Drug-Induced Hepatic Steatosis

 

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Abstract

Several drugs have been associated with the potential for drug-induced hepatic steatosis (DIHS) and/or phospholipidosis (DIPL), a lysosomal storage disorder. Drug-induced hepatic steatosis is generally a chronic but reversible affliction and may involve drug accumulation in the liver. Fat accumulation may be either macrovesicular or microvesicular in nature. Commonly used medications associated with DIHS include amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents. Two recently approved medications for the treatment of hereditary homozygous hypercholesterolemia have also been noted to cause hepatic steatosis. For some compounds such as methotrexate and tamoxifen, the underlying metabolic risk factors such as obesity and metabolic syndrome may exacerbate their potential to cause DIHS and its progression. In this article, the authors discuss the preclinical screening and mechanisms of DIHS and DIPL, and review specific examples of drugs commonly used in clinical practice that are known to cause DIHS.

• References

• 1 Hoyumpa Jr AM, Greene HL, Dunn GD, Schenker S. Fatty liver: biochemical and clinical considerations. Am J Dig Dis 1975; 20 (12) 1142-1170
  CrossrefPubMedGoogle Scholar
• 2 Kleiner DE, Brunt EM, Van Natta M , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (6) 1313-1321
  CrossrefPubMedGoogle Scholar
• 3 Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 2007; 46 (2) 582-589
  CrossrefPubMedGoogle Scholar
• 4 Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003; 37 (5) 1202-1219
  CrossrefPubMedGoogle Scholar
• 5 Levene AP, Kudo H, Thursz MR, Anstee QM, Goldin RD. Is oil red-O staining and digital image analysis the gold standard for quantifying steatosis in the liver?. Hepatology 2010; 51 (5) 1859 , author reply 1859–1860
  PubMedGoogle Scholar
• 6 Bellentani S, Saccoccio G, Masutti F , et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132 (2) 112-117
  PubMedGoogle Scholar
• 7 Gupte P, Amarapurkar D, Agal S , et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol 2004; 19 (8) 854-858
  CrossrefPubMedGoogle Scholar
• 8 Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55 (7) 434-438
  PubMedGoogle Scholar
• 9 Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 2001; 21 (1) 3-16
  Article in Thieme ConnectPubMedGoogle Scholar
• 10 Aravinthan A, Scarpini C, Tachtatzis P , et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol 2013; 58 (3) 549-556
  CrossrefPubMedGoogle Scholar
• 11 Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997; 126 (2) 137-145
  CrossrefPubMedGoogle Scholar
• 12 Gentile CL, Pagliassotti MJ. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem 2008; 19 (9) 567-576
  CrossrefPubMedGoogle Scholar
• 13 Chavez-Tapia NC, Rosso N, Tiribelli C. Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease. BMC Gastroenterol 2012; 12: 20
  CrossrefPubMedGoogle Scholar
• 14 Musso G, Gambino R, Cassader M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog Lipid Res 2013; 52 (1) 175-191
  CrossrefPubMedGoogle Scholar
• 15 Ioannou GN, Haigh WG, Thorning D, Savard C. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J Lipid Res 2013; 54 (5) 1326-1334
  CrossrefPubMedGoogle Scholar
• 16 Buechler C, Weiss TS. Does hepatic steatosis affect drug metabolizing enzymes in the liver?. Curr Drug Metab 2011; 12 (1) 24-34
  CrossrefPubMedGoogle Scholar
• 17 Gómez-Lechón MJ, Jover R, Donato MT. Cytochrome p450 and steatosis. Curr Drug Metab 2009; 10 (7) 692-699
  CrossrefPubMedGoogle Scholar
• 18 McKenzie R, Fried MW, Sallie R , 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 (17) 1099-1105
  CrossrefPubMedGoogle Scholar
