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Cited by 340Drug-Induced Hepatotoxicity and ProtectionComplementary and Alternative Medicine StudiesPharmacovigilance and Adverse Drug Reactions

The DOI matches its Crossref record; 210 of the 212 references it cites were found in a registry or an index; none of the 289 sources its claims cite is checked for support yet.

AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury

Open access
Fontana, Robert J., Liou, Iris, Reuben, Adrian, Suzuki, Ayako, Fiel, M. Isabel, Lee, William, Navarro, Victor·2023·Hepatology
DOI 10.1002/hep.32689PMC PMC9936988
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Abstract

INTRODUCTION There are currently more than 1000 prescription medications available for use in the United States and more than 100,000 over‐the‐counter herbal and dietary supplements (HDS) available for purchase in retail stores and online. In addition, the average adult American receives more than six prescription medications per year.1,2 Many of these drugs and HDS products have been implicated as causes of DILI. Furthermore, DILI is a leading reason for regulatory actions regarding drugs in development as well as those in the marketplace.1 Confidently establishing a diagnosis of DILI is difficult because of the need to exclude more common competing causes of liver injury, the protean clinical manifestations from an individual agent, and the lack of a validated diagnostic biomarker.3–5 This guidance was developed with the support and oversight of the American Association for the Study of Liver Diseases Practice Guidelines Committee, who chose to commission a guidance, rather than a guideline, because of the paucity of randomized controlled trials on this topic. This document was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics and questions related to the needs of patients with drug and supplement–induced liver injury. The aim of this practice guidance is to provide recommendations regarding the common clinical, laboratory, and histological features seen in patients with DILI based on observational and epidemiological data reported in case series or DILI registries. In addition, expert opinion–based recommendations for patient management, including risk stratification, are provided to assist patients and practitioners. DILI classification DILI can be mechanistically classified as being either direct (i.e., dose‐dependent, intrinsic, and predictable) or idiosyncratic (largely dose‐independent, idiosyncratic, and unpredictable) (Table 1). Direct hepatotoxins such as acetaminophen (APAP) (N‐acetyl‐para‐aminophenol) can cause liver injury in nearly all exposed individuals if a threshold dose or duration is exceeded. In contrast, idiosyncratic hepatotoxins are usually neither dose‐related nor duration‐related but rather occur at varying times during or after drug administration.6 Idiosyncratic DILI is uncommon, with most approved drugs occurring in only 1 in 1000 to 1 in a million exposed individuals. Although most patients do not have rash, eosinophilia, or other hypersensitivity features at presentation, aberrant host immunity is implicated in most instances of idiosyncratic DILI.3 TABLE 1 - Proposed classification of DILI Mechanistic classification Direct hepatotoxicity Idiosyncratic hepatotoxicity Indirect hepatotoxicity Incidence Common Rare Intermediate Dose relatedness Yes No No Predictable Yes No Partially Reproduced in animal models Yes No Not usually Latency Rapid (days) Variable (days to years) Delayed (months) Phenotypes of injury Serum AST, ALT, or ALP elevations, hepatic necrosis, acute fatty liver, nodular regeneration Mixed or cholestatic hepatitis, bland cholestasis, chronic hepatitis Immune‐mediated hepatitis, fatty liver, chronic hepatitis Examples Acetaminophen, niacin, intravenous methotrexate Amoxicillin‐clavulanate, cephalosporins, isoniazid, nitrofurantoin Immune checkpoint inhibitors, anti‐CD20 monoclonal Ab, protein kinase inhibitors Touted mechanism of injury Intrinsic hepatotoxicity that is dose‐dependent Idiosyncratic host metabolic or immune reaction Indirect effect on liver or host immunity Source: Adapted from Björnsson et al.5 A third mechanism of hepatotoxicity is called indirect DILI, which arises when the biological action of the drug affects the host immune system, leading to a secondary form of liver injury. Like idiosyncratic DILI, indirect hepatotoxins are generally independent of the dose of medication administered and have a latency of weeks to months with varying clinical manifestations. Examples of indirect hepatotoxicity include the immune‐mediated hepatitis (IMH) observed with immune checkpoint inhibitors (ICIs) and reactivation of HBV infection following rituximab infusions.7,8 Guidance statements Clinicians should be familiar with the three main types of hepatotoxicity when evaluating patients with suspected DILI. Direct hepatotoxins such as APAP can cause liver injury in nearly all exposed individuals once a threshold dose or duration of use is exceeded. Idiosyncratic DILI is largely independent of the dose and duration of medication use and characterized by a low incidence and variable drug latency and clinical and histological features. Idiosyncratic DILI is believed to arise from an aberrant adaptive host immune response to the drug and/or its metabolite(s). Indirect hepatotoxins are generally independent of the dose administered and have a variable latency and manifestations that arise from the biological action of the drug on the liver and/ or host immune system. Ep

Overview

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Written from the paper’s full text.

TL;DR

This AASLD practice guidance summarizes drug-, herbal-, and dietary supplement–induced liver injury (DILI), covering classification, epidemiology, diagnosis, causality assessment, histology, management, and monitoring. It provides consensus guidance statements because randomized controlled trial evidence is sparse.

Key findings

  • Idiosyncratic DILI is uncommon, with an estimated annual incidence of 14–19 per 100,000 in the general population (~60,000 US cases/year), higher in exposure-based electronic medical record studies (32.8–40 per 100,000) and up to 1.4% among medical inpatients.
  • Herbal and dietary supplements (HDS) account for ~20% of adult DILI cases in the DILIN registry; in China, Korea, and Singapore, HDS account for 27%–62% of DILI cases. Amoxicillin-clavulanate is the most frequently implicated individual agent in many Western countries, whereas anti-tuberculosis agents dominate in Asian countries.
  • Acetaminophen (APAP) is a dose-dependent hepatotoxin; in North America, APAP overdose is believed to cause 100,000 poison-control calls, 50,000 emergency room visits, and at least 500 deaths annually, and is the leading cause of acute liver failure among US adults.
  • With drug discontinuation, ~80% of DILI patients fully recover; ~10% with severe hepatocellular DILI and jaundice are at risk of death or transplant, and spontaneous survival in DILI-related acute liver failure is only ~25%. Chronic DILI occurred in 21% of DILIN subjects at 6 months, with 10%–20% persistence beyond 6–12 months in guidance statements.

Methods

  • The American Association for the Study of Liver Diseases Practice Guidelines Committee commissioned a guidance, rather than a guideline, because of the paucity of randomized controlled trials; it was developed by expert panel consensus with formal literature review and analysis.
  • Evidence came largely from observational and epidemiological data in case series and DILI registries (e.g., DILIN, Spanish, Iceland, Latin America, China, India), supplemented by expert opinion for management and risk stratification.
  • The document synthesizes guidance statements, diagnostic algorithms, and tables on DILI classification, etiologies, genetic associations, histologic phenotypes, causality assessment instruments, prognostic indices, and monitoring/management.

Limitations

  • Stated in the paper: there is a paucity of randomized controlled trials on DILI, no validated diagnostic biomarker, and diagnosis remains difficult because it requires excluding more common competing causes of liver injury.
  • Stated in the paper: causality assessment tools have important limitations—RUCAM weighting and risk factors are not evidence-based, RECAM has not been tested in regions with different DILI spectra, in HDS-induced injury, or in cases with more than one suspect drug, and DILIN expert opinion requires specialized expertise that limits generalizability.
  • Stated in the paper and evident from the text: insufficient data exist to confirm age, sex, and race/ethnicity as reliable DILI susceptibility risk factors; HDS compositional complexity, adulteration, mislabeling, and batch variability confound assessment; and many recommendations rely on observational data and expert consensus rather than controlled trials.

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Integrity signals

Registry

Crossref · 10.1002/hep.32689

Cites

210 of 210 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

0 of 289 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    The characteristic laboratory profile of APAP hepatotoxicity includes very high aminotransferase levels with low bilirubin.

    “The characteristic laboratory profile of APAP hepatotoxicity includes very high aminotransferase levels with low bilirubin.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Patients with HDS hepatotoxicity leading to liver failure are more likely to die or undergo transplantation compared to patients with drug hepatotoxicity.

    “Recent studies have shown that patients with HDS hepatoxicity leading to liver failure are more likely to die or undergo transplantation compared to patients with drug hepatoxicity.133,134”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] Kesar V Channen L Masood U Grewal P Ahmad J Roth NC. Liver transplantation for acute liver injury in asians is more likely due to herbal and dietary supplements. Liver Transpl. 2022; 28: 188– 99. 34370392 PMC8792150
    • cites [134] Ghabril M Ma J Patidar KR Nephew L Desai AP Orman E. Eight fold increase in the dietary supplement related liver failure leading to transplant waitlisting over the last quarter century in the US. Liver Transpl. 2022; 28: 169– 79. 34331346
  • Findingcitation

    If NAC is administered within 12 h of ingestion, it virtually assures that the liver damage will be minimal.

    “If NAC is administered within 12 h of ingestion, it virtually assures that the liver damage will be minimal.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Prescott LF Critchley JA. The treatment of acetaminophen poisoning. Annu Rev Pharmacol Toxicol. 1983; 23: 87– 101. 6347057
  • Findingnone given

    Once signs and symptoms of liver failure (encephalopathy, primarily) are present in APAP overdose, nearly one-third of patients either die or require a liver transplant.

    “Development of signs and symptoms of liver failure (encephalopathy, primarily) are concerning, and once they are present, nearly one‐third of patients either die or require a liver transplant.”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    Outcomes of APAP toxicity have generally improved over the past two decades.

    “Outcomes have also generally improved over the past two decades, likely because of improvements in intensive care, with only 8% of patients undergoing transplantation.168,169”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [168] Koch DG Tillman H Durkalski V Lee WM Reuben A. Development of a model to predict transplant‐free survival of patients with acute liver failure. Clin Gastroenterol Hepatol. 2016; 14: 1199– 206. 27085756 PMC6055510
    • cites [169] Larson AM Polson J Fontana RJ Davern TJ Lalani E Hynan LS. Acetaminophen‐induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005; 42: 1364– 72. 16317692
  • Probably not a substantial claim. 84
  • It may state two separate claims as one. 83

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Findingnone given

    In countries in which the over-the-counter sale of APAP has been restricted, the incidence of serious APAP toxicity has fallen.

    “In countries in which the over‐the‐counter sale of APAP has been restricted, the incidence of serious APAP toxicity has fallen.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingcitation

    A focused analysis of GTE cases enrolled in the DILIN has led to recognition of the typical presentation of GTE as being hepatocellular and sometimes fatal, with a strong genetic association with HLA-B*35:01.

    “A focused analysis of GTE cases enrolled in the DILIN has led to recognition of the typical presentation of GTE as being hepatocellular and sometimes fatal, with a strong genetic association with HLA‐B*35:01.72”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Hoofnagle JH Bonkovsky HL Phillips EJ Li YJ Ahmad J Barnhart H. HLA‐B*35:01 and green tea‐induced liver injury. Hepatology. 2021; 73: 2484– 93. 32892374 PMC8052949

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

    Findingcitation

    Based on DILIN Registry data, HDS comprise approximately 20% of all cases of liver injury encountered in adults.

    “Based on DILIN Registry data, HDS comprise approximately 20% of all cases of liver injury encountered in adults.28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Navarro VJ Barnhart H Bonkovsky HL Davern T Fontana RJ Grant L. Liver injury from herbals and dietary supplements in the U.S. drug‐induced liver injury network. Hepatology. 2014; 60: 1399– 408. 25043597 PMC4293199

  • It may state two separate claims as one.

