serum ALT, AST, and ALP levels are markers of liver injury, whereas TBil, albumin, and international normalized ratio (INR) are markers of severity.

    “Serum ALT, AST, and ALP levels are the markers of liver injury, whereas TBil, albumin, and international normalized ratio (INR) are markers of severity.”

  • The paper relies on this without support.

    The histologic features of DILI are complex and include almost all pathologic changes in the liver.

    “The histologic features of DILI are complex and include almost all pathologic changes in the liver.”

  • The paper relies on this without support.

    The type of injured target cell at the onset of DILI largely determines the clinical phenotype.

    “The type of injured target cell at the onset of DILI largely determines the clinical phenotype.”

  • The paper relies on this without support.

    Currently, there is no uniform histologic scoring system for DILI.

    “Currently, there is no uniform histologic scoring system for DILI.”

  • The paper relies on this without support.

    Usually, DILI occurs within the first 6 months after starting a new medication; however, there are exceptions.

    “Usually, DILI occurs within the first 6 months after starting a new medication; however, there are exceptions.”

  • The paper relies on this without support.

    DILI remains a diagnosis of exclusion based on a detailed history, clinical manifestations, serum biochemistry, imaging, and liver biopsy, owing to the lack of specific diagnostic biomarkers.

    “DILI remains a diagnosis of exclusion based on a detailed history, clinical manifestations, serum biochemistry, imaging, and liver biopsy, owing to the lack of specific diagnostic biomarkers.”

  • The paper relies on this without support.

    Causality assessment is the key to DILI diagnosis and can be used to determine whether a drug is the cause of liver injury.

    “Causality assessment is the key to DILI diagnosis and can be used to determine whether a drug is the cause of liver injury.”

  • The paper relies on this without support.

    In most cases, the diagnosis of DILI cannot be made solely based on pathology.

    “Although in most cases, the diagnosis of DILI cannot be made solely based on pathology, liver biopsy is of great value for providing information on the histopathological type, area, and severity of injury.”

  • The paper relies on this without support.

    In certain clinical scenarios (TCM/HDS-DILI, multiple suspected drugs, pre-existing liver disease, clinical trials of new drugs), rote use of the RUCAM score may result in misdiagnosis or missed diagnosis owing to lowered reliability.

    “In certain clinical scenarios (e.g., TCM/HDS-DILI, DILI caused by multiple suspected drugs, DILI in patients with pre-existing liver disease, and evaluation of hepatotoxicity in clinical trials of new drugs), rote use of the RUCAM score may result in misdiagnosis or missed diagnosis owing to lowered reliability.”

  • The paper relies on this without support.

    Expert opinion is an important causality assessment method for the diagnosis of DILI.

    “Expert opinion is an important causality assessment method for the diagnosis of DILI.”

  • The paper relies on this without support.

    The advantages of expert opinion include the ability to account for different or rare-specific phenotypes of DILI, thereby achieving a more detailed differential diagnosis.

    “The advantages of expert opinion include the ability to account for different or rare-specific phenotypes of DILI, thereby achieving a more detailed differential diagnosis.”

  • The paper relies on this without support.

    The SEOP overcomes some shortcomings of the RUCAM score, is not externally validated, and is not suitable for daily clinical practice because of its complex procedures.

    “Although the SEOP overcomes some shortcomings of the RUCAM score, it is not externally validated and is not suitable for daily clinical practice because of its complex procedures.”

  • The paper relies on this without support.

    In clinical practice, most rechallenges are performed unintentionally or because of their importance in the treatment of the primary disease.

    “In clinical practice, most rechallenges are performed unintentionally or because of their importance in the treatment of the primary disease.”

  • The paper relies on this without support.

    A positive rechallenge is the most powerful evidence in the causality assessment of suspected DILI and helps in a definite diagnosis.

    “A positive rechallenge is the most powerful evidence in the causality assessment of suspected DILI and helps in a definite diagnosis.”

  • The paper relies on this without support.

    Rechallenge may result in a rapid and severe liver injury that may progress to ALF, particularly when the initial exposure has already caused liver injury fulfilling Hy's law or when the liver injury after initial exposure is due to immune-related reactions.

    “However, rechallenge may result in a rapid and severe liver injury that may progress to ALF, particularly when the initial exposure has already caused liver injury fulfilling Hy's law or when the liver injury after initial exposure is due to immune-related reactions.”

  • The paper relies on this without support.

    Most patients with acute DILI can recover from liver injury with a good prognosis within 6 months of discontinuation of the suspected drug.

