Drug-Induced Fatty Liver Disease
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Purpose of Review
Drug-induced fatty liver disease (DIFLD) is one of the manifestations of drug-induced liver injury (DILI) based on histopathology findings of steatosis or steatohepatitis. DIFLD has high semblance to nonalcoholic fatty liver disease (NAFLD), where similar histopathological features are seen. As NAFLD is a commonly occurring disease, differentiating DIFLD from NAFLD requires a thorough history of medication use. Outcomes in DIFLD vary with the clinical presentation, with extremely high mortality in acute fatty liver presentations and indolent course in the rest. Pathophysiology in almost all cases of DIFLD encompasses one of the following: increased uptake or decreased output of triglycerides from hepatocytes or decreased metabolism of triglycerides (such as fatty acid oxidation) or electron transport chain. DIFLD may present as acute fatty liver or more commonly as indolent fatty liver disease. In this article, we outline pathophysiology, diagnosis, management, and common medications associated with DIFLD.
Recent findings give insights into new technologies that may help us understand common pathways that are associated with drugs that cause and factors that modify susceptibility to DIFLD. Latest research has also allowed for identification of genetic polymorphisms associated with increased risk for DIFLD using genome-wide association studies (GWAS).
Drugs associated with DIFLD may have distinct clinical presentations, disease progression, and outcomes, timely identification of which is crucial to clinical management. We provide a succinct read for anyone interested in DIFLD phenotype of DILI, pathophysiology, clinical presentation, and management.
KeywordsDrug-induced steatosis Drug-induced steatohepatitis Mitochondrial injury Nonalcoholic fatty liver disease
Compliance with Ethical Standards
Conflict of Interest
Niharika Samala declares no conflicts of interest; Naga Chalasani reports several consulting agreements and research grants from Pharmaceutical Companies but declares that they are not relevant for the submitted work.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
- 1.On behalf of the Practice Parameters Committee of the American College of Gastroenterology, Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109:950–66.Google Scholar
- 4.•• Clinical course and diagnosis of drug induced liver disease [Internet]. National Library Of Medicine and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Available from: https://livertox.nih.gov/ClinicalCourse.html. LiverTox is an authoritative online resource for drug-induced liver injury developed by Liver Diseases Branch, NIDDK in collaboration with Division of Specialized Information Services, National Library of Medicine.
- 5.•• Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95. Landmark population-based study in the USA reporting prevalence of nonalcoholic fatty liver disease based in a multi-ethnic population based on magnetic resonance spectroscopy imaging. CrossRefGoogle Scholar
- 10.• Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47:2003–9. A study demonstrating the interesting relationship between dose of a drug and DILI. PubMedGoogle Scholar
- 12.Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the Liver 1978.Google Scholar
- 17.Young RSK. Reye’s syndrome associated with long-term aspirin therapy. JAMA J Am Med Assoc. 1984;251:754–6.Google Scholar
- 18•.. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM, Park Y, et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med. 1995;333:1099–105. This study reports acute fatty liver associated with high mortality rate, associated with an investigational drug, fialuridine, during phase 2 study. Interestingly, this manifestation of hepatotoxicity was not seen during prior pilot studies where the drug was used at shorter intervals. PubMedGoogle Scholar
- 19.• Lewis JH, Ranard RC, Caruso A, Jackson LK, Mullick F, Ishak KG, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology. 1989;9:679–85. A prospective study to characterize liver toxicity in 104 individuals who received amiodarone in the long term. PubMedGoogle Scholar
- 25.Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin N Am. 1997;23:739–55.Google Scholar
- 26.Baggott JE, Vaughn WH, Hudson BB. Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5′-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem J. 1986;236:193–200.PubMedPubMedCentralGoogle Scholar