    Findingcitation

    The coagulopathy in APAP hepatotoxicity can be severe, and a prolonged INR is a bad prognostic sign.

    “The coagulopathy can be severe, and a prolonged INR is a bad prognostic sign.168”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Koch DG Tillman H Durkalski V Lee WM Reuben A. Development of a model to predict transplant‐free survival of patients with acute liver failure. Clin Gastroenterol Hepatol. 2016; 14: 1199– 206. 27085756 PMC6055510

  • It may state two separate claims as one.

    Findingcitation

    The apoptotic index, which incorporates full-length serum cytokeratin 18 and caspase-cleaved CK18 levels, may be more sensitive than serum ALT in detecting liver injury and may also be of prognostic value.

    “The apoptotic index, which incorporates full‐length serum cytokeratin 18 (CK18) and caspase‐cleaved CK18 levels, may also be more sensitive than serum ALT in detecting liver injury and also be of prognostic value.212,213”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [212] Thulin P Nordahl G Gry M Yimer G Aklillu E Makonnen E. Keratin‐18 and microRNA‐122 complement alanine aminotransferase as novel safety biomarkers for drug‐induced liver injury in two human cohorts. Liver Int. 2014; 34: 367– 78. 24118944
    • cites [213] Rutherford A King LY Hynan LS Vedvyas C Lin W Lee WM. Development of an accurate index for predicting outcomes of patients with acute liver failure. Gastroenterology. 2012; 143: 1237– 43. 22885329 PMC3480539

  • It may state two separate claims as one.

    Findingcitation

    The DILIN tested a multiplex lymphocyte proliferation assay but did not obtain informative results.

    “The DILIN tested a multiplex lymphocyte proliferation assay but did not obtain informative results.217”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Whritenour J Ko M Zong Q Wang J Tartaro K Schneider P. Development of a modified lymphocyte transformation test for diagnosing drug induced liver injury associated with an adaptive immune response. J Immunotoxicol. 2017; 14: 28– 31. PMC5505862 28121193

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Findingnone given

    Rarely, ICI-related sclerosing cholangitis can present with a cholestatic pattern of liver test elevations.

    “Rarely, ICI‐related sclerosing cholangitis can present with a cholestatic pattern of liver test elevations.”
    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.

    Findingcitation

    Fatalities arise in < 1% of patients with IMH and almost exclusively occur in those with jaundice.

    “Fatalities arise in < 1% of patients with IMH and almost exclusively occur in those with jaundice.207”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Schneider BJ Naidoo J Santomasso BD Lacchetti C Adkins S Anadkat M. Management of immune‐related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021; 39: 4073– 126. 34724392

  • It may state two separate claims as one.

    Findingcitation

    In general, statins are safe to administer, but myalgias and myopathy may lead to early dose reduction or termination in up to 10% of treated patients.

    “In general, statins are safe to administer, but myalgias and myopathy may lead to early dose reduction or termination in up to 10% of treated patients.197”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Zhang H Plutzky J Skentzos S Morrison F Mar P Shubina M. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013; 158: 526– 34. 23546564 PMC3692286

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

    Findingnone given

    Although many medications have been associated with liver-related fatalities, only a minority carry a black box warning for hepatotoxicity.

    “Although many medications have been associated with liver‐related fatalities, only a minority carry a black box warning for hepatotoxicity.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingcitation

    Underreporting and poor adherence to American Thoracic Society guidelines are common in cases of isoniazid hepatotoxicity and are associated with hospitalization, death, and liver transplantation.

    “Underreporting and poor adherence to American Thoracic Society guidelines are common in cases of isoniazid hepatotoxicity and are associated with hospitalization, death, and liver transplantation.187,188”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [187] Singanayagam A Sridhar S Dhariwal J Abdel‐Aziz D Munro K Connell DW. A comparison between two strategies for monitoring hepatic function during antituberculous therapy. Am J Respir Crit Care Med. 2012; 185: 653– 9. 22198973
    • cites [188] Hayashi PH Fontana RJ Chalasani NP Stolz AA Talwalkar JA Navarro VJ. Under‐reporting and poor adherence to monitoring guidelines for severe cases of isoniazid hepatotoxicity. Clin Gastroenterol Hepatol. 2015; 13: 1676– 82.e1. 25724701 PMC4653068

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

    Findingcitation

    Other groups are exploring the development of in vitro test systems derived from circulating macrophages and human liver organoids, but further validation is needed.

    “Other groups are exploring the development of in vitro test systems derived from circulating macrophages and human liver organoids, but further validation is needed.218,219”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [218] Benesic A Rotter I Dragoi D Weber S Buchholtz ML Gerbes AL. Development and validation of a test to identify drugs that cause idiosyncratic drug‐induced liver injury. Clin Gastroenterol Hepatol. 2018; 16: 1488– 94. 29723689
    • cites [219] Shinozawa T Kimura M Cai Y Saiki N Yoneyama Y Ouchi R. High‐fidelity drug‐induced liver injury screen using human pluripotent stem cell‐derived organoids. Gastroenterology. 2021; 160: 831– 46.e10. 33039464 PMC7878295

  • It may state two separate claims as one.

    Findingcitation

    Although the incidence of severe DILI appears to be lower than previously appreciated, isoniazid continues to be a leading cause of DILI-related acute liver failure in the United States and worldwide.

    “Although the incidence of severe DILI appears to be lower than previously appreciated,180 isoniazid continues to be a leading cause of DILI‐related ALF in the United States and worldwide (Table 2).181–184”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [180] Jiang F Yan H Liang L Du J Jin S Yang S. Incidence and risk factors of anti‐tuberculosis drug induced liver injury (DILI): large cohort study involving 4652 Chinese adult tuberculosis patients. Liver Int. 2021; 41: 1565– 75. 33866661
    • cites [181] Nolan CM Goldberg SV Buskin SE. Hepatotoxicity associated with isoniazid preventative therapy. A 7‐year survey from a public health tuberculosis clinic. JAMA. 1999; 281: 1014– 8. 10086436
    • cites [182] Sotgiu G Matteelli A Getahun H Girardi E Sañé Schepisi M Centis R. Monitoring toxicity in individuals receiving treatment for latent tuberculosis infection: a systematic review versus expert opinion. Eur Respir J. 2015; 45: 1170– 3. 25700378 PMC4391659
    • cites [183] Saukkonen JJ Cohn DL Jasmer RM Schenker S Jereb JA Nolan CM. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006; 174: 935– 52. 17021358
    • cites [184] Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax. 1998; 53: 536– 48. 9797751 PMC1745276

  • It may state two separate claims as one.

    Findingcitation

    Recent studies suggest that bona fide DILI is only responsible for 30% of cases of demonstrable liver injury in patients with advanced cancer, whereas hepatic metastases, sepsis, and other causes of liver disease account for the remainder.

    “Recent studies suggest that bona fide DILI is only responsible for 30% of cases of demonstrable liver injury in patients with advanced cancer, whereas hepatic metastases, sepsis, and other causes of liver disease account for the remainder, emphasizing the importance of contrast‐enhanced CT and MR scanning in evaluation of these patients.205”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Tsung I Dolan R Lao CD Fecher L Riggenbach K Yeboah‐Korang A. Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy. Aliment Pharmacol Ther. 2020; 50: 800– 8. 31309615

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

    Findingcitation

    ICIs are prescribed to more than 50% of oncology patients with advanced solid organ tumors.

    “They are prescribed to more than 50% of oncology patients with advanced solid organ tumors.8,203”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Lombardi A Mondelli MU. Review article: immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects. Aliment Pharm Ther. 2019; 50: 872– 84. 31378985
    • cites [203] Haslam A Prasad V. Estimation of the percentage of us patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Net Open. 2019; 2: e192535. PMC6503493 31050774

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

    Findingnone given

    DILI biomarkers in development are currently being directed toward improved DILI diagnosis and prognosis as well as to provide mechanistic insight into DILI pathogenesis.

    “DILI biomarkers in development are currently being directed toward improved DILI diagnosis and prognosis as well as to provide mechanistic insight into DILI pathogenesis.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingnone given

    Currently available serum markers of liver injury (AST, ALT, ALP) are neither sensitive nor specific enough to detect early DILI, nor are they able to reliably predict clinical outcomes.

    “Currently available serum markers of liver injury (i.e., AST, ALT, ALP) are neither sensitive nor specific enough to detect early DILI, nor are they able to reliably predict clinical outcomes.”
    • Also stated in: § DILI biomarkers · plain
      “Currently available serum markers of liver injury such as serum AST, ALT, and ALP levels are not sensitive or specific enough to detect early DILI.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Other studies have suggested that statins in patients with compensated chronic liver disease and cirrhosis may reduce the risk of hepatocellular cancer and decompensation.

    “In addition, other studies have suggested that statins in patients with compensated chronic liver disease and cirrhosis may even reduce the risk of hepatocellular cancer and decompensation.201”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Athyros VG Boutari C Stavropoulos K Anagnostis P Imprialos KP Doumas M. Statins: an under‐appreciated asset for the prevention and treatment of NAFLD and NASH and the related cardiovascular risk. Cur Vasc Pharmacol. 2018; 16: 246– 53. 28676019

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

    Premisecitation

    The incidence of idiosyncratic DILI appears higher in exposure-based studies using electronic medical records: 32.8 per 100,000 adult patients who received one of the top implicated drugs in the United States and 40 per 100,000 patients at a pediatric hospital.

    “For example, the incidence appears to be higher in exposure‐based studies using electronic medical records (32.8 per 100,000 adult patients who received one of the top implicated drugs in the United States and 40 per 100,000 patients at a pediatric hospital).11,12”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Shin J Hunt CM Suzuki A Papay JI Beach KJ Cheetham TC. Characterizing phenotypes and outcomes of drug‐associated liver injury using electronic medical record data. Pharmacoepidemiol Drug Saf. 2013; 22: 190– 8. 23258383
    • cites [12] Sandritter TL Goldman JL Habiger CJ Daniel JF Lowry J Fischer RT. An electronic medical records‐based approach to identify idiosyncratic drug‐induced liver injury in children. Sci Rep. 2019; 9: 18090. 31792283 PMC6888850

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

    Premisenone given

    DILI can be mechanistically classified as being either direct (dose-dependent, intrinsic, predictable) or idiosyncratic (largely dose-independent, idiosyncratic, unpredictable).

    “DILI can be mechanistically classified as being either direct (i.e., dose‐dependent, intrinsic, and predictable) or idiosyncratic (largely dose‐independent, idiosyncratic, and unpredictable) (Table 1).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Indirect DILI arises when the biological action of the drug affects the host immune system, leading to a secondary form of liver injury.

    “A third mechanism of hepatotoxicity is called indirect DILI, which arises when the biological action of the drug affects the host immune system, leading to a secondary form of liver injury.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Loomba R Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017; 152: 1297– 309. 28219691 PMC5501983
    • cites [8] Lombardi A Mondelli MU. Review article: immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects. Aliment Pharm Ther. 2019; 50: 872– 84. 31378985

  • It may state two separate claims as one.

    Premisecitation

    Immune-mediated hepatitis observed with immune checkpoint inhibitors and reactivation of HBV infection following rituximab infusions are examples of indirect hepatotoxicity.