    “Most patients with acute DILI can recover from liver injury with a good prognosis within 6 months of discontinuation of the suspected drug.”

  • The paper relies on this without support.

    A small number of patients with acute DILI can become critically ill or progress to ALF/SALF requiring liver transplantation or even death.

    “However, a small number of patients can become critically ill or progress to ALF/SALF requiring liver transplantation or even death.”

  • The paper relies on this without support.

    Some patients may present with chronic manifestations after an acute DILI episode, which eventually transforms into chronic liver injury as a clinical outcome.

    “Some patients may present with chronic manifestations after an acute DILI episode, which eventually transforms into chronic liver injury as a clinical outcome.”

  • The paper relies on this without support.

    The updated RUCAM score remains to be validated.

    “The updated score was published in 2016 [58], but remains to be validated.”

  • The paper relies on this without support.

    RECAM's reliability in herb-induced liver injury (HILI) remains unknown since there is still insufficient data regarding these HMs/HDS.

    “In addition, its reliability in herb-induced liver injury (HILI) remains unknown since there is still insufficient data regarding these HMs/HDS.”

  • The paper relies on this without support.

    Some patients with chronic DILI may develop varying degrees of liver fibrosis or cirrhosis despite discontinuation of the suspected drug, which is an important etiology of cryptogenic cirrhosis.

    “Some patients with chronic DILI may develop varying degrees of liver fibrosis or cirrhosis despite discontinuation of the suspected drug, which is an important etiology of cryptogenic cirrhosis.”

  • The paper relies on this without support.

    DILI in AIH belongs to the category of DILI with pre-existing liver disease.

    “Notably, DILI in AIH also presents with liver injury with autoimmune features, but it belongs to the category of DILI with pre-existing liver disease.”

  • The paper relies on this without support.

    In most cases, the mechanism of injury of DILI in AIH differs from that of DI-ALH, which is under the category of indirect DILI.

    “In most cases, the mechanism of injury differs from that of DI-ALH which is under the category of indirect DILI and should be distinguished.”

  • The paper relies on this without support.

    Pretreatment with high-dose chemotherapy after HSCT, chemotherapy for solid tumors, and post-transplantation immunosuppressive therapy are important causes of HSOS.

    “Pretreatment with high-dose chemotherapy after hematopoietic stem cell transplantation (HSCT), chemotherapy for solid tumors, and post-transplantation immunosuppressive therapy are also important causes of HSOS.”

  • The paper relies on this without support.

    The RUCAM score may have reduced reliability in patients with pre-existing liver disease.

    “The RUCAM score may have reduced reliability in this setting and expert opinion may be useful for making a comprehensive judgment after obtaining detailed information about the suspected drug, liver injury, and underlying liver disease.”

  • The paper relies on this without support.

    HBV reactivation is more common among cases of drug-induced reactivation of hepatitis virus because of the heavy HBV burden in China.

    “HBV reactivation (HBVr) is more common among cases of drug-induced reactivation of hepatitis virus because of the heavy HBV burden in China.”

  • The paper relies on this without support.

    Reactivation is caused by risk drugs such as immunosuppressants, high-dose glucocorticoids, cytotoxic chemotherapeutic agents, anti-CD20 monoclonal antibody, and anti-tumor necrosis factor drugs that alter the original liver and immune status of HBV-infected patients or carriers, leading to increased viral replication and immune-mediated liver injury.

    “Reactivation is caused by risk drugs such as immunosuppressants, high-dose glucocorticoids, cytotoxic chemotherapeutic agents, anti-CD20 monoclonal antibody, and anti-tumor necrosis factor drugs that alter the original liver and immune status of HBV-infected patients or carriers, leading to increased viral replication and immune-mediated liver injury.”

  • The paper relies on this without support.

    Patients with HBVr may present with significant elevation in ALT levels with or without jaundice, positive HBV DNA, or increased viral load compared with pre-exposure to risky drugs and may progress to ALF and even death in severe cases.

    “Patients may present with a significant elevation in ALT levels with or without jaundice, positive HBV DNA, or increased viral load compared with pre-exposure to risky drugs and may progress to ALF and even death in severe cases.”

  • The paper relies on this without support.

    Immunosuppressive therapy such as chemotherapy is usually suspended once HBVr occurs, owing to possible severe clinical outcomes, thereby delaying the treatment of the primary disease.

    “Immunosuppressive therapy such as chemotherapy is usually suspended once HBVr occurs, owing to possible severe clinical outcomes, thereby delaying the treatment of the primary disease.”