- 27.Dolezalová P, Krijt J, Chládek J, Nemcová D, Hoza J. Adenosine and methotrexate polyglutamate concentrations in patients with juvenile arthritis. Rheumatol Oxf Engl. 2005;44:74–9.Google Scholar
- 30.Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013:CD000951.Google Scholar
- 34.• Stewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, et al. Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010;52:1791–6. In this study, POLG variant was shown to be associated with valproate toxicity. PubMedPubMedCentralGoogle Scholar
- 35.Eadie MJ, Hooper WD, Dickinson RG. Valproate-associated hepatotoxicity and its biochemical mechanisms. Med Toxicol. 1988;3:85–106.Google Scholar
- 36.Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet Lond. Engl. 1984;1:689.Google Scholar
- 41.Raal FJ, Santos RD, Blom DJ, Marais AD, Charng M-J, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2010;375:998–1006.Google Scholar
- 42.Li N, Li Q, Tian X-Q, Qian H-Y, Yang Y-J. Mipomersen is a promising therapy in the management of hypercholesterolemia: a meta-analysis of randomized controlled trials. Am J Cardiovasc Drugs Drugs Devices Interv. 2014;14:367–76.Google Scholar
- 45.Burnett J, Bell, Hooper, Watts. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia. Vasc Health Risk Manag 2012;651.Google Scholar
- 48.JUXTAPID (lomitapide) Risk Evaluation and Mitigation Strategy (REMS) Program [Internet]. Available from: https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM361072.pdf
- 50.Gurzu S, Jung I, Comsulea M, Kadar Z, Azamfirei L, Molnar C. Lethal cardiotoxicity, steatohepatitis, chronic pancreatitis, and acute enteritis induced by capecitabine and oxaliplatin in a 36-year-old woman. Diagn. Pathol. [Internet]. 2013 [cited 2018 Apr 25]; 8. Available from: http://diagnosticpathology.biomedcentral.com/articles/10.1186/1746-1596-8-150
- 57.• Sahini N, Selvaraj S, Borlak J. Whole genome transcript profiling of drug induced steatosis in rats reveals a gene signature predictive of outcome. PLoS One. 2014;9:e114085. Study using whole genome transcription of rat models with DIFLD to identify differentially expressed genes to predict DIFLD. PubMedPubMedCentralGoogle Scholar
- 62.Pessayre D, Mansouri A, Berson A, Fromenty B. Mitochondrial involvement in drug-induced liver injury. Handb Exp Pharmacol. 2010:311–65.Google Scholar
- 70.Estrada V, Serrano-Ríos M, Martínez Larrad MT, Villar NGP, González López A, Téllez MJ, et al. Leptin and adipose tissue maldistribution in HIV-infected male patients with predominant fat loss treated with antiretroviral therapy. J Acquir Immune Defic Syndr 1999. 2002;29:32–40.Google Scholar
- 71.Schilling C, Gilles M, Blum WF, Daseking E, Colla M, Weber-Hamann B, et al. Leptin plasma concentrations increase during antidepressant treatment with amitriptyline and mirtazapine, but not paroxetine and venlafaxine: leptin resistance mediated by antihistaminergic activity? J Clin Psychopharmacol. 2013;33:99–103.PubMedGoogle Scholar
- 72.• Domecq JP, Prutsky G, Leppin A, Sonbol MB, Altayar O, Undavalli C, et al. Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100:363–70. Meta-analysis provides a comprehensive list of drugs that cause either weight gain or weight loss. PubMedPubMedCentralGoogle Scholar
- 76.Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatol. Baltim. Md. 2010;51:1209–17.Google Scholar
- 78.•• Guzman CB, Duvvuru S, Akkari A, Bhatnagar P, Battioui C, Foster W, et al. Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist. Hepatol Commun. 2018;2:561–70. In this study, authors resourcefully conducted target gene approach of selected variants among diabetic subjects treated with glucagon receptor antagonists in two phase 2 trials, identifying a significant association of PNPL3 and TM6SF2 with drug-induced fatty liver. PubMedPubMedCentralGoogle Scholar
- 83.Lewis JH, Ranard RC, Caruso A, Jackson LK, Mullick F, Ishak KG, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatol Baltim Md. 1989;9:679–85.Google Scholar
- 90.Huang C-C, Hsu P-C, Hung Y-C, Liao Y-F, Liu C-C, Hour C-T, et al. Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis Int J Program Cell Death. 2005;10:895–907.Google Scholar
- 91.Tabassum H, Parvez S, Pasha ST, Banerjee BD, Raisuddin S. Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2010;48:1973–9.Google Scholar