    “Examples of indirect hepatotoxicity include the immune‐mediated hepatitis (IMH) observed with immune checkpoint inhibitors (ICIs) and reactivation of HBV infection following rituximab infusions.7,8”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Loomba R Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017; 152: 1297– 309. 28219691 PMC5501983
    • cites [8] Lombardi A Mondelli MU. Review article: immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects. Aliment Pharm Ther. 2019; 50: 872– 84. 31378985

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

    Premisecitation

    The incidence of idiosyncratic DILI is even higher in hospitalized patients, reported as high as 1.4% among medical inpatients.

    “The incidence of idiosyncratic DILI is even higher in hospitalized patients, being reported as high as 1.4% among medical inpatients.13–16”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13] Meier Y Cavallaro M Roos M Pauli‐Magnus C Folkers G Meier PJ. Incidence of drug‐induced liver injury in medical inpatients. Eur J Clin Pharmacol. 2005; 61: 135– 43. 15726344
    • cites [14] Xu H Chen Y Xu J Zhou Q. Drug‐induced liver injury in hospitalized patients with notably elevated alanine aminotransferase. World J Gastroenterol. 2012; 18: 5972– 8. 23139615 PMC3491606
    • cites [15] Björnsson HK Olafsson S Bergmann OM Björnsson ES. A prospective study on the causes of notably raised alanine aminotransferase (ALT). Scand J Gastroenterol. 2016; 51: 594– 600. 26653080
    • cites [16] Sistanizad M Peterson GM. Drug‐induced liver injury in the Australian setting. J Clin Pharm Ther. 2013; 38: 115– 20. 23350857

  • It may state two separate claims as one.

    Premisecitation

    Indirect hepatotoxins are generally independent of the dose administered and have a latency of weeks to months with varying clinical manifestations.

    “Like idiosyncratic DILI, indirect hepatotoxins are generally independent of the dose of medication administered and have a latency of weeks to months with varying clinical manifestations.”
    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 estimated annual incidence of idiosyncratic DILI in the general population is 14 to 19 events per 100,000 inhabitants, or 60,000 cases per year in the general US population.

    “Idiosyncratic DILI is uncommon, with an estimated annual incidence in the general population of 14 to 19 events per 100,000 inhabitants or 60,000 cases per year in the general US population.9,10”
    • Also stated in: § Leading causes of idiosyncratic DILI worldwide · hedged
      “The estimated annual incidence of idiosyncratic DILI in the general population is low (14–19/100,000) but higher in exposure‐based studies using electronic medical record data (33–40/100,000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 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: 1419– 25. 23419359
    • cites [10] Sgro C Clinard F Ouazir K Chanay H Allard C Guilleminet C. Incidence of drug‐induced hepatic injuries: a French population‐based study. Hepatology. 2002; 36: 451– 5. 12143055

  • It may state two separate claims as one.

    Premisecitation

    HDS products surpass pharmaceuticals in China, Korea, and Singapore, accounting for 27%-62% of their DILI cases.

    “For instance, HDS products surpass pharmaceuticals in China, Korea, and Singapore, accounting for 27%–62% of their DILI cases.22,25,26”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Shen T Liu Y Shang J Xie Q Li J Yan M. Incidence and etiology of drug‐induced liver injury in mainland China. Gastroenterology. 2019; 156: 2230– 41.e11. 30742832
    • cites [25] Suk KT Kim DJ Kim CH Park SH Yoon JH Kim YS. A prospective nationwide study of drug‐induced liver injury in Korea. Am J Gastroenterol. 2012; 107: 1380– 7. 22733303
    • cites [26] Wai CT. Presentation of drug‐induced liver injury in Singapore. Singapore Med J. 2006; 47: 116– 20. 16435052

  • It may state two separate claims as one.

    Premisecitation

    Histologic features typically observed in AIH-interface hepatitis, emperipolesis, and rosette formation-are also observed in DILI cases (89%, 34%, and 40%, respectively) and are not pathognomonic for AIH.

    “Histologic features typically observed in AIH, such as interface hepatitis, emperipolesis (the presence of an intact cell within the cytoplasm of another), and rosette formation, are also observed among DILI cases (89%, 34%, and 40%, respectively, in DILI cases) and are not pathognomonic for AIH.89”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Suzuki A Brunt EM Kleiner DE Miquel R Smyrk TC Andrade RJ. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug‐induced liver injury. Hepatology. 2011; 54: 931– 939. 21674554 PMC3192933

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Exposure to an intravenous agent, such as monoclonal antibodies, may also cause DILI.

    “Although DILI is often attributed to repeated exposure to an oral agent, it is important to recognize that exposure to an intravenous agent, such as monoclonal antibodies, may also cause DILI.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Insufficient data exist to confirm subject age, sex, and race and ethnicity as reliable risk factors for DILI susceptibility; however, some drugs are more likely to cause DILI in older individuals (e.g., amoxicillin-clavulanate, isoniazid), whereas others are more commonly implicated in children (valproate, minocycline).

    “Insufficient data exist to confirm subject age, sex, and race and ethnicity as reliable risk factors for DILI susceptibility. However, some drugs are more likely to cause DILI in older individuals (e.g., amoxicillin‐clavulanate, isoniazid), whereas others are more commonly implicated in children (valproate, minocycline).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The available observational and epidemiological data from case series and DILI registries are adequate to support recommendations on the clinical, laboratory, and histological features of DILI.

  • It may state two separate claims as one.

    Premisecitation

    DI-AIH may show more portal neutrophilic infiltrates and be accompanied by cholestasis, whereas sporadic AIH may show a chronic 'hepatitis' pattern with interface hepatitis dominated by plasma cells.

    “DI‐AIH may show more portal neutrophilic infiltrates and be accompanied by cholestasis, whereas sporadic AIH may show a chronic “hepatitis” pattern, and the interface hepatitis will be dominated by plasma cells.89”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Suzuki A Brunt EM Kleiner DE Miquel R Smyrk TC Andrade RJ. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug‐induced liver injury. Hepatology. 2011; 54: 931– 939. 21674554 PMC3192933

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

    Premisereasoning

    Topical formulations of medications to the skin, eyes, or ears rarely, if ever, cause DILI because of the low dose of medication absorbed.

    “However, topical formulations of medications to the skin, eyes, or ears rarely, if ever, cause DILI because of the low dose of medication absorbed.”
    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.

    Premisenone given

    Patients with recent hypotension, sepsis, or heart failure are at risk for ischemic liver injury, usually characterized by rapid and marked increase in serum aminotransferase values followed by rapid decline with normal or near-normal bilirubin levels.

    “Patients with recent hypotension, sepsis, or heart failure are at risk for ischemic liver injury, usually characterized by rapid and a marked increase in serum aminotransferase values followed by rapid decline with normal or near‐normal bilirubin levels.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Women experience more frequent and severe hepatotoxicity than men.

    “Noticeable differences also exist between sexes, with women experiencing more frequent and severe hepatotoxicity.44,45”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Zopf Y Rabe C Neubert A Gassmann KG Rascher W Hahn EG. Women encounter ADRs more often than do men. Eur J Clin Pharmacol. 2008; 64: 999– 1004. 18604529
    • cites [45] George N Chen M Yuen N Hunt CM Suzuki A. Interplay of gender, age and drug properties on reporting frequency of drug‐induced liver injury. Regul Toxicol Pharmacol. 2018; 94: 101– 7. 29407200

  • It may state two separate claims as one.

    Premisecitation

    Standardized DILI incidence increases with patient age, which may be explained in part by greater medication use with increasing age.

    “Although standardized DILI incidence increases with patient age, this may be explained, in part, by greater medication use with increasing age.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] 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: 1419– 25. 23419359

  • It may state two separate claims as one.

    Premisecitation

    DILIN has demonstrated that trimethoprim-sulfamethoxazole is the most common suspect drug among African Americans, whereas amoxicillin-clavulanate is the leading cause in White populations.

    “The Drug‐Induced Liver Injury Network (DILIN) has demonstrated that trimethoprim‐sulfamethoxazole is the most common suspect drug among African Americans, whereas amoxicillin‐clavulanate is the leading cause in White populations.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Fontana RJ Hayashi PH Gu J Reddy KR Barnhart H Watkins PB. Idiosyncratic drug‐induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014; 147: 96– 108.e4. 24681128 PMC4285559
    • cites [49] Chalasani N Reddy KRK Fontana RJ Barnhart H Gu J Hayashi PH. Idiosyncratic drug induced liver injury in African‐Americans is associated with greater morbidity and mortality compared to Caucasians. Am J Gastroenterol. 2017; 112: 1382– 8. 28762375 PMC5667647

  • It may state two separate claims as one.

    Premisecitation

    Dose escalation may increase the risk of developing idiosyncratic DILI as seen with azathioprine, whereas dose reduction or increasing the dosing interval may improve tolerability.

    “In some instances, dose escalation may also increase the risk of developing idiosyncratic DILI as seen with azathioprine, whereas dose reduction or increasing the dosing interval may improve tolerability.35–37”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Carrascosa MF Salcines‐Caviedes JR Lucena MI Andrade RJ. Acute liver failure following atorvastatin dose escalation: is there a threshold dose for idiosyncratic hepatotoxicity? J Hepatol. 2015; 62: 751– 2. 25463547
    • cites [36] Seki N Uematsu K Shibakuki R Eguchi K. Promising new treatment schedule for gefitinib responders after severe hepatotoxicity with daily administration. J Clin Oncol. 2006; 24: 3213– 5. 16809744
    • cites [37] Otani K Kaneko S Tasaki H Fukushima Y. Hepatic injury caused by mianserin. BMJ. 1989; 299: 519. PMC1837346 2507056

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Hypersensitivity reactions can have very short latency periods of only 24-72 h.

    “In contrast, hypersensitivity reactions can have very short latency periods of only 24–72 h.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    African Americans were more likely to have adverse outcomes and develop chronic DILI.

    “In addition, African Americans were more likely to have adverse outcomes and develop chronic DILI.48,49”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Fontana RJ Hayashi PH Gu J Reddy KR Barnhart H Watkins PB. Idiosyncratic drug‐induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014; 147: 96– 108.e4. 24681128 PMC4285559
    • cites [49] Chalasani N Reddy KRK Fontana RJ Barnhart H Gu J Hayashi PH. Idiosyncratic drug induced liver injury in African‐Americans is associated with greater morbidity and mortality compared to Caucasians. Am J Gastroenterol. 2017; 112: 1382– 8. 28762375 PMC5667647

  • It may state two separate claims as one.

    Premisenone given

    Patients with pre-existing liver disease are at increased risk of developing liver injury with selected drugs (e.g., methotrexate, anti-TB therapy) and at increased risk of poor outcomes with a DILI episode.

    “Patients with pre‐existing liver disease are at increased risk of developing liver injury with selected drugs (e.g., methotrexate, anti‐TB therapy). In addition, subjects with pre‐existing liver disease are at increased risk of poor outcomes with a DILI episode.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The available observational and epidemiological data from case series and DILI registries are adequate to support recommendations on the clinical, laboratory, and histological features of DILI.

  • It may state two separate claims as one.

    Premisecitation

    The predominant histological pattern in ICI DILI is hepatocellular injury, with approximately 70% showing panlobular hepatitis and approximately 20% with centrilobular coagulative necrosis on liver biopsy.