  • The paper relies on this without support.

    Stratified management of high-risk drugs and patients can effectively reduce the incidence of HBVr.

    “Stratified management of high-risk drugs and patients can effectively reduce the incidence of HBVr.”

  • The paper relies on this without support.

    Lamivudine increases the risk of drug resistance.

    “Lamivudine is not recommended as the first-line treatment because it increases the risk of drug resistance.”

  • The paper relies on this without support.

    The discontinuation of NAs may result in HBV relapse.

    “The discontinuation of NAs may result in HBV relapse.”

  • The paper relies on this without support.

    The incidence of HDS-DILI is rapidly increasing worldwide and is becoming a key concern for academics and regulatory agencies.

    “The incidence of HDS-DILI is rapidly increasing worldwide and is becoming a key concern for academics and regulatory agencies.”

  • The paper relies on this without support.

    Most patients with mild elevation of liver enzymes after anti-tuberculosis treatment can tolerate reintroduction of first-line drugs.

    “For patients who present with mild elevation of liver enzymes after ATT, although most can tolerate the reintroduction of first-line drugs, a comprehensive assessment of benefits/risks should be performed before planning to use the same ATT regimen”

  • The paper relies on this without support.

    Most patients with grade ≥3 immune checkpoint inhibitor-related hepatitis respond well to high-daily-dose corticosteroids without relapse after discontinuation.

    “Most patients with grade ≥ 3 ICI-related hepatitis respond well to high-daily-dose corticosteroids (1-2 mg/kg day methylprednisolone or equivalents) without relapse after discontinuation.”

  • The paper relies on this without support.

    DILI in patients with chronic liver disease is usually severe.

    “Because DILI in patients with chronic liver disease is usually severe, conservative thresholds should be used in this population”

  • The paper relies on this without support.

    In most cases, the risk of DILI and associated risk factors for new drugs in clinical development are unknown and information and literature on previous liver injury caused by these drugs are limited.

    “In most cases, the risk of DILI and the associated risk factors for new drugs in the clinical development phase are unknown, information and literature on previous liver injury caused by these drugs are limited”

  • The paper relies on this without support.

    Once participants in clinical trials develop liver injury, they are usually not rechallenged.

    “once participants in clinical trials develop a liver injury, they are usually not rechallenged.”

  • The paper relies on this without support.

    Liver injury in most acute DILI cases is self-limiting after discontinuation of the suspected drug.

    “Liver injury in most acute DILI cases is self-limiting after discontinuation of the suspected drug.”

  • The paper relies on this without support.

    A small number of patients with acute DILI become critically ill or develop chronic injuries that require other therapies.

    “A small number of patients become critically ill or develop chronic injuries that require other therapies.”

  • The paper relies on this without support.

    The DILI prevention and treatment situation in China is serious.

    “The DILI prevention and treatment situation in China is serious”

  • The paper relies on this without support.

    China is becoming an aging society with a huge population taking multiple medications for multiple morbidities.

    “China is becoming an aging society with a huge population taking multiple medications for multiple morbidities”

  • The paper relies on this without support.

    Widespread irrational medication use exists.

    “widespread irrational medication use”

  • The paper relies on this without support.

    Healthcare providers other than hepatologists are unfamiliar with the diagnosis and management of DILI.

    “healthcare providers other than hepatologists are unfamiliar with the diagnosis and management of DILI”

  • The paper relies on this without support.

    Post-market surveillance of pharmaceutical companies is poorly developed.

    “the post-market surveillance of pharmaceutical companies is poorly developed”

  • The paper relies on this without support.

    There is a lack of public awareness concerning drug safety, particularly DILI.

    “lack of public awareness concerning drug safety, particularly DILI”

  • The paper relies on this without support.

    N-acetylcysteine is the only antidote approved by the FDA for the treatment of APAP-induced intrinsic DILI.

    “N-Acetylcysteine (NAC) is the only antidote approved by the FDA for the treatment of APAP-induced intrinsic DILI.”

  • The paper relies on this without support.

    Currently, magnesium isoglycyrrhizinate is the only drug indicated for acute DILI.

    “Currently, MgIG is the only drug indicated for acute DILI.”

  • The paper relies on this without support.

    Bicyclol is the first oral drug indicated for acute DILI registered for clinical trial.

    “Bicyclol is the first oral drug indicated for acute DILI registered for clinical trial.”

  • The paper relies on this without support.

    There is no standardized dose or duration for immune-mediated DILI.

    “However, there is no standardized dose or duration for iDILI.”