• 19 Kleiner DE, Gaffey MJ, Sallie R , et al. Histopathologic changes associated with fialuridine hepatotoxicity. Mod Pathol 1997; 10 (3) 192-199
  PubMedGoogle Scholar
• 20 Honkoop P, Scholte HR, de Man RA, Schalm SW. Mitochondrial injury. Lessons from the fialuridine trial. Drug Saf 1997; 17 (1) 1-7
  CrossrefPubMedGoogle Scholar
• 21 Lai Y, Tse CM, Unadkat JD. Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs. J Biol Chem 2004; 279 (6) 4490-4497
  PubMedGoogle Scholar
• 22 Donato MT, Martínez-Romero A, Jiménez N , et al. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem Biol Interact 2009; 181 (3) 417-423
  CrossrefPubMedGoogle Scholar
• 23 Fujimura H, Murakami N, Kurabe M, Toriumi W. In vitro assay for drug-induced hepatosteatosis using rat primary hepatocytes, a fluorescent lipid analog and gene expression analysis. J Appl Toxicol 2009; 29 (4) 356-363
  CrossrefPubMedGoogle Scholar
• 24 Amacher DE, Martin BA. Tetracycline-induced steatosis in primary canine hepatocyte cultures. Fundam Appl Toxicol 1997; 40 (2) 256-263
  CrossrefPubMedGoogle Scholar
• 25 Barone LR, Boyer S, Damewood Jr JR, Fikes J, Ciaccio PJ. Phospholipogenic pharmaceuticals are associated with a higher incidence of histological findings than nonphospholipogenic pharmaceuticals in preclinical toxicology studies. J Toxicol 2012; (2012) : Article ID 308594
  PubMedGoogle Scholar
• 26 Hanumegowda UM, Wenke G, Regueiro-Ren A, Yordanova R, Corradi JP, Adams SP. Phospholipidosis as a function of basicity, lipophilicity, and volume of distribution of compounds. Chem Res Toxicol 2010; 23 (4) 749-755
  CrossrefPubMedGoogle Scholar
• 27 Reasor MJ, Hastings KL, Ulrich RG. Drug-induced phospholipidosis: issues and future directions. Expert Opin Drug Saf 2006; 5 (4) 567-583
  CrossrefPubMedGoogle Scholar
• 28 Kodavanti UP, Mehendale HM. Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol Rev 1990; 42 (4) 327-354
  PubMedGoogle Scholar
• 29 Muehlbacher M, Tripal P, Roas F, Kornhuber J. Identification of drugs inducing phospholipidosis by novel in vitro data. ChemMedChem 2012; 7 (11) 1925-1934
  CrossrefPubMedGoogle Scholar
• 30 Choi SS, Kim JS, Valerio Jr LG, Sadrieh N. In silico modeling to predict drug-induced phospholipidosis. Toxicol Appl Pharmacol 2013; 269 (2) 195-204
  CrossrefPubMedGoogle Scholar
• 31 Rao MS, Reddy JK. Peroxisomal beta-oxidation and steatohepatitis. Semin Liver Dis 2001; 21 (1) 43-55
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Okumura T. Role of lipid droplet proteins in liver steatosis. J Physiol Biochem 2011; 67 (4) 629-636
  CrossrefPubMedGoogle Scholar
• 33 Straub BK, Stoeffel P, Heid H, Zimbelmann R, Schirmacher P. Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology 2008; 47 (6) 1936-1946
  CrossrefPubMedGoogle Scholar
• 34 Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 2008; 22 (4) 335-353
  CrossrefPubMedGoogle Scholar
• 35 Kawano Y, Nishiumi S, Tanaka S , et al. Activation of the aryl hydrocarbon receptor induces hepatic steatosis via the upregulation of fatty acid transport. Arch Biochem Biophys 2010; 504 (2) 221-227
  CrossrefPubMedGoogle Scholar
• 36 Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114 (2) 147-152
  CrossrefPubMedGoogle Scholar
• 37 Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol 2011; 54 (4) 773-794
  CrossrefPubMedGoogle Scholar
• 38 Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ 2005; 172 (7) 899-905
  CrossrefPubMedGoogle Scholar
• 39 Ishak KG, Zimmerman HJ, Ray MB. Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. Alcohol Clin Exp Res 1991; 15 (1) 45-66
  CrossrefPubMedGoogle Scholar
• 40 Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci 2002; 65 (2) 166-176
  CrossrefPubMedGoogle Scholar