    “The predominant histological pattern in ICI DILI is hepatocellular injury, with approximately 70% showing panlobular hepatitis and approximately 20% with centrilobular coagulative necrosis on liver biopsy.95–97”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [95] Sawada K Hayashi H Nakajima S Hasebe T Fujiya M Okumura T. Non‐alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor. J Gastroenterol Hepatol. 2020; 35: 1042– 8. 31752049
    • cites [96] Zen Y Yeh MM. Checkpoint inhibitor‐induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019; 36: 434– 440. 31358424
    • cites [97] Zen Y Chen YY Jeng YM Tsai HW Yeh MM. Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes. Histopathology. 2020; 76: 470– 80. 31550390

  • It may state two separate claims as one.

    Interpretationreasoning

    Identified HLA alleles generally have low positive predictive value because of the low incidence of DILI in the general population, but a high negative predictive value.

    “In general, the identified HLA alleles have low positive predictive value, because of the low incidence of DILI in the general population, but a high negative predictive value.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Antimicrobials, central nervous system agents, and anti-inflammatory agents are the most commonly implicated agents in DILI series worldwide; HDS are most commonly implicated in some Asian countries and are increasingly implicated in Western countries.

    “Antimicrobials, central nervous system agents, and anti‐inflammatory agents are the most commonly implicated agents in the DILI series worldwide. However, HDS are most commonly implicated in some Asian countries and are increasingly implicated in Western countries as well.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The available observational and epidemiological data from case series and DILI registries are adequate to support recommendations on the clinical, laboratory, and histological features of DILI.

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

    Interpretationnone given

    There are limited data exploring the impact of diet, tobacco use, and coffee consumption on DILI susceptibility.

    “Furthermore, there are limited data exploring the impact of diet, tobacco use, and coffee consumption on DILI susceptibility.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    HDS products represent only a minority of DILI cases in Japan, the United States, and Spain but with an increasing incidence over time.

    “In contrast, HDS products represent only a minority of cases in Japan, the United States, and Spain but with an increasing incidence over time.23,27–31”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [23] Takikawa H Murata Y Horiike N Fukui H Onji M. Drug‐induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006. Hepatol Res. 2009; 39: 427– 31. 19207579
    • cites [27] Andrade RJ Medina‐Caliz I Gonzalez‐Jimenez A Garcia‐Cortes M Lucena ML. Hepatic damage by natural remedies. Semin Liver Dis. 2018; 38: 21– 40. 29471563
    • cites [28] Navarro VJ Barnhart H Bonkovsky HL Davern T Fontana RJ Grant L. Liver injury from herbals and dietary supplements in the U.S. drug‐induced liver injury network. Hepatology. 2014; 60: 1399– 408. 25043597 PMC4293199
    • cites [29] Stephens C Robles‐Diaz M Medina‐Caliz I Garcia‐Cortes M Ortega‐Alonso A Sanabria‐Cabrera J. Comprehensive analysis and insights gained from long‐term experience of the Spanish DILI registry. J Hepatol. 2021; 75: 86– 97. 33539847
    • cites [30] Chalasani N Bonkovsky HL Fontana RJ Lee W Stolz A Talwalkar J. Features and outcomes of 899 patients with drug‐induced liver injury: the DILIN prospective study. Gastroenterology. 2015; 148: 1340– 52.e7. 25754159 PMC4446235
    • cites [31] Devarbhavi H Joseph T Kumar NS Rathi C Thomas V Singh SP. 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– 98. 33994711 PMC8103312

  • It may state two separate claims as one.

    Premisecitation

    Medical comorbidities such as obesity and diabetes are associated with increased incidence and severity of DILI with specific drugs; however, the role of alcohol, tobacco, and diet in DILI susceptibility is not established.

    “Medical comorbidities such as obesity and diabetes are associated with increased incidence and severity of DILI with specific drugs. However, the role of alcohol, tobacco, and diet in DILI susceptibility is not established.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The available observational and epidemiological data from case series and DILI registries are adequate to support recommendations on the clinical, laboratory, and histological features of DILI.

  • It may state two separate claims as one.

    Premisecitation

    DILI caused by anti-TB therapy has been associated with abnormal baseline serum aminotransferases, showing a stronger dose-dependent association with the severity of liver enzyme elevation than older age.

    “However, DILI caused by anti‐TB therapy has been associated with abnormal baseline serum aminotransferases, showing a stronger dose‐dependent association with the severity of liver enzyme elevation than older age.55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Gray EL Goldberg HF. Baseline abnormal liver function tests are more important than age in the development of isoniazid‐induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection. Intern Med J. 2016; 46: 281– 7. 26648478

  • It may state two separate claims as one.

    Interpretationreasoning

    Pretreatment HLA testing will likely not prove useful in most circumstances to prevent DILI, but HLA testing may be helpful in DILI diagnosis and causality assessment.

    “Therefore, pretreatment HLA testing will likely not prove useful in most circumstances to prevent DILI, but HLA testing may be helpful in DILI diagnosis and causality assessment.59,60”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Kullak‐Ublick GA Andrade RJ Merz M End P Benesic A Gerbes AL. Drug‐induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017; 66: 1154– 64. 28341748 PMC5532458
    • cites [60] Koido M Kawakami E Fukumura J Noguchi Y Ohori M Nio Y. Polygenic architecture informs potential vulnerability to drug‐induced liver injury. Nat Med. 2020; 26: 1541– 8. 32895570 PMC8482794

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    A given drug may be associated with more than one clinical profile.

    “Moreover, a given drug may be associated with more than one clinical profile.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Up to 20% of individuals in the general population have mildly increased liver biochemistries because of NAFLD, alcohol, and other common conditions.

    “Although DILI may present with lower levels of laboratory abnormalities, up to 20% of individuals in the general population have mildly increased liver biochemistries because of NAFLD, alcohol, and other common conditions.74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Fontana RJ Watkins PB Bonkovsky HL Chalasani N Davern T Serrano J. Drug‐induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009; 32: 55– 68. 19132805 PMC3637941

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

    Premisecitation

    LiverTox provides a brief synopsis of the clinical features of idiosyncratic DILI due to more than 1000 prescription drugs and 60 HDS culled from the world's literature.

    “The LiverTox website provides a brief synopsis of the clinical features of idiosyncratic DILI due to more than 1000 prescription drugs and 60 HDS that are culled from the world's literature.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Björnsson ES Hoofnagle JH. Categorization of drugs implicated in causing liver injury: critical assessment based on published case reports. Hepatology. 2016; 63: 590– 603. 26517184

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

    Premisenone given

    LiverTox provides a likelihood scale summarizing how many reports of bona fide hepatotoxicity have been attributed to a product, with categories A (50 or more reports), B (12-49 cases), C (4-11 cases), D (1-3 plausible cases), E (no reports), and X (newly approved agents).

    “In addition, LiverTox provides a likelihood scale summarizing how many reports of bona fide hepatotoxicity have been attributed to a product as follows: category A, 50 or more reports; category B, 12–49 cases; category C, 4–11 cases; category D, 1–3 plausible cases; category E, no reports of liver injury; and category X, newly approved agents.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisenone given

    Amoxicillin-clavulanate is the most frequently implicated individual agent in many western countries, whereas anti-tuberculosis agents dominate in Asian countries.

    “Amoxicillin‐clavulanate is the most frequently implicated individual agent in many western countries, whereas anti‐tuberculosis (TB) agents dominate in Asian countries (Table 2).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Older subjects appear to be at increased risk of isoniazid and amoxicillin-clavulanate hepatotoxicity, whereas younger individuals are more prone to develop DILI from anticonvulsants and minocycline.

    “In addition, older subjects appear to be at increased risk of isoniazid and amoxicillin‐clavulanate hepatotoxicity, whereas younger individuals are more prone to develop DILI from anticonvulsants and minocycline.45,46”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] George N Chen M Yuen N Hunt CM Suzuki A. Interplay of gender, age and drug properties on reporting frequency of drug‐induced liver injury. Regul Toxicol Pharmacol. 2018; 94: 101– 7. 29407200
    • cites [46] Fountain FF Tolley E Chrisman CR Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7‐year evaluation from a public health tuberculosis clinic. Chest. 2005; 128: 116– 23. 16002924

  • It may state two separate claims as one.

    Interpretationcitation

    The R-value is best calculated at the time of presentation, but the pattern of injury can change as the condition progresses.

    “The R‐value is best calculated at the time of presentation, but the pattern of injury can change as the condition progresses.77”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Benichou C Danan G Flahault A. Causality assessment of adverse reactions to drugs. Part II: an original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993; 46: 1331– 6. 8229111

  • It may state two separate claims as one.

    Premisenone given

    Typically, DILI appears within 6 months of starting a new medication, although certain drugs have longer latency periods (e.g., nitrofurantoin, methotrexate).

    “Typically, DILI appears within 6 months of starting a new medication, although certain drugs have longer latency periods (e.g., nitrofurantoin, methotrexate).”
    • Also stated in: § Competing causes of liver injury · plain
      “Most hepatotoxic drugs cause liver injury within the first 6 months of use but occasionally have longer latency intervals or may even present after drug discontinuation (e.g., amoxicillin‐clavulanate).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    In a French population-based study, standardized DILI incidence was more than 2 times higher in women than men older than 50 years, with no sex differences under age 50.

    “A French population‐based study showed that the standardized DILI incidence was more than 2 times higher in women than men older than 50 years, although no sex differences were noted under age 50.9,10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 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: 1419– 25. 23419359
    • cites [10] Sgro C Clinard F Ouazir K Chanay H Allard C Guilleminet C. Incidence of drug‐induced hepatic injuries: a French population‐based study. Hepatology. 2002; 36: 451– 5. 12143055

  • It may state two separate claims as one.

    Premisecitation

    Being overweight, having diabetes, alcohol use, and chronic viral hepatitis have been associated with progressive fibrosis in methotrexate-treated patients.

    “Being overweight, having diabetes, alcohol use, and chronic viral hepatitis have also been associated with progressive fibrosis in methotrexate‐treated patients.51,52”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] Laharie D Seneschal J Schaeverbeke T Doutre MS Longy‐Boursier M Pellegrin JL. Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case‐control study. J Hepatol. 2010; 53: 1035– 40. 20801541
    • cites [52] Rosenberg P Urwitz H Johannesson A Ros AM Lindholm J Kinnman N. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol. 2007; 46: 1111– 8. 17399848

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

    Premisecitation

    The Maria-Victorino Clinical Diagnostic Scale (CDS) uses similar variables to the RUCAM but excludes concomitant medications and includes points for extrahepatic manifestations.

    “The Maria‐Victorino Clinical Diagnostic Scale (CDS)109 uses similar variables to the RUCAM but excludes concomitant medications and includes points for extrahepatic manifestations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Maria VA Victorino RM. Development and validation of a clinical scale for the diagnosis of drug‐induced hepatitis. Hepatology. 1997; 26: 664– 9. 9303497

  • It may state two separate claims as one.

    Premisenone given

    RECAM has not yet been tested in regions of the world where the spectrum of DILI agents differs from that seen in the United States and Spain, or in cases with more than a single suspect drug.

    “Notwithstanding, RECAM has yet to be tested in regions of the world where the spectrum of DILI agents differs from that seen in the United States and Spain (Table 2) or in cases with more than a single suspect drug.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    The RECAM is a semiautomated, computerized platform with a dynamic range of −6 to +20 points and performs at least as well as the RUCAM in independent data sets.