  • The paper relies on this without support.

    There is no evidence suggesting better efficacy of a combination of two or more drugs that reduce ALT levels.

    “There is no evidence suggesting better efficacy of a combination of two or more of these drugs.”

  • The paper relies on this without support.

    The prophylactic use of these drugs for liver injury to reduce the occurrence of DILI in the context of high-risk drug therapies such as antineoplastic therapy and anti-tuberculosis treatment is not well documented.

    “The prophylactic use of these drugs for liver injury to reduce the occurrence of DILI in the context of high-risk drug therapies such as antineoplastic therapy and ATT is not well documented.”

  • The paper relies on this without support.

    Evidence of the efficacy of other drugs in DILI is mostly provided by small-sample-size randomized controlled trials or retrospective real-world studies.

    “Evidence of the efficacy of other drugs in DILI is mostly provided by small-sample-size RCTs or retrospective realworld studies.”

  • The paper relies on this without support.

    The LiverTox and Hepatox websites provide healthcare providers and the public with information on several hepatotoxic drugs.

    “The Liver-Tox and Hepatox websites provide healthcare providers and the public with information on several hepatotoxic drugs.”

  • The paper relies on this without support.

    The combination of orally targeted drugs with CYP3A4 inhibitors (e.g., erythromycin and itraconazole) may lead to increased blood levels of targeted drugs and increase the risk of DILI.

    “For example, the combination of orally targeted drugs with CYP3A4 inhibitors (e.g., erythromycin and itraconazole) may lead to increased blood levels of targeted drugs and increase the risk of DILI.”

  • The paper relies on this without support.

    Inappropriate medication habits may increase the risk of DILI.

    “In addition, inappropriate medication habits may increase the risk of DILI.”

  • The paper relies on this without support.

    Catechol and caffeine in tea and coffee beverages can lead to increased concentrations of drugs metabolized by CYP2E1, such as acyclovir and quinolone.

    “For example, catechol and caffeine in tea and coffee beverages can lead to increased concentrations of drugs metabolized by CYP2E1, such as acyclovir and quinolone.”

  • The paper relies on this without support.

    Grapefruit juice can increase the concentration of immunosuppressants, statins, and other drugs metabolized by CYP3A4.

    “Grapefruit juice can increase the concentration of immunosuppressants, statins, and other drugs metabolized by CYP3A4.”
74 of 74

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting biopsy timing for cholestatic DILI

    Major

    The diagnostic discussion recommends considering liver biopsy if peak ALP has not fallen by more than 50% within 30-60 days after stopping the suspected drug. Recommendation 9 gives 180 days for the same cholestatic criterion.

1 of 1

Citations

Cites

Flagged first, then by citations

2 of the 198 references couldn’t be matched to a known paper.

