Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review
Abstract
:1. Introduction
2. APAP Hepatotoxicity
2.1. General Overview
2.2. Predisposing Factors
3. APAP Hepatotoxicity in NAFLD
3.1. Main Features of NAFLD
3.2. Clinical Investigations on Acute APAP Hepatotoxicity in Obesity and NAFLD
3.3. Rodent Studies on Acute APAP Hepatotoxicity in Obesity and NAFLD
3.4. In Vitro Studies on Acute APAP Hepatotoxicity in Models of Fatty Acid Exposure and NAFLD
3.5. Investigations on Chronic APAP Hepatotoxicity in Obesity and NAFLD
4. Factors Modulating APAP Hepatotoxicity in Obesity and NAFLD
4.1. Factors That Could Favor APAP Hepatotoxicity in Obesity and NAFLD
4.1.1. CYP2E1 Induction
4.1.2. Low Basal Levels of GSH
4.1.3. Extent of Steatosis and Accumulation of Deleterious Fatty Acids and Lipid Species
4.1.4. Mitochondrial Dysfunction
4.1.5. Presence of Lobular Inflammation
4.2. Factors That Could Mitigate APAP Hepatotoxicity in Obesity and NAFLD
4.2.1. Alteration in APAP Absorption and Distribution
4.2.2. Lack of CYP2E1 Induction or CYP2E1 Downregulation
4.2.3. Reduced CYP3A4 and CYP1A2 Activity
4.2.4. Increased APAP Glucuronidation
4.2.5. Exposure and Accumulation of Protective Fatty Acids
5. APAP-Induced Liver Injury after Bariatric Surgery
6. APAP-Hepatotoxicity in Type 1 Diabetes Mellitus
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Authors, Year [References] | Design of the Study | Presence of NAFLD | Hepatic CYP2E1 Activity | APAP Overdose | APAP-Induced Acute Liver Injury |
---|---|---|---|---|---|
Rutherford et al., 2006 [44] | Prospective | Not reported in this study 1 | Not reported in this study | Yes | Lower incidence (but poorer outcomes) in obese patients |
Nguyen et al., 2008 [40] | Retrospective | Yes | Not reported in this study | Yes | Higher prevalence in patients with NAFLD |
Myers and Shaheen, 2009 [41] | Retrospective | Yes | Not reported in this study | Yes | Higher prevalence in patients with NAFLD |
Radosevich et al., 2016 [45] | Retrospective | Not reported in this study 1 | Not reported in this study | Yes | Equal prevalence between obese and nonobese patients |
Van Rongen et al., 2016 [43] | Prospective | Not reported in this study 1 | Increased | No (4 to 5 g) | Increased plasma ALT and AST in morbidly obese patients but not in nonobese individuals |
Chomchai and Chomchai, 2018 [42] | Retrospective | Not reported in this study 1 | Not reported in this study | Yes | Higher prevalence in overweight and obese patients |
Authors, Year [References] | Rodent Models of Obesity and NAFLD | Presence of NAFLD | Hepatic CYP2E1 Activity | Dose of APAP | APAP-Induced Hepatotoxicity |
---|---|---|---|---|---|
Corcoran and Wong, 1987 [47] | Male Sprague–Dawley rats fed a high-fat diet for 24 weeks | Not reported in this study 1 | Not reported in this study | 710 mg/kg (i.p.) | Higher hepatotoxicity after 48 h, compared to rats fed a standard diet |
Blouin et al., 1987 [58] | Male obese Zucker fa/fa rats | Not reported in this study 2 | Not reported in this study 2 | 1300 mg (p.o.) | Similar hepatotoxicity after 48 h, compared to lean rats |
Tuntaterdtum et al., 1993 [54]. | Male obese Zucker fa/fa rats | Not reported in this study 2 | Not reported in this study 2 | 3000 mg/kg (p.o) | Lower hepatotoxicity after 48 h, compared to lean rats |
Ito et al., 2006 [55] | Male C57Bl/6 mice fed a Western-style diet for 16 weeks Male ob/ob mice | Yes Not reported in this study 3 | Not reported in this study Not reported in this study 3 | 300 mg/kg (p.o.) 300 mg/kg (p.o.) | Lower hepatotoxicity after 6 h, compared to mice fed a standard diet Lower hepatotoxicity after 6 h, compared to wild-type mice |
Donthamsetty et al., 2008 [59] | Male Swiss Webster mice fed a MCD diet for 1 month 4 | Yes | Unchanged | 360 mg/kg (i.p.) | Higher hepatotoxicity from 6 to 48 h after overdose, compared to mice fed a standard diet |
Kon et al., 2010 [48] | Male KK-Ay mice | Yes | Not reported in this study 5 | 300 or 600 mg/kg (p.o.) | Higher hepatotoxicity after 6 h, compared to wild-type mice |
Kucera et al., 2012 [50] | Male Sprague-Dawley rats fed a high-fat diet for 6 weeks | Yes | Not reported in this study | 1 g/kg (p.o) | Higher hepatotoxicity after 24 and 48 h, compared to rats fed a standard diet |
Aubert et al., 2012 [49] | Female db/db mice Female ob/ob mice | Yes Yes | Increased Unchanged | 500 mg/kg (p.o.) 500 mg/kg (p.o.) | Higher hepatotoxicity after 8 h, compared to wild-type mice Similar hepatotoxicity after 8 h, compared to wild-type mice |
Kim et al., 2017 [56] | Male C57Bl/6 mice fed a fast food diet for 14 weeks | Yes | Not reported in this study (but higher CYP2E1 protein levels) | 200 mg/kg (i.p.) | Lower hepatotoxicity compared to wild-type mice (timing not specified) |
Piccinin et al., 2019 [51] | Male FVB/N mice fed a high-fat diet for 1 month | Yes | Not reported in this study | 300 mg/kg (i.p.) | Higher hepatotoxicity after 6 h, compared to wild-type mice |
Shi et al., 2019 [52] | Male C57Bl/6 mice fed a high-fat diet for 8 weeks | Yes | Not reported in this study | 50, 100 or 200 mg/kg (p.o.) | Significant hepatotoxicity after 24 h but no comparison with wild-type mice |
Wang et al., 2021 [53] | Male C57Bl/6J mice fed a high-fat diet for 8 weeks | Yes | Not reported in this study | 100 mg/kg (p.o.) | Significant hepatotoxicity after 24 h but no comparison with wild-type mice |
Ghallab et al., 2021 [57] | Male C57Bl/6N mice fed a Western diet for 48 to 50 weeks | Yes | Not reported in this study (but lower CYP2E1 immunostaining) | 300 mg/kg (i.p.) | Lower hepatotoxicity compared to wild-type mice (timing not specified) |
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Begriche, K.; Penhoat, C.; Bernabeu-Gentey, P.; Massart, J.; Fromenty, B. Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review. Livers 2023, 3, 33-53. https://doi.org/10.3390/livers3010003
Begriche K, Penhoat C, Bernabeu-Gentey P, Massart J, Fromenty B. Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review. Livers. 2023; 3(1):33-53. https://doi.org/10.3390/livers3010003
Chicago/Turabian StyleBegriche, Karima, Clémence Penhoat, Pénélope Bernabeu-Gentey, Julie Massart, and Bernard Fromenty. 2023. "Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review" Livers 3, no. 1: 33-53. https://doi.org/10.3390/livers3010003
APA StyleBegriche, K., Penhoat, C., Bernabeu-Gentey, P., Massart, J., & Fromenty, B. (2023). Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review. Livers, 3(1), 33-53. https://doi.org/10.3390/livers3010003