Hepatology


Rarely, rosiglitazone and pioglitazone have been reported to cause hepatotoxicity, including cases of hepatic failure.133–137 sulfonylureas, glimepiride is associated with cholestatic DILI.138–140


Lipid-lowering Agents


Statins induce a reversible, dose-dependent rise in aminotransferase levels and very rarely result in liver failure.2,141,142


beginning and during statin therapy is under debate.143,144


Monitoring the liver tests at the Autoimmune-like


hepatitis has been reported in several cases and may be correlated with HLA-DR3, DR4, or DR5.145–148


Interestingly, HCV infection did not significantly increase aminotransferase levels during statin treatment.149,150


Ezetimibe (which inhibits the intestinal absorbtion of cholesterol) was initially reported to be safe.151–153


shown to induce cholestatic DILI or an autoimmune-like hepatitis when employed alone or in combination with a simvastatin.154


Among


loss product containing norephedrine, caffeine, yohimbine, diiodothyronine and sodium usniate, leading to its withdrawal from the US market in 2001.161,162


Chinese herbal medicines comprised of multiple


compounds have been shown to result in liver injury; for example, Dai- Saiko-To and Sho-Saiko-To can induce acute hepatitis.163–165


Conclusions However, ezetimibe was recently Despite these


associations, statins can often be safely used in patients with chronic liver disease.


Herbal or Traditional Remedies


Herbal remedies are widely used for a multitude of purposes and evidence about their hepatotoxicity is accumulating.155


of herbal products has been consistently rising, no regulatory guidelines or standards are issued for their composition.156,157


Although the use These factors make it


difficult to clearly establish their hepatic toxicities. A notable case of herbal toxicity is reported for Herbalife® products. Interestingly, Herbalife ingestion has resulted in different patterns of liver injury including one case of fulminant hepatic failure.158


Further research


revealed that contamination with Bacillus subtilis was thought to be responsible for the liver toxicity of Herbalife.159


Surprisingly, Spirulina,


taken for its broad range of protective effects, was also recorded as the culprit for one case of DILI.160


Several other more common examples of liver injury due to herbal compounds are provided in Table 3. Further complicating the identification of individual toxic components, alternative medicine frequently employs mixtures of several components. For example, acute hepatitis and liver failure were reported for LipoKinetix, a weight


1. Smith DA, et al., Drug withdrawals and the lessons within, Curr Opin Drug Discov Devel, 2006;9:38–46.


2.


Ostapowicz G, et al., Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States, Ann Intern Med, 2002;137:947–54.


3. Erlinger S, Drug-induced cholestasis, J Hepatol, 1997;26(Suppl 1):1–4.


4. 5.


Alazmi WM, et al., Chemotherapy-induced sclerosing cholangitis: long-term response to endoscopic therapy, J Clin Gastroenterol, 2006;40:353–7.


Sandrasegaran K, et al., Chemotherapy-induced sclerosing cholangitis, Clin Radiol, 2006;61:670–8.


6. Chitturi S, et al., Drug-induced cholestasis, Semin Gastrointest Dis, 2001;12:113–24.


7. Lammert C, et al., Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events, Hepatology, 2010;51:615-20.


9.


8. Antoine DJ, et al., Understanding the role of reactive metabolites in drug-induced hepatotoxicity: state of the science, Expert Opin Drug Metab Toxicol, 2008;4:1415–27. Park BK, et al., The role of metabolic activation in drug-


James P Hamilton, MD, is an Assistant Professor of medicine in the Division of Gastroenterology and Hepatology at Johns Hopkins University School of Medicine. His clinical specialties include liver transplantation, hepatocellular carcinoma, and acute and chronic viral, alcoholic, non-alcoholic, autoimmune, and cholestatic liver disease. His research interests are the molecular genetics of liver fibrosis and hepatocellular carcinoma and early detection biomarkers for these diseases. Dr. Hamilton


attended medical school at the University of Maryland in Baltimore, MD. He completed a residency in internal medicine at Northwestern University in Chicago, IL, and returned to the University of Maryland for a Fellowship in gastroenterology and hepatology. He then completed a Fellowship in advanced hepatology at The Johns Hopkins Hospital in Baltimore.


Stefan David, MD, is Research Fellow at Johns Hopkins School of Medicine, Department of Gastroenterology. He received his MD from the Carol Davila University in Romania. His current research focuses on identifying perturbed mechanisms controlling cell proliferation, differentiation migration and death that can be used as biomarkers for predicting gastrointestinal neoplastic disease. Dr David presented his results at international scientific meetings (FASEB, AACR, DDW) and published in the area of neurodegeneration and GI tract carcinogenesis.


Hepatotoxicity is a potential complication of nearly all classes of medication. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or fulminant hepatic failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Treatment of drug- and herbal-induced liver injury consists of rapid drug discontinuation and supportive care targeted to alleviate unwanted symptoms. n


induced hepatotoxicity, Annu Rev Pharmacol Toxicol, 2005;45:177–202.


10. Wu D, et al., Oxidative stress and alcoholic liver disease, Semin Liver Dis, 2009;29:141–54.


11. Zimmerman HJ, et al., Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure, Hepatology, 1995;22:767–73.


12. Berson A, et al., Uncoupling of rat and human mitochondria: a possible explanation for tacrine-induced liver dysfunction, Gastroenterology, 1996;110:1878–90.


13. Fromenty B, et al., Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity, Pharmacol Ther, 1995;67:101–54.


14. Setzer B, et al., Pyrimidine nucleoside depletion sensitizes to the mitochondrial hepatotoxicity of the reverse transcriptase inhibitor stavudine, Am J Pathol, 2008;172:681–90.


15. Lee AU, et al., Mechanism of azathioprine-induced injury to hepatocytes: roles of glutathione depletion and mitochondrial injury, J Hepatol, 2001;35:756–64.


16. Leist M, et al., Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis, J Exp Med, 1997;185:1481–6.


17. Njoku DB, et al., Autoantibodies associated with volatile anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists, Anesth Analg, 2002;94:243–9.


18. Holt MP, et al., Mechanisms of drug-induced liver injury, Aaps J, 2006;8:E48–54.


19. Liu ZX, et al., Immune-mediated drug-induced liver disease, Clin Liver Dis, 2002;6:755–74.


20. Lucena MI, et al., Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex, Hepatology, 2009;49:2001–9.


21. Russo MW, et al., Liver transplantation for acute liver failure from drug induced liver injury in the United States, Liver Transpl, 2004;10:1018–23.


22. Lee BH, et al., Inactive hepatitis B surface antigen carrier state and hepatotoxicity during antituberculosis chemotherapy, Chest, 2005;127:1304–11.


23. Seeff LB, et al., Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure, Ann Intern Med,


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