    “This semiautomated, computerized platform has a dynamic range of −6 to +20 points and performs at least as well as the RUCAM in independent data sets.113”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Hayashi PH Lucena MI Fontana RJ Bjornsson E Aithal GP Barnhart H. A revised electronic version of RUCAM for the diagnosis of drug induced liver injury. Hepatology. 2022; 76: 18– 31. 35014066 PMC9233102

  • It may state two separate claims as one.

    Premisecitation

    Although the DDW-J was shown to be superior to the original RUCAM in Japanese patients, it is not currently used outside of Japan because of the lack of widely available and reproducible DLST assays.

    “Although the DDW‐J was shown to be superior to the original RUCAM in Japanese patients, it is not currently used outside of Japan because of the lack of widely available and reproducible DLST assays.112”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Hanatani T Sai K Tohkin M Segawa K Kimura M Hori K. A detection algorithm for drug‐induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of medical sciences/the Roussel Uclaf causality assessment method scale. Pharmacoepidemiol Drug Saf. 2014; 23: 984– 8. 24596340

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

    Premisenone given

    The updated RUCAM provides more specific guidance in ascertaining the hepatotoxicity profile of the suspect drug.

    “The updated RUCAM also provides more specific guidance in ascertaining the hepatotoxicity profile of the suspect drug”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The updated RUCAM specifies criteria for rechallenge.

    “specifies criteria for rechallenge”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [108] Danan G Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016; 27: 14– 30. PMC4730261 26712744
    • cites [119] Teschke R Frenzel C Schulze J Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013; 19: 2864– 82. 23704820 PMC3660812

  • It may state two separate claims as one.

    Premisecitation

    In acute cholestatic DILI, cholestasis without accompanying inflammation (bland cholestasis) may be the sole histological presentation and manifests as bile in dilated canaliculi and within hepatocyte cytoplasm.

    “In the acute cholestatic type, cholestasis without accompanying inflammation (so‐called bland cholestasis) may be the sole histological presentation and manifests as bile present in dilated canaliculi and within the hepatocyte cytoplasm.98”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Zhang X Ouyang J Thung SN. Histopathologic manifestations of drug‐induced hepatotoxicity. Clin Liver Dis. 2013; 17: 547– 64. 24099017

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

    Premisenone given

    RECAM is a newly developed, computerized causality assessment instrument.

    “The RECAM is a newly developed, computerized causality assessment instrument”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Contemporary HDS are commonly multi-ingredient products marketed under the guise of delivering some improvement in appearance, performance, or sense of well-being.

    “contemporary HDS are commonly multi‐ingredient products that are marketed under the guise of delivering some improvement in appearance, performance, or sense of well‐being.124”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Huang YS Chang TT Peng CY Lo GH Hsu CW Hu CT. Herbal and dietary supplement‐induced liver injury in Taiwan: comparison with conventional drug‐induced liver injury. Hepatol Int. 2021; 15: 1456– 65. 34382132

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

    Interpretationnone given

    Advantages of expert opinion include the ability to account for atypical cases, interrupted drug exposure, and synthesis of subtle clues including liver histology in relationship to published literature.

    “Advantages of expert opinion include the ability to account for atypical cases, interrupted drug exposure, and synthesis of subtle clues including liver histology in relationship to published literature.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    In DILI due to ICI, jaundice and liver failure are rare, and approximately one-third of those with severe grades of DILI may regress spontaneously.

    “Overall, jaundice and liver failure are rare in DILI because of ICI, and approximately a third of those with severe grades of DILI may even regress spontaneously.97”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Zen Y Chen YY Jeng YM Tsai HW Yeh MM. Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes. Histopathology. 2020; 76: 470– 80. 31550390

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

    Premisenone given

    The RECAM is currently available online.

    “The RECAM is currently available online.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The semiquantitative scale developed by DILIN categorizes the likelihood of DILI into five probability groups that vary from < 25% to > 95% probability.

    “Structured expert opinion: The semiquantitative scale developed by DILIN categorizes the likelihood of DILI into five probability groups that vary from < 25% to > 95% probability (Table 6).74,116,117”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Fontana RJ Watkins PB Bonkovsky HL Chalasani N Davern T Serrano J. Drug‐induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009; 32: 55– 68. 19132805 PMC3637941
    • cites [116] Tillmann HL Suzuki A Barnhart HX Serrano J Rockey DC. Tools for causality assessment in drug‐induced liver disease. Curr Opin Gastroenterol. 2019; 35: 183– 90. 30865042 PMC6452904
    • cites [117] Hayashi PH Barnhart HX Fontana RJ Chalasani N Davern TJ Talwalkar JA. Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the drug‐induced liver injury network (DILIN). Liver Int. 2015; 35: 1623– 32. 24661785 PMC4305346

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

    Premisenone given

    RECAM's interrater and intrarater reliability needs to be determined.

    “and its interrater and intrarater reliability needs to be determined.”
    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

    Peliosis hepatis appears as blood-filled lacunar spaces, and its development is associated with androgens and oral contraceptive agents.

    “Peliosis hepatis appears as blood‐filled lacunar spaces, and its development is associated with androgens and oral contraceptive agents.102”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Tsirigotis P Sella T Shapira MY Bitan M Bloom A Kiselgoff D. Peliosis hepatis following treatment with androgen‐steroids in patients with bone marrow failure syndromes. Haematologica. 2007; 92: e106– 10. 18024386

  • Probably not a substantial claim.

    Premisecitation

    Causality assessment by expert opinion addresses the unique clinical features of a particular patient along with knowledge of the hepatotoxic potential of the suspect agent versus other causes of liver injury.

    “Causality assessment by expert opinion addresses the unique clinical features of a particular patient along with knowledge of the hepatotoxic potential of the suspect agent versus other causes of liver injury.122”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Rochon J Protiva P Seeff LB Fontana RJ Liangpunsakul S Watkins PB. Reliability of the Roussel Uclaf causality assessment method for assessing causality in drug‐induced liver injury. Hepatology. 2008; 48: 1175– 83. 18798340 PMC3618289

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

    Premisecitation

    In a 2017-2018 study, more than 50% of adults over the age of 20 used dietary supplements in the preceding 30 days.

    “more than 50% of adults over the age of 20 used dietary supplements in the preceding 30 days in a 2017–2018 study.123”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Mishra S Stierman B Gahche JJ Potischman N. Dietary supplement use among adults: United States, 2017–2018. NCHS Data Brief. 2021; 399: 1– 8. 33663653

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

    Premisecitation

    The Digestive Disease Week-Japan 2004 (DDW-J) score is a modification of the RUCAM with inclusion of drug-lymphocyte stimulation test (DLST) results and peripheral eosinophilia.

    “The Digestive Disease Week–Japan 2004 (DDW‐J) score is a modification of the RUCAM with the inclusion of drug‐lymphocyte stimulation test (DLST) results and peripheral eosinophilia.111,112”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Takikawa H Takamori Y Kumagi T Onji M Watanabe M Shibuya A. Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the international consensus meeting. Hepatol Res. 2003; 27: 192– 5. 14585395
    • cites [112] Hanatani T Sai K Tohkin M Segawa K Kimura M Hori K. A detection algorithm for drug‐induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of medical sciences/the Roussel Uclaf causality assessment method scale. Pharmacoepidemiol Drug Saf. 2014; 23: 984– 8. 24596340

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

    Premisenone given

    The semiquantitative expert opinion causality assessment scale developed by the DILIN is frequently used in clinical practice and in prospective research studies.

    “The semiquantitative expert opinion causality assessment scale developed by the DILIN is frequently used in clinical practice and in prospective research studies”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The updated RUCAM has improved user instructions compared with the original RUCAM.

    “The updated RUCAM has improved user instructions and more complete diagnostic evaluation compared with the original RUCAM”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Intentional suspect drug rechallenge is rarely undertaken in clinical practice.

    “Intentional suspect drug rechallenge is rarely undertaken in clinical practice”
    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.

    Premisereasoning

    The CDS has five likelihood categories, but its dynamic range of possible scores is more compressed compared with the RUCAM and RECAM.

    “There are five likelihood categories, but the dynamic range of possible scores is more compressed compared with the RUCAM and the Revised Electronic Causality Assessment Method (RECAM).”
    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 updated RUCAM score was published in 2016, has several modifications, and generates a score ranging from −9 to +14 points with the same five likelihood categories.

    “The updated RUCAM score was published in 2016 and has several modifications that generates a score ranging from −9 to +14 points with the same five likelihood categories.108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Danan G Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016; 27: 14– 30. PMC4730261 26712744

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

    Premisecitation

    A liver biopsy defines chronic liver disease when there is significant fibrosis or even cirrhosis noted on histology.

    “In contrast, a liver biopsy defines chronic liver disease when there is significant fibrosis or even cirrhosis noted on histology.104”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Kleiner DE. Liver histology in the diagnosis and prognosis of drug‐induced liver injury. Clin Liver Dis (Hoboken). 2014; 4: 12– 6. 30992912 PMC6448725

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

    Premisecitation

    The updated RUCAM has more complete diagnostic evaluation compared with the original RUCAM.

    “The updated RUCAM has improved user instructions and more complete diagnostic evaluation compared with the original RUCAM”
    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

    According to DILIN, chronic DILI is the perpetuation of liver damage after 6 months from DILI onset, independent of the pattern of liver injury, whereas the Spanish DILI Group considers 1 year as the best cutoff point.

    “According to DILIN, chronic DILI is the perpetuation of liver damage after 6 months from DILI onset, independent of the pattern of liver injury, whereas the Spanish DILI Group considers 1 year as the best cutoff point.48,106”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Fontana RJ Hayashi PH Gu J Reddy KR Barnhart H Watkins PB. Idiosyncratic drug‐induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014; 147: 96– 108.e4. 24681128 PMC4285559
    • cites [106] Medina‐Caliz I Robles‐Diaz M Garcia‐Munoz B Stephens C Ortega‐Alonso A Garcia‐Cortes M. Definition and risk factors for chronicity following acute idiosyncratic drug‐induced liver injury. J Hepatol. 2016; 65: 532– 42. 27184533 PMC7458366

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

    Premisecitation

    The RUCAM provides a score varying from −10 to +14 points and groups scores into five likelihood categories with stratification by hepatocellular versus cholestatic/mixed injury.

    “It provides a score varying from −10 to +14 points and groups the scores into five likelihood categories with stratification by hepatocellular versus cholestatic/mixed injury.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Danan G Benichou C. Causality assessment of adverse reactions to drugs. Part I: a novel method based on the conclusions of international consensus meetings: application to drug‐induced liver injuries. J Clin Epidemiol. 1993; 46: 1323– 30. 8229110
    • cites [77] Benichou C Danan G Flahault A. Causality assessment of adverse reactions to drugs. Part II: an original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993; 46: 1331– 6. 8229111

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

    Premisecitation

    HDS are used widely around the world on a daily basis.

    “HDS are used widely around the world on a daily basis.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisenone given

    NRH and OPV may clinically present insidiously, whereas SOS may manifest as either acute or chronic disease.

    “NRH and OPV may clinically present insidiously, whereas SOS may manifest as either acute or chronic disease.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Structured causality assessment instruments incorporate the dose, duration, and timing of suspect drug and other concomitant drug or HDS product use; an assessment of the laboratory, radiological, and histological features at presentation; and exclusion of competing causes of liver injury.

    “Structured causality assessment instruments incorporate the dose, duration, and timing of suspect drug and other concomitant drug or HDS product use; an assessment of the laboratory, radiological, and histological features at presentation; and exclusion of competing causes of liver injury.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Most marketed supplements are safe.