Research works printed but not linked: 18

  1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. https://www.ncbi.nlm.nih.gov/books/NBK547852/. Accessed 1 Apr 2023
  2. Mao Y. HepaTox: a professional website that promotes clincial and translational research of DILI in China. Gan Zang. 2014;8:575–576
  3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Obeticholic Acid. https://www.ncbi.nlm.nih.gov/books/NBK548806/. Accessed 10 Dec 2019.
  4. Dakhoul L, Ghabril M, Gu J, Navarro V, Chalasani N, Serrano J. Heavy consumption of alcohol is not associated with worse outcomes in patients with idiosyncratic drug-induced liver injury compared to non-drinkers. Clin Gastroenterol Hepatol. 2018;16(5):722–729 · DOI · Paper page
  5. Zhu C, Wang H, Yuan J. Clinical features of drug-induced liver injury: an analysis of 445 cases. Lin Chuang Gan Dan Bing Za Zhi. 2018;34:354–358
  6. Cui H-R, Bai Z-F, Song H-B, Jia T-Z, Wang J-B, Xiao X-H. Investigation of potential toxic factors for fleece-flower root: from perspective of processing methods evolution. Zhong Guo Zhong Yao Za Zhi. 2016;41:333–339
  7. Wu S-X, Sun H-F, Yang X-H, et al. “Re-evaluation upon suspected event” is an approach for post-marketing clinical study: lessons from adverse drug events related to Bupleuri Radix preparations. Zhong Guo Zhong Yao Za Zhi. 2014;39:2983–2988
  8. Tian D. Huang Di Nei Jing Su Wen. Beijing: People’s Medical Publishing House; 2005. p. 189–190
  9. Song H-B, Han L. Epidemiologic characteristics, risk factors and safety evaluation of traditional Chinese medicine induced liver injury. Zhong Guo Yao Li Xue Yu Du Li Xue Za Zhi. 2016;30:291–305
  10. China State Drug Administration. Technical guidelines for clinical evaluation of liver injury induced by traditional Chinese medicine. Lin Chuang Gan Dan Bing Za Zhi 2018;34:1403–9
  11. Chinese society for tuberculosis. Guidelines for anti-tuberculosis drug-induced liver injury (2019 version). Zhong Hua Jie He He Hu Xi Za Zhi. 2019;42:343–56
  12. Liu W, Chen Z, Chen J. Efficacy of liver protection of Wuling Pills in outpatient anti-tuberculosis treatment: an observational study. Zhong Xi Yi Jie He Gan Bing Za Zhi. 2012;22:122–123
  13. Yan Y, Mo Y, Zhang D. Magnesium isoglycyrrhizinate prevention of chemotherapy-induced liver damage during initial treatment of patients with gastrointestinal tumors. (Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi) Chin J Hepatol. 2015;23:204–208
  14. Li G, Chen R, Wang W. A multicenter study of magnesium isoglycyrrhizinate injection to prevent liver injury induced by chemotherapy in hematological malignancies. Shaan Xi Yi Xue Za Zhi. 2019;48:787–790
  15. Wu Y, Zhang J, Yang Y. Systematic review of efficacy and safety of magnesium lsoglycyrrhizinate in the prevention of liver injury induced by chemotherapy. Zhong Guo Yi Yuan Yong Yao Ping Jia Yu Fen Xi 2021;21:333–7
  16. Qin S, Yang L, Wang K, et al. Efficacy and safety of magnesium isoglycyrrhizinate injection to prevent chemotherapy-induced acute liver injury (MAGIC-301): a multicenter, randomized, controlled clinical study. Lin Chuang Zhong Liu Xue Za Zhi. 2017;22:97–106
  17. Leng N, Liu Y, Qiu Y, et al. Network meta-analysis of five liver protective drugs in the treatment of drug-induced liver injury. Zhong Guo Yi Yao Ke Xue. 2022;12:42–47
  18. Li T, Chen R, Li J-R, Song Q-Y, Wu B. Economic evaluation of protecting liver and lowering transaminase regimens for chronic hepatitis B with elevated ALT. Zhong Guo Yao Fang. 2013;24:4321–4324

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Metadata

Authors
Mao, Y., Ma, S., Liu, C., Liu, X., Su, M., Li, D., Li, Y., Chen, G., Chen, J., Chen, J., Zhao, J., Guo, X., Tang, J., Zhuge, Y., Xie, Q., Xie, W., Lai, R., Cai, D., Cai, Q., Zhi, Y., Li, X., & the Technology Committee on DILI Prevention, M.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Shanghai University of Traditional Chinese Medicine (CN)
  • First Affiliated Hospital of GuangXi Medical University (CN)
  • Chinese People's Liberation Army (CN)
  • First Hospital of China Medical University (CN)
  • Affiliated Hospital of Hangzhou Normal University (CN)
  • Nanfang Hospital (CN)
  • Chinese PLA General Hospital (CN)
  • Second Affiliated Hospital of Xi'an Jiaotong University (CN)
  • Nanjing Drum Tower Hospital (CN)
  • Capital Medical University (CN)
  • Second Affiliated Hospital of Chongqing Medical University (CN)
  • Shenzhen Third People’s Hospital (CN)
Corresponding author
Mao, Yimin
ORCID
Venue
Hepatology International
Publisher
Springer Science and Business Media LLC
Published
2024-02-24
Volume
18
Issue
2
Pages
384-419
ISSN
  • 1936-0533 (ISSN-L)
  • 1936-0541
DOI
10.1007/s12072-023-10633-7
OpenAlex
W4392146720
Cited by
62
References
198
Citations by year
2026: 28 · 2025: 26 · 2024: 8
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology International (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Key Technologies Research and Development Program (2022YFC3502101)
  • National Major Science and Technology Projects of China (2017ZX09304016)
  • National Natural Science Foundation of China (NSFC 81970513, NSFC 82270619)
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 Disease Diagnosis and Treatment
Keywords
drug-induced liver injury, adverse drug reactions, acute liver failure, diagnosis of exclusion, chronic liver disease, herbal and dietary supplements, antitubercular agents, anticancer agents, diagnosis and treatment
MeSH terms
Antineoplastic Agents, China, Humans, Risk Factors, Liver Failure, Acute, Chemical and Drug Induced Liver Injury

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