Cited by 168Drug-Induced Hepatotoxicity and ProtectionPharmacovigilance and Adverse Drug ReactionsLiver physiology and pathology

The DOI matches its Crossref record; 145 of the 145 references it cites were found in a registry or an index; none of the 157 sources its claims cite is checked for support yet.

Drug induced liver injury – a 2023 update

Open access
Allison, Rebecca, Guraka, Asha, Shawa, Isaac Thom, Tripathi, Gyan, Moritz, Wolfgang, Kermanizadeh, Ali·2023·Journal of Toxicology and Environmental Health, Part B

Abstract

Drug-Induced Liver Injury (DILI) constitutes hepatic damage attributed to drug exposure. DILI may be categorized as hepatocellular, cholestatic or mixed and might also involve immune responses. When DILI occurs in dose-dependent manner, it is referred to as intrinsic, while if the injury occurs spontaneously, it is termed as idiosyncratic. This review predominately focused on idiosyncratic liver injury. The established molecular mechanisms for DILI include (1) mitochondria dysfunction, (2) increased reactive oxygen species levels, (3) presence of elevated apoptosis and necrosis, (4) and bile duct injuries associated with immune mediated pathways. However, it should be emphasized that the underlying mechanisms responsible for DILI are still unknown. Prevention strategies are critical as incidences occur frequently, and treatment options are limited once the injury has developed. The aim of this review was to utilize retrospective cohort studies from across the globe to gain insight into epidemiological patterns. This review considers (1) what is currently known regarding the mechanisms underlying DILI, (2) discusses potential risk factors and (3) implications of the coronavirus pandemic on DILI presentation and research. Future perspectives are also considered and discussed and include potential new biomarkers, causality assessment and reporting methods.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review updates understanding of drug-induced liver injury (DILI), focusing on idiosyncratic DILI (iDILI), its molecular mechanisms, global epidemiological patterns, risk factors, and clinical management. It concludes that mechanisms remain incompletely understood, diagnosis relies on exclusion and tools like RUCAM, and treatment is largely limited to withdrawing the offending drug.

Key findings

  • DILI accounts for approximately 15% of acute liver failure cases in the United States and Europe, and roughly half of preclinical drugs with early evidence of hepatotoxicity are terminated before market authorization.
  • Global incidence varies widely: 19.1 per 100,000 inhabitants in Iceland (amoxicillin-clavulanate most implicated at 22%, diclofenac 6%, azathioprine 4%, infliximab 4%, nitrofurantoin 4%), 13.9 (±2.4) per 100,000 in France, 2.4 per 100,000 person-years in the UK GPRD (1,636,792 individuals; 128 confirmed cases), 2.7 per 100,000 adults in Delaware (43% attributed to herbal dietary supplements, 36% to antibiotics), and 12 per 100,000 in South Korea (herbal medications 27.5%). Herbal medicines accounted for up to 53.63% of DILI in some Chinese cohorts, while antitubercular drugs (49%) and antiepileptics (12%) predominated in an Indian tertiary hospital, and ART (35%) and anti-TB drugs (27%) in South Africa.
  • Among drugs implicated in iDILI, 61.1% are metabolized by CYP450 isoforms, 49.6% by CYP3A4/5 and 24.6% by CYP2C8/9; flucloxacillin-associated DILI is linked to HLA-B*57:01 (OR 80.6).
  • Upon drug discontinuation, approximately 80% of DILI cases resolve spontaneously; about 20% develop chronic liver disease, DILI-related mortality is 5–10%, iDILI showed a 3-week transplant-free survival of 27%, and 5-year post-transplant survival in DILI-ALF patients is 70–80%.

Methods

  • Narrative review with an extensive literature search of PubMed and Cochrane Library using terms including "Drug Induced Liver Injury," "DILI," "DILI mechanisms," "DILI incidence," "Idiosyncratic DILI," "DILI causality assessment," "Drug Injury" and "Drug Discovery"; last search conducted 16 May 2023.
  • Exclusion criteria were publications focused on hepatic injury primarily from alcohol and studies of autoimmune hepatitis; paracetamol-induced injury was excluded from the global incidence review to focus on idiopathic DILI.
  • No new data were created or analyzed (per the data availability statement); the review synthesizes retrospective cohort studies, registry data, and meta-analysis findings.

