Current Papers in Liver Disease - July, 1998

By Howard J. Worman, M. D.
Columbia University

This is a past issue of Current Papers in Liver Disease.

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Imai, T., Kawata, S., Tamura, S., Yabuuchi, I., Noda, S., Inada, M., Maeda, Y., Shirai, Y., Fukuzaki, T., Kaji, I., Ishikawa, H., Matsuda, Y., Nishikawa, M., Seki, K., and Matsuzawa, Y., for the Osaka Hepatocellular Carcinoma Prevention Study Group. 1998. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Annals of Internal Medicine. 129:94-99.

In 1995, Nishiguchi et al. reported that interferon treatment reduced the risk of developing hepatocellular carcinoma [primary liver cancer] in patients with cirrhosis and hepatitis C (Nishiguchi et al. 1995. Lancet. 277:570-574; See February, 1996 Current Papers in Liver Disease). And in 1998, Kasahara et al. reported that patients with hepatitis C who did not respond to treatment with interferon were at increased risk for the development of hepatocellular carcinoma (Kasahara et al. 1998. Hepatology. 27:1394-1402; See May, 1998 Current Papers in Liver Diseases). In this retrospective study, Imai et al. followed 419 patients with chronic hepatitis C who received interferon (either human lymphoblastoid, recombinant alpha-2a or recombinant alpha-2b) and 144 who did not for the development of hepatocellular carcinoma. Patients were followed for approximately 47 months. During follow-up, hepatocellular carcinoma was detected in 28 interferon-treated subjects and 19 who did not receive interferon. The risk ratio for the development of cancer was lower in individuals who had sustained responses (normal serum alanine aminotransferase activity after treatment) to interferon than in those who did not. Although it is always important to be cautious in interpreting retrospective studies, these results, along with those of the other two studies mentioned above, suggest that response to treatment with interferon alpha may decrease the risk of developing hepatocellular carcinoma in individuals with chronic hepatitis C.

Lai, C.-L., Chien, R.-N., Leung, N. W. Y., Chang, T.-T., Guan, R., Tai, D.-I., Ng, K.-Y., Wu, P.-C., Dent, J. C., Barber, J., Stephenson, S. L., and Gray, D. F. for the Asia Hepatitis Lamivudine Study Group. 1998. A one-year trial of lamivudine for chronic hepatitis B. New England Journal of Medicine. 339:61-68.

Lamivudine (2'-deoxy-3'-thiacytidine, 3TC) is effective in reducing the viral loads of hepatitis B virus and human immunodeficiency virus in infected individuals. This paper reports a trial of lamivudine in 358 Chinese patients with chronic hepatitis B and detectable serum hepatitis Be antigen (HBeAg). Patients were randomized to receive either 25 mg of lamivudine a day (142 patients), 100 mg of lamivudine a day (143 patients) or placebo. The patients underwent liver biopsies before entering the study and at the end of one year of treatment. Liver necroinflammatory activity on biopsy, measured by a system known as the Knodell score, improved by at least 2 points in 56% of patients receiving 100 mg of lamivudine, 49% receiving 25 mg of lamivudine and only 25% of those receiving placebo (P < 0.001 and P = 0.001, respectively compared to placebo). Of those receiving placebo, 32% had worsening biopsy findings after one year compared to 10% receiving 25 mg and 7% receiving 100 mg of lamivudine daily. The proportion of patients with worsening liver fibrosis was significantly lower in the group receiving 100 mg of lamivudine than in the placebo group (P = 0.01). The rate of losing serum HBeAg was 16% in the group receiving 100 mg lamivudine compared to 4% in the placebo group (P = 0.02). Fourteen percent of patients treated with lamivudine developed viral strains resistant to the drug, but this was not associated with a decrease in histological response. The rate of sustaining a normalization of serum alanine aminotransferase activity was also highest in the group receiving 100 mg of lamivudine. The incidence of adverse events was similar in all groups and 96% of patients completed the study. These results demonstrate that many patients with chronic hepatitis B (with serum HBeAg), in this case difficult-to-treat Chinese subjects who were likely infected at or near birth, have improved histological findings on liver biopsy after one year of treatment with lamivudine. Lamivudine treatment is well-tolerated and several patients also lose serum HBeAg, which is associated with an improved long-term prognosis.