• 41 Jolly RA, Ciurlionis R, Morfitt D , et al. Microvesicular steatosis induced by a short chain fatty acid: effects on mitochondrial function and correlation with gene expression. Toxicol Pathol 2004; 32 (Suppl. 02) 19-25
  CrossrefPubMedGoogle Scholar
• 42 Grieco A, Forgione A, Miele L , et al. Fatty liver and drugs. Eur Rev Med Pharmacol Sci 2005; 9 (5) 261-263
  PubMedGoogle Scholar
• 43 Mattar W, Juliar B, Gradus-Pizlo I, Kwo PY. Amiodarone hepatotoxicity in the context of the metabolic syndrome and right-sided heart failure. J Gastrointestin Liver Dis 2009; 18 (4) 419-423
  PubMedGoogle Scholar
• 44 Kneeman JM, Misdraji J, Corey KE. Secondary causes of nonalcoholic fatty liver disease. Therap Adv Gastroenterol 2012; 5 (3) 199-207
  CrossrefPubMedGoogle Scholar
• 45 Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2003; 2 (3) 205-213
  CrossrefPubMedGoogle Scholar
• 46 Saphner T, Triest-Robertson S, Li H, Holzman P. The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer. Cancer 2009; 115 (14) 3189-3195
  CrossrefPubMedGoogle Scholar
• 47 Nguyen MC, Stewart RB, Banerji MA, Gordon DH, Kral JG. Relationships between tamoxifen use, liver fat and body fat distribution in women with breast cancer. Int J Obes Relat Metab Disord 2001; 25 (2) 296-298
  CrossrefPubMedGoogle Scholar
• 48 Bruno S, Maisonneuve P, Castellana P , et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005; 330 (7497) 932
  CrossrefPubMedGoogle Scholar
• 49 Larosche I, Lettéron P, Fromenty B , et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther 2007; 321 (2) 526-535
  CrossrefPubMedGoogle Scholar
• 50 Lelliott CJ, López M, Curtis RK , et al. Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. FASEB J 2005; 19 (9) 1108-1119
  CrossrefPubMedGoogle Scholar
• 51 Ohnishi T, Ogawa Y, Saibara T , et al. CYP17 polymorphism and tamoxifen-induced hepatic steatosis. Hepatol Res 2005; 33 (2) 178-180
  CrossrefPubMedGoogle Scholar
• 52 Lindsay K, Gough A. Psoriatic arthritis, methotrexate and the liver—are rheumatologists putting their patients at risk?. Rheumatology (Oxford) 2008; 47 (7) 939-941
  CrossrefPubMedGoogle Scholar
• 53 Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol Hepatol 2001; 16 (12) 1395-1401
  CrossrefPubMedGoogle Scholar
• 54 Aithal GP, Haugk B, Das S, Card T, Burt AD, Record CO. Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified?. Aliment Pharmacol Ther 2004; 19 (4) 391-399
  CrossrefPubMedGoogle Scholar
• 55 Luef GJ, Waldmann M, Sturm W , et al. Valproate therapy and nonalcoholic fatty liver disease. Ann Neurol 2004; 55 (5) 729-732
  CrossrefPubMedGoogle Scholar
• 56 Luef G, Rauchenzauner M, Waldmann M , et al. Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment. Epilepsy Res 2009; 86 (1) 42-47
  CrossrefPubMedGoogle Scholar
• 57 Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid—1988. Clin Pharmacokinet 1988; 15 (6) 367-389
  CrossrefPubMedGoogle Scholar
• 58 Knapp AC, Todesco L, Beier K , et al. Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores. J Pharmacol Exp Ther 2008; 324 (2) 568-575
  PubMedGoogle Scholar
• 59 Aires CC, Ijlst L, Stet F , et al. Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis. Biochem Pharmacol 2010; 79 (5) 792-799
  CrossrefPubMedGoogle Scholar
• 60 Cuchel M, Bloedon LT, Szapary PO , et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007; 356 (2) 148-156
  CrossrefPubMedGoogle Scholar
• 61 Bell DA, Hooper AJ, Watts GF, Burnett JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia. Vasc Health Risk Manag 2012; 8: 651-659
  PubMedGoogle Scholar
• 62 Gelsinger C, Steinhagen-Thiessen E, Kassner U. Therapeutic potential of mipomersen in the management of familial hypercholesterolaemia. Drugs 2012; 72 (11) 1445-1455
  CrossrefPubMedGoogle Scholar
• 63 McGowan MP, Tardif JC, Ceska R , et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS ONE 2012; 7 (11) e49006