Limitations

  • Stated: the authors note that due to the "inevitable limitations and exclusionary nature of any literature search," investigations that did not include the search terms in the title or lacked adequate abstract information might have been unintentionally omitted.
  • Stated: findings across incidence studies are difficult to compare directly because diagnostic parameters, cohort demographics, and regional prescribing/epidemiological patterns differ.
  • Evident from the text: the review is narrative rather than systematic, and several cited incidence figures derive from single-hospital or single-region retrospective studies with differing biochemical thresholds (e.g., ALT > 3× ULN vs. ALT > 10× ULN), limiting generalizability.

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Integrity signals

Registry

Crossref · 10.1080/10937404.2023.2261848

Cites

145 of 145 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

134 Sources not found · 61 Own interpretation · 3 No basis given · 1 Not checked yet

Show all 35 claims

  • Probably not a substantial claim. 124
  • It may state two separate claims as one. 82
164 of 164
  • The paper relies on this without support.

    Incidences of DILI occur frequently.

    “Prevention strategies are critical as incidences occur frequently, and treatment options are limited once the injury has developed.”
  • The paper relies on this without support.

    Treatment options are limited once DILI has developed.

    “Prevention strategies are critical as incidences occur frequently, and treatment options are limited once the injury has developed.”
  • The paper relies on this without support.

    The cited retrospective cohort studies are representative of global DILI epidemiology.

    “The aim of this review was to utilize retrospective cohort studies from across the globe to gain insight into epidemiological patterns.”
  • The paper relies on this without support.

    Animal models of DILI are informative for human DILI mechanisms.

    “Lorincz et al. (Citation2015) noted that challenge with ferrostatin-1 (specific ferroptosis inhibitor) in primary mouse hepatocytes treated with acetaminophen increased cell viability.”
  • The paper relies on this without support.

    DILI diagnosis requires exclusion of other hepatic disorders.

    “Symptoms may mimic other hepatic disorders such as autoimmune hepatitis which emphasizes the need for DILI diagnosis by exclusion.”
  • The paper relies on this without support.

    Between 5% and 20% of a normal population have preexisting liver impairment or abnormal baseline serum enzyme activity levels.

    “It is worth noting that between 5% and 20% of a normal population fall into this category.”
  • The paper relies on this without support.

    Higher dosage is a risk factor for DILI development.

    “Higher dosage has also been linked as a potential risk factor for DILI development.”
  • The paper relies on this without support.

    The clinical efficacy and safety of anti-viral drugs used in COVID-19 have potential for hepatotoxicity resulting in DILI after repeated dosing.

    “The clinical efficacy and safety of these anti-viral drugs have shown potential for hepatotoxicity resulting in DILI after repeated dosing.”
  • The paper relies on this without support.

    Inhibition of CYP3A4 enzyme activity and liver transporter proteins are important factors leading to disruption of drug metabolism and subsequent manifestation of DILI.

    “Inhibition of CYP3A4 enzyme activity and liver transporter proteins are suspected as being important factors leading to disruption of drug metabolism and subsequent manifestation of DILI.”
  • The paper relies on this without support.

    Treatment of DILI is aimed at detoxification, scavenging free radicals, anti-oxidation, hepatocyte protection and immune regulation.

    “Treatment is aimed at detoxification, scavenging free radicals, anti-oxidation, hepatocyte protection and immune regulation.”
  • The authors state this as an assumption.

    Clinically asymptomatic MASLD might render patients under medication to a higher risk for developing liver injury.

    “Assuming that clinically asymptomatic MASLD might render patients under medication to a higher risk for developing liver injury, then this cohort is clearly underrepresented in clinical safety studies.”
  • The authors state this as an assumption.

    Heavy drinkers might be more susceptible to developing acute DILI.