Gitlin, N., Julie, N. L., Spurr, C. L., Lim, K. N., and Juarbe, H. M. 1998. Two cases of severe clinical and histological hepatotoxicity associated with troglitazone. Annals of Internal Medicine. 129:36-36.

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Neuschwander-Tetri, B., A., Isley, W. L., Oki, J. C., Ramrakhiani, S., Quiason, S. G., Phillips, N. J., and Brunt, E. M. 1998. Troglitazone-induced hepatic failure leading to liver transplantation. A case report. Annals of Internal Medicine. 129:38-41.

Troglitazone is a relatively new oral agent approved for the treatment of type 2 diabetes mellitus. In clinical trials, less than 2% of subjects with diabetes mellitus treated with troglitazone developed biochemical evidence of liver inflammation or cell damage that resolved when stopping the medication. After approval, there have been scattered reports of liver transplantation and death from liver failure in patients taking troglitazone. These two papers in the Annals of Internal Medicine describe three case reports of individuals who developed liver toxicity while taking troglitazone. The two patients reported by Gitlin et al. were concurrently taking other medications but symptoms of liver disease resolved after stopping troglitazone. The patient described by Neuschwander-Tetri et al. developed severe liver failure and underwent orthotopic liver transplantation. This patient developed nausea, vomiting and dark urine after taking troglitazone for less than two months, however, did not report these symptoms to her doctor and continued taking the medication. As with all case reports, caution must be used when attributing liver injury to a specific drug. In prospective clinical trials of troglitazone, liver chemistry abnormalities were noted in less than 2% of patients but liver failure was not observed. These case reports suggest that although liver failure while taking troglitazone is rare, patients taking this medication should be monitored as recommended for possible liver problems.

Baumert, T. F., Ito, S., Wong, D. T.,and Liang, T. J. 1998. Hepatitis C virus structural proteins assemble into viruslike particles in insect cells. Journal of Virology. 72:3827-3839.

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Moradpour, D., Kary, P., Rice, C. M., and Blum, H. E. 1998. Continuous human cell lines inducibly expressing hepatitis C virus structural and nonstructural proteins. Hepatology. 28:192-201.

A major limitation in the study of the hepatitis C virus (HCV) is that an efficient cell culture has not been developed. For this reason, little is know about how HCV infects and harms liver cells. In addition, there are no simple ways to initially test novel antiviral drugs. These two papers report on the development of new model systems to study HCV. Baumert et al. used recombinant baculovirus to express HCV structural proteins in insect cells. The expressed structural proteins assembled into enveloped viruslike particles that had physical properties similar to those of putative virions isolated from infected humans. These viruslike particles selectively incorporated HCV RNA over non-viral cellular RNAs. Moradpour et al. report on the establishment of cell lines permanently transfected with full-length HCV transgenes that inducibly express viral structural and nonstructural proteins. They examined the intracellular localization of various HCV proteins and also demonstrated that high-level expression of HCV proteins was toxic to cells. These models, along with one showing transmission of hepatitis C by intrahepatic inoculation with transcribed RNA (Kolykhalov et al. 1997. Science. 277:570-574; See September, 1997 Current Papers in Liver Disease), should prove useful for future studies on HCV as well as for the testing of novel therapeutic agents.

Howard, M. J., Fuller, C., Broadhurst, R. W., Perham, R. N., Tang, J.-G., Quinn, J., Diamond, A. G., and Yeaman, S. J. 1998. Three-dimensional structure of the major autoantigen in primary biliary cirrhosis. Gastroenterology. 115:139-146.

Approximately 95% of individuals with primary biliary cirrhosis (PBC) have autoantibodies directed against the E2 subunit of the pyruvate dehydrogenase enzyme complex of the mitochondria (so-called antimitochondrial antibodies). Antibodies of this specificity are highly specific for PBC. These antibodies have been shown to recognize a portion of the E2 subunit called the inner lipoyl domain. In this paper, the authors use nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure of the inner lipoyl domain of the E2 subunit of the human pyruvate dehydrogenase complex. Three dimensional structures of bacterial lipoyl domains have already been determined and are similar. Although nothing highly information is immediately obvious from this published structure, studies such as this one may ultimately provide insights into the autoimmune response in PBC.

Copyright, 1998, Howard J. Worman, M. D. All rights reserved. Printing or other reproduction is prohibited without the written authorization of Howard J. Worman.