    “Although most marketed supplements are safe”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Steatosis in DILI may be purely microvesicular (primarily related to mitochondrial injury), mixed microvesicular and macrovesicular, or purely macrovesicular.

    “Steatosis may be purely microvesicular, which is primarily related to mitochondrial injury, mixed microvesicular and macrovesicular, or purely macrovesicular.100”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Rabinowich L Shibolet O. Drug induced steatohepatitis: an uncommon culprit of a common disease. Biomed Res Int. 2015; 2015: 168905. 26273591 PMC4529891

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

    Premisecitation

    The updated RUCAM retains risk factors of age, alcohol, and pregnancy.

    “but retains risk factors of age, alcohol, and pregnancy that are of unclear value.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisenone given

    The RECAM removed several risk factors, has an expanded list of competing causes to exclude, and uses categorical and menu-driven diagnostic testing to reduce interobserver variability.

    “The RECAM removed several risk factors and has an expanded list of competing causes to exclude, and diagnostic testing is categorical and menu‐driven to reduce interobserver variability.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    The DILIN expert opinion approach has been shown to be as useful as the RUCAM, although expert opinion is rarely available in routine clinical practice.

    “This approach has been shown to be as useful as the RUCAM, although expert opinion is rarely available in routine clinical practice.117”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Hayashi PH Barnhart HX Fontana RJ Chalasani N Davern TJ Talwalkar JA. Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the drug‐induced liver injury network (DILIN). Liver Int. 2015; 35: 1623– 32. 24661785 PMC4305346

  • It may state two separate claims as one.

    Premisecitation

    Phospholipidosis is a form of DILI seen as hepatocytes with foamy granular cytoplasm; it represents an adaptive response to cationic amphophilic drugs like amiodarone and antimalarial agents via inhibition of lysosome-specific phospholipase A2.

    “Phospholipidosis is another form of DILI seen as hepatocytes with foamy granular cytoplasm. Similar to induction hepatocytes, phospholipidosis represents an adaptive response to cationic amphophilic drugs like amiodarone and antimalarial agents, via the inhibition of lysosome‐specific phospholipase A2.100,101”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Rabinowich L Shibolet O. Drug induced steatohepatitis: an uncommon culprit of a common disease. Biomed Res Int. 2015; 2015: 168905. 26273591 PMC4529891
    • cites [101] Bessone F Dirchwolf M Rodil MA Razori MV Roma MG. Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease—a physiopathological and clinical integrated view. Aliment Pharmacol Ther. 2018; 48: 892– 913. 30194708

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

    Premisenone given

    The updated RUCAM is not intended for use in patients with chronic liver disease.

    “but is not intended for use in patients with chronic liver disease.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationnone given

    The presence of eosinophils and granulomas on liver biopsy in a patient with suspected DILI is associated with a more favorable outcome, whereas those who have necrosis or fibrosis have poorer outcomes.

    “The presence of eosinophils and granulomas on a liver biopsy in a patient with suspected DILI is associated with a more favorable outcome, whereas those who have necrosis or fibrosis have poorer outcomes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Generic causality assessment models include the World Health Organization Collaborating Center for International Drug Monitoring system by the Uppsala Monitoring Center, which have not gained traction in DILI research or clinical practice because of their lack of liver specificity.

    “Generic causality assessment models include the World Health Organization Collaborating Center for International Drug Monitoring system by the Uppsala Monitoring Center, which have not gained traction in DILI research or clinical practice because of their lack of liver specificity.114,115”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [114] The use of the WHO–UMC system for standardised case causality assessment. 2021. [cited 2021 Sep 29]. Available from: http://www.who‐umc.org/graphics/4409.pdf
    • cites [115] Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30: 239– 45. 7249508

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

    Premisecitation

    The DDW-J score ranges from −5 to +17 points.

    “Scores range from −5 to +17 points.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Takikawa H Takamori Y Kumagi T Onji M Watanabe M Shibuya A. Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the international consensus meeting. Hepatol Res. 2003; 27: 192– 5. 14585395
    • cites [112] Hanatani T Sai K Tohkin M Segawa K Kimura M Hori K. A detection algorithm for drug‐induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of medical sciences/the Roussel Uclaf causality assessment method scale. Pharmacoepidemiol Drug Saf. 2014; 23: 984– 8. 24596340

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

    Premisenone given

    There are currently three commonly used causality assessment methods.

    “Currently there are three commonly used causality assessment methods”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Each of the three commonly used causality assessment methods has its own strengths and limitations.

    “and each has its own strengths and limitations.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    In ICI DILI, unlike AIH, plasma cell infiltration is not predominant, and the inflammatory infiltrate consists mostly of T lymphocytes, with CD8+ cells greater in number than CD4+ cells.

    “Unlike AIH, plasma cell infiltration is not predominant, and the inflammatory infiltrate consists mostly of T lymphocytes, with CD8+ cells being greater in number than CD4+ cells.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [95] Sawada K Hayashi H Nakajima S Hasebe T Fujiya M Okumura T. Non‐alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor. J Gastroenterol Hepatol. 2020; 35: 1042– 8. 31752049
    • cites [96] Zen Y Yeh MM. Checkpoint inhibitor‐induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019; 36: 434– 440. 31358424
    • cites [97] Zen Y Chen YY Jeng YM Tsai HW Yeh MM. Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes. Histopathology. 2020; 76: 470– 80. 31550390

  • It may state two separate claims as one.

    Premisecitation

    In chronic cholestatic DILI, cholestasis persists and may have severe bile duct injury or progress to bile duct loss.

    “In chronic cholestasis, the cholestasis persists and may have severe bile duct injury or progress to bile duct loss.88”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Kleiner DE Chalasani NP Lee WM Fontana RJ Bonkovsky HL Watkins PB. Hepatic histological findings in suspected drug‐induced liver injury: systematic evaluation and clinical associations. Hepatology. 2014; 59: 661– 70. 24037963 PMC3946736

  • It may state two separate claims as one.

    Interpretationnone given

    A broad spectrum of histological patterns has been reported in patients with DILI, and a given drug may be associated with more than a single histopathological signature.

    “A broad spectrum of histological patterns has been reported in patients with DILI, and a given drug may be associated with more than a single histopathological signature.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Microvesicular steatosis usually does not lead to increased echogenicity on ultrasound or manifest with hepatomegaly, and only liver biopsy can confirm its presence.

    “Of note, microvesicular steatosis usually does not lead to increased echogenicity on ultrasound, nor does it manifest with hepatomegaly, and only liver biopsy can confirm its presence.101”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Bessone F Dirchwolf M Rodil MA Razori MV Roma MG. Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease—a physiopathological and clinical integrated view. Aliment Pharmacol Ther. 2018; 48: 892– 913. 30194708

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

    Premisenone given

    Cholestatic DILI histology includes acute cholestasis, chronic cholestasis, and acute cholestatic hepatitis.

    “Cholestatic DILI histology includes acute cholestasis, chronic cholestasis, and acute cholestatic hepatitis.”
    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.

    Premisenone given

    Marketed supplements comprise single-ingredient products as well as mixtures of many different ingredients that may be both natural and synthetic.

    “Marketed supplements comprise single‐ingredient products as well as mixtures of many different ingredients that may be both natural and synthetic.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The updated RUCAM stratifies causality assessment by the R-value.

    “which stratifies causality assessment by the R‐value”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [108] Danan G Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016; 27: 14– 30. PMC4730261 26712744
    • cites [119] Teschke R Frenzel C Schulze J Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013; 19: 2864– 82. 23704820 PMC3660812

  • It may state two separate claims as one.

    Premisecitation

    The degree of necrosis and presence of prominent ductular reaction are associated with poor outcome, whereas the presence of eosinophils and granulomas is associated with better outcome in DILI.

    “The degree of necrosis and presence of prominent ductular reaction are associated with poor outcome, whereas the presence of eosinophils and granulomas is associated with better outcome.104”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Kleiner DE. Liver histology in the diagnosis and prognosis of drug‐induced liver injury. Clin Liver Dis (Hoboken). 2014; 4: 12– 6. 30992912 PMC6448725

  • It may state two separate claims as one.

    Interpretationcitation

    Genetic polymorphisms in the HLA region and the conditions under which a product is consumed may influence the likelihood of an individual patient developing HDS hepatotoxicity.

    “Genetic polymorphisms in the HLA region and the conditions under which a product is consumed may influence the likelihood of an individual patient developing HDS hepatotoxicity.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    A short course of corticosteroids (1-3 months) with rapid tapering may be of benefit in patients with autoimmune features on biopsy as well as for patients with DILI from ICIs and tyrosine kinase inhibitors.

    “In some instances, a short course of corticosteroids (i.e., 1–3 months) with rapid tapering may be of benefit in patients with autoimmune features on biopsy as well as for patients with DILI from ICIs and tyrosine kinase inhibitors (Table 9).153,154”
    • Also stated in: § Medical management of idiosyncratic patients with DILI · hedged
      “Corticosteroids given for 1–3 months may be of benefit in selected patients with idiosyncratic DILI, including those with severe hypersensitivity features, DRESS, and autoimmune features on liver biopsy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [153] Hu PF Wang PQ Chen H Hu XF Xie QP Shi J. Beneficial effect of corticosteroids for patients with severe drug‐induced liver injury. J Dig Dis. 2016; 17: 618– 27. 27426618
    • cites [154] Wree A Dechêne A Herzer K Hilgard P Syn WK Gerken G. Steroid and ursodesoxycholic acid combination therapy in severe drug‐induced liver injury. Digestion. 2011; 84: 54– 9. 21304237

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

    Premisereasoning

    An example of intentional adulteration is the inclusion of sildenafil in products marketed for sexual performance.

    “An example is the inclusion of sildenafil in products marketed for sexual performance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    The composition of HDS may change over time as a result of varying growing conditions, leading to batch-to-batch variability.

    “the composition of HDS may change over time as a result of varying growing conditions, leading to batch‐to‐batch variability.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Recent data suggest that APAP hepatotoxicity may occur even when therapeutic doses are used, but particularly in association with other cofactors.

    “Recent data suggest that APAP hepatotoxicity may occur even when therapeutic doses are used, but particularly in association with these other cofactors.165”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Louvet A Wandji LCN Lemaître E Khaldi M Lafforgue C Artru F. Acute liver injury with therapeutic doses of acetaminophen: a prospective study. Hepatology. 2021; 73: 1634– 6. 33306215

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Latency of exposure to a product before the onset of injury can be quite variable because of the accumulation of product within the body.

    “latency of exposure to a product before the onset of injury can be quite variable because of the accumulation of product within the body.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Supplements are vulnerable to intentional or inadvertent inclusion of ingredients.

    “it is well known that supplements are vulnerable to intentional or inadvertent inclusion of ingredients.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Ursodeoxycholic acid may improve symptoms of pruritus and hasten DILI recovery.

    “Ursodeoxycholic acid may improve symptoms of pruritus and hasten DILI recovery, but large, randomized controlled trials are needed to determine the optimal dose and duration.155”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Lang SM Ortmann J Rostig S Schiffl H. Ursodeoxycholic acid attenuates hepatotoxicity of multidrug treatment of mycobacterial infections: a prospective pilot study. Int J Mycobacterol. 2019; 8: 89– 92. 30860185

  • It may state two separate claims as one.

