Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation

Sony Tuteja, Nikolaos T. Pyrsopoulos, William R. Wolowich, Kamran Khanmoradi, David M. Levi, Gennaro Selvaggi, Geoffrey Weisbaum, Andreas G. Tzakis, Eugene R Schiff

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatin-ezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatin-ezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.

Original languageEnglish
Pages (from-to)1188-1193
Number of pages6
JournalPharmacotherapy
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2008
Externally publishedYes

Fingerprint

Simvastatin
Liver Failure
Liver Transplantation
Transaminases
Uridine Diphosphate
simvastatin acid
Serum
Ezetimibe
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Citalopram
Hydroxy Acids
Acute Liver Failure
Liver
Drug-Related Side Effects and Adverse Reactions
Hispanic Americans
Intestines
Oxidoreductases
Lipids
Biopsy

Keywords

  • Adverse drug reactions
  • Drug-induced liver failure
  • Ezetimibe
  • Hepatic failure
  • Liver transplantation
  • Simvastatin

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation. / Tuteja, Sony; Pyrsopoulos, Nikolaos T.; Wolowich, William R.; Khanmoradi, Kamran; Levi, David M.; Selvaggi, Gennaro; Weisbaum, Geoffrey; Tzakis, Andreas G.; Schiff, Eugene R.

In: Pharmacotherapy, Vol. 28, No. 9, 01.09.2008, p. 1188-1193.

Research output: Contribution to journalArticle

Tuteja, S, Pyrsopoulos, NT, Wolowich, WR, Khanmoradi, K, Levi, DM, Selvaggi, G, Weisbaum, G, Tzakis, AG & Schiff, ER 2008, 'Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation', Pharmacotherapy, vol. 28, no. 9, pp. 1188-1193. https://doi.org/10.1592/phco.28.9.1188
Tuteja S, Pyrsopoulos NT, Wolowich WR, Khanmoradi K, Levi DM, Selvaggi G et al. Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation. Pharmacotherapy. 2008 Sep 1;28(9):1188-1193. https://doi.org/10.1592/phco.28.9.1188
Tuteja, Sony ; Pyrsopoulos, Nikolaos T. ; Wolowich, William R. ; Khanmoradi, Kamran ; Levi, David M. ; Selvaggi, Gennaro ; Weisbaum, Geoffrey ; Tzakis, Andreas G. ; Schiff, Eugene R. / Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation. In: Pharmacotherapy. 2008 ; Vol. 28, No. 9. pp. 1188-1193.
@article{7498336f9b964205931b999d9c5c7b43,
title = "Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation",
abstract = "Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatin-ezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatin-ezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.",
keywords = "Adverse drug reactions, Drug-induced liver failure, Ezetimibe, Hepatic failure, Liver transplantation, Simvastatin",
author = "Sony Tuteja and Pyrsopoulos, {Nikolaos T.} and Wolowich, {William R.} and Kamran Khanmoradi and Levi, {David M.} and Gennaro Selvaggi and Geoffrey Weisbaum and Tzakis, {Andreas G.} and Schiff, {Eugene R}",
year = "2008",
month = "9",
day = "1",
doi = "10.1592/phco.28.9.1188",
language = "English",
volume = "28",
pages = "1188--1193",
journal = "Pharmacotherapy",
issn = "0277-0008",
publisher = "Pharmacotherapy Publications Inc.",
number = "9",

}

TY - JOUR

T1 - Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation

AU - Tuteja, Sony

AU - Pyrsopoulos, Nikolaos T.

AU - Wolowich, William R.

AU - Khanmoradi, Kamran

AU - Levi, David M.

AU - Selvaggi, Gennaro

AU - Weisbaum, Geoffrey

AU - Tzakis, Andreas G.

AU - Schiff, Eugene R

PY - 2008/9/1

Y1 - 2008/9/1

N2 - Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatin-ezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatin-ezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.

AB - Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatin-ezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatin-ezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.

KW - Adverse drug reactions

KW - Drug-induced liver failure

KW - Ezetimibe

KW - Hepatic failure

KW - Liver transplantation

KW - Simvastatin

UR - http://www.scopus.com/inward/record.url?scp=51849089642&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=51849089642&partnerID=8YFLogxK

U2 - 10.1592/phco.28.9.1188

DO - 10.1592/phco.28.9.1188

M3 - Article

C2 - 18752389

AN - SCOPUS:51849089642

VL - 28

SP - 1188

EP - 1193

JO - Pharmacotherapy

JF - Pharmacotherapy

SN - 0277-0008

IS - 9

ER -