  CrossrefPubMedGoogle Scholar
• 64 Visser ME, Wagener G, Baker BF , et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J 2012; 33 (9) 1142-1149
  CrossrefPubMedGoogle Scholar
• 65 Sahebkar A, Watts GF. New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin Ther 2013; 35 (8) 1082-1098
  CrossrefPubMedGoogle Scholar
• 66 Cuchel M, Meagher EA, du Toit Theron H , et al; Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381 (9860) 40-46
  CrossrefPubMedGoogle Scholar
• 67 Montessori V, Press N, Harris M, Akagi L, Montaner JS. Adverse effects of antiretroviral therapy for HIV infection. CMAJ 2004; 170 (2) 229-238
  PubMedGoogle Scholar
• 68 Sulkowski MS, Mehta SH, Torbenson M , et al. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS 2005; 19 (6) 585-592
  CrossrefPubMedGoogle Scholar
• 69 Chariot P, Drogou I, de Lacroix-Szmania I , et al. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol 1999; 30 (1) 156-160
  CrossrefPubMedGoogle Scholar
• 70 Banerjee A, Abdelmegeed MA, Jang S, Song BJ. Zidovudine (AZT) and hepatic lipid accumulation: implication of inflammation, oxidative and endoplasmic reticulum stress mediators. PLoS ONE 2013; 8 (10) e76850
  CrossrefPubMedGoogle Scholar
• 71 Cindoruk M, Karakan T, Unal S. Hepatic steatosis has no impact on the outcome of treatment in patients with chronic hepatitis B infection. J Clin Gastroenterol 2007; 41 (5) 513-517
  CrossrefPubMedGoogle Scholar
• 72 Bani-Sadr F, Carrat F, Bedossa P , et al; ANRS HC02 - Ribavic Study team. Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors. AIDS 2006; 20 (4) 525-531
  CrossrefPubMedGoogle Scholar
• 73 Borghi V, Bisi L, Manzini L, Cossarizza A, Mussini C. Absence of liver steatosis in HIV-HCV co-infected patients receiving regimens containing tenofovir or abacavir. Infection 2013; 41 (2) 425-429
  CrossrefPubMedGoogle Scholar
• 74 Martinez V, Ta TD, Mokhtari Z , et al. Hepatic steatosis in HIV-HCV coinfected patients receiving antiretroviral therapy is associated with HCV-related factors but not antiretrovirals. BMC Res Notes 2012; 5: 180
  CrossrefPubMedGoogle Scholar
• 75 Miyake K, Hayakawa K, Nishino M, Morimoto T, Mukaihara S. Effects of oral 5-fluorouracil drugs on hepatic fat content in patients with colon cancer. Acad Radiol 2005; 12 (6) 722-727
  CrossrefPubMedGoogle Scholar
• 76 Aloia T, Sebagh M, Plasse M , et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006; 24 (31) 4983-4990
  CrossrefPubMedGoogle Scholar
• 77 Wolf PS, Park JO, Bao F , et al. Preoperative chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience. J Am Coll Surg 2013; 216 (1) 41-49
  CrossrefPubMedGoogle Scholar
• 78 Pilgrim CH, Satgunaseelan L, Pham A , et al. Correlations between histopathological diagnosis of chemotherapy-induced hepatic injury, clinical features, and perioperative morbidity. HPB (Oxford) 2012; 14 (5) 333-340
  CrossrefPubMedGoogle Scholar
• 79 Raman M, Allard J. Non alcoholic fatty liver disease: a clinical approach and review. Can J Gastroenterol 2006; 20 (5) 345-349
  PubMedGoogle Scholar
• 80 Anthérieu S, Rogue A, Fromenty B, Guillouzo A, Robin MA. Induction of vesicular steatosis by amiodarone and tetracycline is associated with up-regulation of lipogenic genes in HepaRG cells. Hepatology 2011; 53 (6) 1895-1905
  CrossrefPubMedGoogle Scholar
• 81 Khan AZ, Morris-Stiff G, Makuuchi M. Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases. J Hepatobiliary Pancreat Surg 2009; 16 (2) 137-144
  CrossrefPubMedGoogle Scholar
• 82 Maor Y, Malnick S. Liver injury induced by anticancer chemotherapy and radiation therapy. Int J Hepatol 2013; 2013; : Article ID 815105
  PubMedGoogle Scholar
• 83 Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009; 62 (6) 481-492
  CrossrefPubMedGoogle Scholar