    Premisecitation

    In a randomized trial of 102 patients with antitubercular DILI, NAC demonstrated a shorter length of stay but no survival benefit.

    “Another randomized trial of 102 patients with antitubercular DILI also demonstrated a shorter length of stay but no survival benefit with NAC.149”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Moosa MS Maartens G Gunter H Allie S Chughlay MF Setshedi M. A randomized controlled trial of intravenous N‐acetylcysteine in the management of anti‐tuberculosis drug‐induced liver injury. Clin Infect Dis. 2021; 73: e3377– 83. 32845997

  • It may state two separate claims as one.

    Premisecitation

    Detection of serum APAP-protein adducts has been proposed as a more specific way to diagnose APAP hepatotoxicity particularly in patients presenting late or with an unintentional overdose, but this assay is not commercially available.

    “More recently, detection of serum APAP‐protein adducts has been proposed as a more specific way to diagnose APAP hepatotoxicity particularly in patients presenting late or with an unintentional overdose, but this assay is not commercially available.166”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] James LP Letzig L Simpson PM Capparelli E Roberts DW Hinson JA. Pharmacokinetics of acetaminophen‐protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009; 37: 1779– 84. 19439490 PMC2712440

  • It may state two separate claims as one.

    Premisecitation

    Most adults and children with idiosyncratic DILI present with a drug latency of 2-24 weeks, although some drugs have an ultrashort (<7 days) latency.

    “Most adults and children with idiosyncratic DILI present with a drug latency of 2–24 weeks, although some drugs have an ultrashort (< 7 days) latency.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Chalasani N Bonkovsky HL Fontana RJ Lee W Stolz A Talwalkar J. Features and outcomes of 899 patients with drug‐induced liver injury: the DILIN prospective study. Gastroenterology. 2015; 148: 1340– 52.e7. 25754159 PMC4446235

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

    Premisecitation

    When the veracity of a report is verified, regulatory actions can be taken against the manufacturer.

    “when the veracity of a report is verified, regulatory actions can be taken against the manufacturer”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

  • 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 European Union, the allowance of a product on the market requires a demonstrated history of safe use, along with periodic chemical verification of the labeled ingredients.

    “in the European Union, the allowance of a product on the market requires a demonstrated history of safe use, along with periodic chemical verification of the labeled ingredients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Food supplements. European Commission website. 2021. [cited 2021 Sep 19]. Available from: https://ec.europa.eu/food/safety/labelling‐and‐nutrition/food‐supplements_en

  • It may state two separate claims as one.

    Premisecitation

    APAP is a dose-related hepatotoxin, with all mammalian species susceptible to liver injury at doses only 2 to 3 times therapeutic dosing.

    “The reason for this widespread toxicity is that, unlike drugs associated with idiosyncrasy, APAP is a dose‐related hepatotoxin, with all mammalian species susceptible to liver injury in doses only 2 to 3 times therapeutic dosing.161”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002; 40: 3– 20. 11990202

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Botanical ingredients include plant parts and other herbs that are not listed on the product label.

    “Botanical ingredients include plant parts and other herbs that are not listed on the product label.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    American consumers spent more than $9.6 billion on herbal products in 2019.

    “American consumers spent more than $9.6 billion on herbal products in 2019.125”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] US herbal supplement sales increase by 8.6% in 2019, record‐breaking sales predicted for 2020. 2020. [cited 2021 Sep 19]. Available from: http://herbalgram.org/news/press‐releases/2020/us‐herbal‐supplement‐sales‐2019/

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

    Premisenone given

    Nonbotanical ingredients include chemicals, pesticides, and heavy metals.

    “Nonbotanical ingredients include chemicals, pesticides, and heavy metals.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The increased mortality or transplantation in HDS hepatotoxicity leading to liver failure may be due to delayed recognition of the product as the cause of liver injury or reluctance of HDS consumers to seek medical care.

    “This may be due to delayed recognition of the product as the cause of liver injury or reluctance of HDS consumers to seek medical care.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The regulatory environment in non-US markets varies.

    “The regulatory environment in non‐US markets varies, as summarized in a recent review.127”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Food supplements. European Commission website. 2021. [cited 2021 Sep 19]. Available from: https://ec.europa.eu/food/safety/labelling‐and‐nutrition/food‐supplements_en

  • It may state two separate claims as one.

    Premisecitation

    A diagnosis of APAP hepatotoxicity relies on a history of excessive APAP ingestion, detection of an elevated serum APAP level following single-time-point ingestion, and exclusion of competing causes of acute hepatocellular liver injury.

    “A diagnosis of APAP hepatotoxicity relies on a history of excessive APAP ingestion, detection of an elevated serum APAP level following single‐time‐point ingestion, and exclusion of competing causes of acute hepatocellular liver injury.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    HDS are commonly used worldwide.

    “HDS are commonly used worldwide”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Withdrawal of a product from the market is the most extreme regulatory action.

    “including withdrawal of a product from the market in the most extreme circumstance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Lack of knowledge and awareness of potential liver injury from widely used, over-the-counter supplements may cause the injury to go unrecognized by patients and providers.

    “the lack of knowledge and awareness of potential liver injury from these widely used, over‐the‐counter supplements may cause the injury to go unrecognized by patients and providers.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    The incidence of chronic DILI in 598 subjects enrolled in DILIN was 21% at 6 months, with African Americans and patients with cholestatic liver injury at presentation at increased risk.

    “The incidence of chronic DILI in 598 subjects enrolled into the DILIN was 21% at 6 months, with African Americans and patients with a cholestatic liver injury at presentation being at increased risk.147”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Fontana RJ Hayashi PH Barnhart H Kleiner DE Reddy KR Chalasani N. Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug‐induced liver injury. Am J Gastroenterol. 2015; 110: 1450– 9. 26346867 PMC4784423

  • It may state two separate claims as one.

    Premisecitation

    Supplements can cause severe hepatotoxicity that can have variable clinical, laboratory, and histological phenotypes.

    “Supplements can cause severe hepatotoxicity that can have variable clinical, laboratory, and histological phenotypes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    Intentional adulteration usually results from the inclusion of substances, usually pharmaceuticals, to achieve some pharmacodynamic effect in keeping with the supplement's marketed purpose for use.

    “Intentional adulteration usually results from the inclusion of substances, usually pharmaceuticals, to achieve some pharmacodynamic effect in keeping with the supplement's marketed purpose for use.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationnone given

    The polyphenolic backbone of the catechins is exploited for its antioxidant potential but is likely also responsible for liver injury.

    “The polyphenolic backbone of the catechins is exploited for its antioxidant potential but is likely also responsible for liver injury.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Several cases of liver injury due to GTE have been published, with the most convincing cases being those in which injury recurred following rechallenge.

    “Several cases of liver injury due to GTE have been published, with the most convincing cases being those in which injury recurred following rechallenge.131,132”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med. 2006; 144: 68– 71. 16389263
    • cites [132] Oketch‐Rabah HA Roe AL Rider CV Bonkovsky HL Giancaspro GI Navarro V. United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicol Rep. 2020; 7: 386– 402. 32140423 PMC7044683

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

    Premisecitation

    Allegations of injury attributable to a dietary supplement can be reported by consumers and providers to the US Food and Drug Administration (FDA) through the MedWatch passive reporting system.

    “Allegations of injury attributable to a dietary supplement can be reported by consumers and providers to the US Food and Drug Administration (FDA), through the MedWatch passive reporting system.128”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

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

    Premisenone given

    The DILIN's current efforts are directed to understand the toxicity that may result from specific ingredients sold individually or as ingredients in product mixtures.

    “The DILIN's current efforts are being directed to understand the toxicity that may result from specific ingredients that are sold individually or as ingredients in product mixtures (Table 7).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Reports to MedWatch are investigated by the FDA's Center for Food Safety and Applied Nutrition.

    “These reports are investigated by the FDA's Center for Food Safety and Applied Nutrition”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

  • It may state two separate claims as one.

    Premisecitation

    Risk factors for APAP toxicity include fasting and malnutrition, which can lead to depletion of intrahepatic glutathione stores, as well as use of alcohol and other medications that can induce the cytochrome P-450 system and lead to enhanced production of the toxic metabolite N-acetyl-p-benzoquinone imine.

    “Other risk factors for APAP toxicity include fasting and malnutrition, which can lead to depletion of intrahepatic glutathione stores, as well as use of alcohol and other medications that can induce the cytochrome P‐450 system and lead to enhanced production of the toxic metabolite, N‐acetyl‐p‐benzoquinone imine.164”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Whitcomb DC Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994; 272: 1845– 50. 7990219

  • It may state two separate claims as one.

    Premisenone given

    HLA-B*35:01 has been associated with hepatotoxicity attributed to GTE in White populations and P. multiflorum hepatotoxicity in Asian populations.

    “HLA‐B 35:01 has been associated with hepatotoxicity attributed to GTE in White populations and P. multiflorum hepatotoxicity in Asian populations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The 1994 Dietary Supplement Health and Education Act provides the current regulatory framework for supplement manufacturing and distribution in the United States.

    “The 1994 Dietary Supplement Health and Education Act provides the current regulatory framework for supplement manufacturing and distribution in the United States.126”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Roytman MM Poerzgen P Navarro V. Botanicals and hepatotoxicity. Clin Pharm Ther. 2018; 104: 458– 69. 29920648

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

    Interpretationnone given

    The key to preventing clinically significant liver injury from DILI is early detection of the signal event before it becomes symptomatic or severe.

    “The key to preventing clinically significant liver injury from DILI is early detection of the signal event before it becomes symptomatic or severe.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    DILI biomarkers in development broadly fall into four categories: dynamic liver injury markers, mechanistic biomarkers, prognostic biomarkers, and diagnostic biomarkers including single-nucleotide polymorphisms.

    “DILI biomarkers in development broadly fall into four categories: (A) dynamic liver injury markers that quantify the extent or severity of hepatocyte damage; (B) mechanistic biomarkers that aim to elucidate the intracellular pathways of liver injury; (C) prognostic biomarkers; and (D) diagnostic biomarkers including single‐nucleotide polymorphisms.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    ICD-10 codes and natural language processing algorithms may help identify DILI cases from administrative databases, but further refinement is needed.

    “International Classification of Diseases, Tenth Revision codes and natural language processing algorithms may help identify DILI cases from administrative databases, but further refinement is needed.208,209”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [208] Yeboah‐Korang A Louissant J Tsung I Prabhu S Fontana RJ. Utility of computerized ICD‐10 algorithm to identify idiosyncratic drug‐induced liver injury cases in the electronic medical record. Drug Saf. 2020; 43: 371– 7. 31916081 PMC8487619
    • cites [209] Heidemann L Law J Fontana RJ. A text searching tool to identify patients with idiosyncratic drug‐induced liver injury. Dig Dis Sci. 2017; 62: 615– 25. 26597192 PMC4877288

  • 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, an estimated 13 million individuals have latent TB, but > 10,000 individuals are treated for active TB each year.

    “In the United States, an estimated 13 million individuals have latent TB, but > 10,000 individuals are treated for active TB each year.179”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Talwar A Tsang CA Price SF Pratt RH Walker WL Schmit KM. Tuberculosis– United States 2018. MMWR Morb Mortal Wkly Rep. 2019; 68: 257– 62.30897076

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

    Premisecitation

    The treatment for active TB still consists of isoniazid, rifamycin, pyrazinamide, and ethambutol, and alternative strategies are now available that depend on various individual patient characteristics.