    “It is not unreasonable to assume the same argument might be valid for heavy drinkers who might be more susceptible to developing acute DILI.”
  • The paper relies on this without support.

    Treatment for DILI is limited.

    “As treatment for DILI is limited, focus has shifted toward prevention.”
  • The paper relies on this without support.

    Most cases of DILI are self-limiting and resolve upon withdrawal of the offending drug.

    “Most cases of DILI are self-limiting and resolve upon withdrawal of the offending drug, but treatments for more serious reactions are limited.”
  • The paper relies on this without support.

    There is no standardized clinical guidance for the treatment of DILI as most treatments are nonspecific.

    “There is no standardized clinical guidance for the treatment of DILI as most treatments are nonspecific.”
  • The paper relies on this without support.

    Current causality assessment models may be ambiguous, lacking data to comprehensively evidence some of their components.

    “Current causality assessment models may be ambiguous, lacking data to comprehensively evidence some of their components.”
  • The paper relies on this without support.

    The lack of specific biomarkers makes distinguishing DILI cases from other hepatic conditions difficult.

    “The lack of specific biomarkers makes distinguishing DILI cases from other hepatic conditions difficult.”
  • The paper relies on this without support.

    The diagnosis of DILI relies upon the exclusion of alternative causes.

    “This problem is worsened as the diagnosis of DILI relies upon the exclusion of alternative causes.”
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2 of 2

Citations

Cites

Show all 145 references

Research works printed but not linked: 7

  1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. 2012b. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Amoxicillin-Clavulanate. [Updated 2020 Oct 20]. https://www.ncbi.nlm.nih.gov/books/NBK548517/
  2. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. 2012c. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Carbamazepine. [Updated 2017 Jan 15]. https://www.ncbi.nlm.nih.gov/books/NBK548097/
  3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. 2012d. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Diclofenac. [Updated 2017b Dec 13]. https://www.ncbi.nlm.nih.gov/books/NBK547953/
  4. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. 2012e. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Erythromycin. [Updated 2017 (C) Aug 10]. https://www.ncbi.nlm.nih.gov/books/NBK547881/
  5. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. 2012f. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Ibuprofen. [Updated 2018 Apr 16]. https://www.ncbi.nlm.nih.gov/books/NBK547845/
  6. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. 2012g. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Sulindac. [Updated 2020 (B) Mar 20]. https://www.ncbi.nlm.nih.gov/books/NBK548315/
  7. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. 2012i. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Valproate. [Updated 2020 (C) Jul 31]. https://www.ncbi.nlm.nih.gov/books/NBK548284/

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Items 101–168 of 168

Metadata

Authors
Allison, R., Guraka, A., Shawa, I. T., Tripathi, G., Moritz, W., & Kermanizadeh, A.
Affiliations
  • University of Derby (GB)
  • Nottingham Trent University (GB)
  • InSphero AG, Schlieren, Switzerland
Corresponding author
Kermanizadeh, Ali
Venue
Journal of Toxicology and Environmental Health, Part B
Published
2023-10-02
Volume
26
Issue
8
Pages
442-467
ISSN
  • 1093-7404 (ISSN-L)
  • 1521-6950
OpenAlex
W4387296925
Cited by
167
References
145
Citations by year
2026: 56 · 2025: 75 · 2024: 32 · 2023: 2
FWCI
5.88
Type
journal article
Language
en
Open access
Locations
  • Journal of Toxicology and Environmental Health Part B (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Animal Free Research UK
  • UK Research and Innovation
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
drug-induced liver injury, idiosyncratic drug reactions, hepatotoxicity mechanisms, mitochondrial dysfunction, reactive oxygen species, apoptosis and necrosis, immune-mediated liver injury, hepatocyte injury, cholestatic liver injury, risk factors, COVID-19 pandemic impact, biomarkers, causality assessment, adverse drug reaction reporting
MeSH terms
Humans, Liver Diseases, Retrospective Studies, Risk Factors, Chemical and Drug Induced Liver Injury

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