    “Whereas the treatment for active TB still consists of isoniazid, rifamycin, pyrazinamide, and ethambutol, alternative strategies are now available that depend on various individual patient characteristics.186”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Nahid P Dorman SE Alipanah N Barry PM Brozek JL Cattamanchi A. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug‐susceptible tuberculosis. Clin Infect Dis. 2016; 63: e147– 95. 27516382 PMC6590850

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

    Premisenone given

    Over the past 40 years, various recommendations for laboratory monitoring while receiving isoniazid have been proposed that begin with baseline liver assessments for all patients.

    “Over the past 40 years, various recommendations for laboratory monitoring while receiving isoniazid have been proposed that begin with baseline liver assessments for all patients.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The 2020 Academy of Dermatology guidelines for managing psoriasis recommends fibrosis-4 serologic testing and transient elastography at baseline and annually while on methotrexate therapy in patients with risk factors for hepatotoxicity.

    “In contrast, the 2020 Academy of Dermatology guidelines for managing psoriasis recommends fibrosis‐4 serologic testing and transient elastography at baseline and annually while on methotrexate therapy in patients with risk factors for hepatotoxicity.196”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Menter A Gelfand JM Connor C Armstrong AW Cordoro KM Davis DMR. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020; 82: 1445– 86. 32119894

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

    Premisecitation

    The 2008 American College of Rheumatology guidelines for rheumatoid arthritis advise laboratory monitoring at baseline and then every 2-4 weeks for the first 3 months, every 8-12 weeks for 3-6 months, and then every 12 weeks beyond 6 months of methotrexate treatment.

    “The 2008 American College of Rheumatology guidelines for the treatment of rheumatoid arthritis advises laboratory monitoring at baseline and then every 2–4 weeks with the first 3 months, every 8–12 weeks for 3–6 months, and then every 12 weeks beyond 6 months of treatment.194”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Saag KG Teng GG Patkar NM Anuntiyo J Finney C Curtis JR. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease‐modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59: 762– 84. 18512708

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

    Interpretationnone given

    Areas of unmet need in DILI clinical care include improved diagnostic and prognostic biomarkers, accurate and reliable causality assessment instruments, and studies of the epidemiology of DILI.

    “Areas of unmet need in DILI clinical care include the need for improved diagnostic and prognostic biomarkers, accurate and reliable causality assessment instruments, and studies of the epidemiology of DILI.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.

    Interpretationnone given

    Improved understanding of the molecular pathogenesis of DILI is needed to minimize future morbidity and mortality and identify therapeutic targets for intervention.

    “In addition, improved understanding of the molecular pathogenesis of DILI is needed to minimize future morbidity and mortality and identify therapeutic targets for intervention.”
    Quote in the paperNot a substantial claim
151 of 151

  • The paper relies on this without support.

    The available observational and epidemiological data from case series and DILI registries are adequate to support recommendations on the clinical, laboratory, and histological features of DILI.

    “The aim of this practice guidance is to provide recommendations regarding the common clinical, laboratory, and histological features seen in patients with DILI based on observational and epidemiological data reported in case series or DILI registries.”

  • The paper relies on this without support.

    Expert opinion is an adequate basis for patient management recommendations when randomized controlled trials are lacking.

    “In addition, expert opinion–based recommendations for patient management, including risk stratification, are provided to assist patients and practitioners.”
    “This guidance was developed with the support and oversight of the American Association for the Study of Liver Diseases Practice Guidelines Committee, who chose to commission a guidance, rather than a guideline, because of the paucity of randomized controlled trials on this topic.”

  • The paper relies on this without support.

    Up to 10% of patients with severe hepatocellular DILI with jaundice may be at risk of death because of their liver condition or underlying medical comorbidities.

    “However, up to 10% of patients with severe hepatocellular DILI with jaundice may be at risk of death because of their liver condition or underlying medical comorbidities.”

  • The paper relies on this without support.

    In registry studies, 10% of patients with idiosyncratic DILI are at risk for adverse hepatic outcomes including ALF, liver transplantation, and death within 6 months of onset.

    “In registry studies, 10% of patients with idiosyncratic DILI are at risk for adverse hepatic outcomes including ALF, liver transplantation, and death within 6 months of onset.”

  • The paper relies on this without support.

    Spontaneous survival in idiosyncratic DILI-related ALF is only 25%.

    “Because of the low likelihood of spontaneous survival in idiosyncratic DILI-related ALF of only 25%, early transfer of these individuals to a liver transplant center is recommended.”

  • The paper relies on this without support.

    Chronic liver injury that persists beyond 6–12 months is observed in 10%–20% of patients with DILI and may be more commonly encountered in those with cholestatic DILI.

    “Chronic liver injury that persists beyond 6–12 months is observed in 10%–20% of patients with DILI and may be more commonly encountered in those with cholestatic DILI.”

  • The paper relies on this without support.

    Individuals at increased risk for adverse outcomes include patients with DILI with severe necrosis and fibrosis on liver biopsy.

    “Individuals at increased risk for adverse outcomes include patients with DILI with higher bilirubin and INR values and lower serum albumin at presentation as well as those with severe necrosis and fibrosis on liver biopsy and those with medical comorbidities and pre-existing liver disease.”

  • The paper relies on this without support.

    Defibrotide is approved for use in adults and children undergoing hematopoietic cell transplantation with moderate to severe SOS.

    “Defibrotide is a profibrolytic that is approved for use in adults and children undergoing hematopoietic cell transplantation with moderate to severe SOS.”

  • The paper relies on this without support.

    Ursodeoxycholic acid is not an established therapy for patients with DILI but is presumably safe to administer.

    “Ursodeoxycholic acid is not an established therapy for patients with DILI but is presumably safe to administer.”

  • The paper relies on this without support.

    A diagnosis of APAP overdose is based on a history of ingestion of excessive doses (usually > 4 g as a single time point) that can lead to variable severity of acute hepatocellular liver injury with towering transaminase levels (often > 1000 U/L) within the first 24 h of observation.

    “A diagnosis of APAP overdose is based on a history of ingestion of excessive doses (usually > 4 g as a single time point) that can then lead to variable severity of acute hepatocellular liver injury with towering transaminase levels (often > 1000 U/L) within the first 24 h of observation (Table 10).”

  • The paper relies on this without support.

    Histologically, APAP toxicity is characterized by a variable degree of pericentral necrosis.

    “Histologically, APAP toxicity is characterized by a variable degree of pericentral necrosis.”
11 of 11

Claims other papers make about this one

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

  • The MetaHeps® test has shown promise as a confirmatory assay in several studies, but further refinement of methodology and validation is required before implementation in clinical practice.

    “While this test has shown promise as a confirmatory assay in several studies, further refinement of the methodology and validation is required for its implementation in clinical practice.”

    From Methods for causality assessment of idiosyncratic drug‐induced liver injury (2025) · cites this paper as [59]

    The DILI biomarkers section (page not provided) says that in vitro tests derived from circulating macrophages are being explored and need further validation. It does not name MetaHeps®, describe it as promising in several studies, or call specifically for methodological refinement before clinical use. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • The lack of reliable diagnostic biomarkers and an evidence-based treatment paradigm has resulted in limited guidance on how to manage this aspect of DILI.

    “The lack of reliable diagnostic biomarkers and an evidence-based treatment paradigm has resulted in limited guidance on how to manage this aspect of DILI.2,25–27”

    From Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report (2023) · cites this paper as [27]

    The DILI biomarkers section says no objective, reliable laboratory test confirms a suspect drug. The Introduction describes patient-management recommendations as expert-opinion based, and the medical-management section notes a lack of controlled trials for some treatments. However, the paper provides management recommendations, so it does not establish the claim that guidance on managing DILI is limited. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Idiosyncratic hepatotoxicity is rare, largely dose-independent, unpredictable, and has variable latency.

    “Idiosyncratic hepatotoxicity is rare, largely dose-independent, unpredictable, and has variable latency.[2]”

    From Drug-induced liver injury: Diagnosis, management and the role of liver transplantation (2025) · cites this paper as [2]

  • Research into DILI is hampered by the lack of an objective, reliable laboratory test that can reliably identify a specific drug or HDS as the cause of liver injury.

    “Research into DILI continues to be hampered by the lack of an objective, reliable laboratory tests that can reliably identify a specific drug or HDS as the cause of liver injury.”

    From Methods for causality assessment of idiosyncratic drug‐induced liver injury (2025) · cites this paper as [59]

  • Idiosyncratic DILI is unpredictable, largely dose-independent, and symptoms may appear after a long latency period.

    “They are unpredictable, largely dose-independent, and symptoms may appear after a long latency period [7, 8].”

    From Drug-induced liver injury. Part I: Classification, diagnosis and treatment (2025) · cites this paper as [8]

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.

  • CDS definite category exceeds its maximum score

    Major

    Table 5 gives the CDS a maximum score of 17 but requires a score greater than 17 for a definite classification. No score in the stated range can meet that criterion.

  • APAP antidote infusion duration does not total 24 hours

    Minor

    The specified intravenous NAC loading infusion lasts 15-60 minutes, followed by infusions lasting 4 and 16 hours. The schedule therefore lasts 20 hours 15 minutes to 21 hours, rather than the stated 24 hours.

  • CDS score of 6 belongs to two categories

    Minor

    Table 5 classifies a CDS score of 6 as both unlikely (6-9) and excluded (≤ 6).

  • Conflicting R-value cutoffs at 2 and 5

    Minor

    The diagnostic text assigns hepatocellular injury to R > 5 and cholestatic injury to R < 2, but guidance statement 15 assigns those categories at R ≥ 5 and R ≤ 2. Cases with an R value of exactly 5 or 2 therefore receive different classifications.

4 of 4

Citations

Cites

Flagged first, then by citations

2 of the 212 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. 2021, Dietary supplement use among adults: United States, 2017–2018, NCHS Data Brief, 399, 1
  2. 2021, A systematic comparison of hepatobiliary adverse drug reactions in FDA and EMA drug labelling reveals discrepancies, Drug Discov Today, 27, 337
  3. 2014, The National Lipid Association's statin safety task force. An assessment by the statin liver safety task force: 2014 update, J Clin Lipidol, 8, S47
  4. 2015, Role of osteopontin in liver diseases, Int J Biol Sci, 12, 1121

Cited by

Sorted by citations

Related

Metadata

Authors
Fontana, R. J., Liou, I., Reuben, A., Suzuki, A., Fiel, M. I., Lee, W., & Navarro, V.
Affiliations
  • University of Michigan (US)
  • University of Washington (US)
  • Medical University of South Carolina (US)
  • Duke University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • The University of Texas Southwestern Medical Center (US)
  • Einstein Healthcare Network (US)
Corresponding author
Fontana, Robert J.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-02-17
Volume
77
Issue
3
Pages
1036-1065
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.32689
PMC
PMC9936988
OpenAlex
W4288077670
Cited by
340
References
212
Citations by year
2026: 152 · 2025: 85 · 2024: 61 · 2023: 38
FWCI
27.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • American Association for the Study of Liver Diseases
  • Gilead Sciences
  • Alexion Pharmaceuticals
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords
drug-induced liver injury, idiosyncratic drug-induced liver injury, acetaminophen hepatotoxicity, liver injury biomarkers, risk stratification, hepatotoxicity
MeSH terms
Humans, Dietary Supplements, Chemical and Drug Induced Liver Injury, Chemical and Drug Induced Liver Injury, Chronic

About these checks

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

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

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