Current Papers in Liver Disease - April, 2000

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

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

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Farci, P., Shimoda, A., Coiana, A., Diaz, G., Peddis, G., Melpolder, J. C., Strazzera, A., Chien, D. Y., Munoz, S. J., Balestrieri, A., Purcell, R. H., and Alter, H. J. 2000. The outcome of acute hepatitis C predicted by the evolution of quasispecies. Science. 288:339-344.

About 85% of individuals infected with the hepatitis C virus (HCV) become chronically infected. In this study, Farci et al. analyzed changes in the HCV genome during the acute phase of infection in 12 patients with different clinical outcomes. Three patients had fulminant hepatic failure, three had self-limited hepatitis that resolved and six developed chronic infection. Progressive hepatitis that become chronic was associated with the evolution of a heterogeneous viral population (quasispecies) whereas resolving hepatitis was associated with relatively little change in the viral population. These results suggest that the evolutionary dynamics of HCV during the acute phase of infection plays a role in establishing whether or no infection will become chronic.

Nelson, D. R., Lauwers, G. Y., Lau, J. Y. N., and Davis, G. L. 2000. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology. 118:655-660.

Interleukin 10 (IL-10) is a naturally occurring human protein that down-regulates the inflammatory response and may alter fibrosis (scarring) in the liver. These investigators from the University of Florida and Schering-Plough (the manufacturer of recombinant IL-10) tested the effects of recombinant IL-10 in 24 patients with chronic hepatitis C who did not respond to previous treatment with interferon alpha or interferon alpha-2b plus ribavirin. Subjects received in 4 or 8 micrograms per kilogram of recombinant IL-10 daily by injection for 3 months. Liver biopsies were performed before and after treatment. Two subjects did not complete the study; the drug was well-tolerated in the other 22. Liver inflammation decreased in 19 of 22 subjects and liver fibrosis decreased in 14. Serum alanine aminotransferase activity became normal in 19 patients by the end of the study. Serum hepatitis C virus RNA concentrations did not change. The results of this pilot study suggest that IL-10 may decrease inflammation and scarring in the livers of subjects infected with the hepatitis C virus. Larger placebo-controlled studies of IL-10 are indicated.

Powell, E. E., Edwards-Smith, C. J., Hay, J. L., Clouston, A. D., Crawford, D. H., Shorthouse, C., Purdie, D. M., and Jonsson, J. R. 2000. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology. 31:828-833.

Subjects infected with the hepatitis C virus may have dramatically different clinical courses. In the some cases, the disease progresses to fibrosis (scarring), cirrhosis and ever liver cancer. In other cases, the infected individuals have minimal liver damage. Presumably, host genetic factors play a major role in determining how people respond to infection with the hepatitis C virus. For the most part, these host genetic factors are unknown. In this study, Powell et al. studied candidate genes that may be involved in fibrosis in 128 subjects with chronic hepatitis C. They detected a statistically significant relationship between the inheritance of high transforming growth factor beta 1 and angiotensinogen producing genotypes and the development of liver fibrosis. This is one of the first of what are likely to be many subsequent studies on the role of host genetic factors in the progression of hepatitis C. As the entire human genome is almost sequenced, large scale and rapid scanning of all human genes will someday be possible.

Shiratori, Y., Imazeki, F. Moriyama, M., Yano, M., Arakawa, Y., Yokosuka, O., Kuroki, T., Nishiguchi, S., Sata, M., Yamada, G., Fujiyama, S., Yoshida, H., and Omata, M. 2000. Histological improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Annals of Internal Medicine. 132:517-524.

Several studies have demonstrated that treatment with interferon alpha may decrease the progression of fibrosis (scarring) in the livers of subjects with chronic hepatitis C. In this retrospective study from Japan, 593 patients with hepatitis C underwent two liver biopsies between 1987 and 1997 and 487 received treatment with interferon alpha between the biopsies. Fibrosis and inflammation were assess in the liver biopsies. Of the interferon-treated patients, 183 had a sustained virological response (no detectable viral RNA in serum after treatment). Inflammatory activity did not change in most of the untreated patients but improved in 89% of treated subjects who had a sustained virological response. In untreated subjects, fibrosis progressed in 38% and regressed in only 5%. On the other hand, fibrosis regressed in 59% of patients who had a sustained virological response to interferon alpha. In treated patients who did not have a sustained virological response, fibrosis regressed in 19% and progressed in 24%. The results of this study suggest that subjects with chronic hepatitis C who have a sustained virological response to treatment with interferon alpha have favorable long-term improvements in liver inflammation and fibrosis.

Cavicchi, M., Beau, P., Crenn, P., Degott, C., and Messing, B. 2000. Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. Annals of Internal Medicine. 132:525-532.

Cholestasis (impaired bile flow) can be a serious complication of parenteral nutrition (intravenous feeding). The prevalence of serious liver disease in patients receiving home parenteral nutrition for intestinal failure is not known. In this study, 90 patients with permanent intestinal failure receiving home parenteral nutrition were followed. Of these, 58 (60%) developed chronic cholestasis after a median of 6 months. Thirty-seven (41.5%) developed severe liver disease. Six patients (22% of all deaths) died from liver failure. The prevalence of complicated liver disease increased with longer duration of parenteral nutrition. The results show that liver disease is a common complication of long-term parenteral nutrition and a frequent cause of death.

Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N., and DePinho, R. A. 2000. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science. 287:1253-1258.

Hepatocytes, the major cell type in the liver, have a tremendous capacity to regenerate. Cirrhosis is characterized by fibrosis and nodular regeneration of hepatocytes. After repeated rounds of cell division, however, hepatocytes lose their ability to proliferate and irreplaceable liver cell death and fibrosis occur. After many rounds of cell division, as occurs in cirrhosis, hepatocytes may no longer be able to divide because of severe shortening of telomeres, DNA sequences at the ends of chromosomes. Most human cells do not have telomerase, a protein-RNA complex essential for replacing telomeres. Rudolph et al. hypothesized that delivery of telomerase to hepatocytes may prevent cell death and inhibit cirrhosis. In contrast to humans, normal adult mice express telomerase in most cells. To test their hypothesis in a mouse model, these investigators used genetically modified mice that lack a component of telomerase. Sixth generation telomerase deficient mice were more susceptible to liver cell death and the development of cirrhosis in three different experimental models of liver damage. Replacement of the missing telomerase component by gene therapy led to a reversal of the increased susceptibility to hepatocyte death and the development of cirrhosis. These results suggest that gene therapy with telomerase may slow the progression of cirrhosis in humans. One possible complication of telomerase therapy is that it is active in many human cancers, suggesting that its expression in hepatocytes may lead to liver carcinoma. Another technical problem that remains to be overcome is the efficient delivery of all the components of telomerase to the patient.

Kobayashi, N., Fujiwara, T., Westerman, K. A., Inoue, Y., Sakaguchi, M., Noguchi, H., Miyazaki, M., Cai, J., Tanaka, N., Fox, I. J., and Leboulch, P. 2000. Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science. 287:1258-1262.

Transplantation of hepatocytes, the primary cells of the liver, has been proposed for the temporary support of patients with acute or chronic liver disease for whom a transplantable organ is not readily available. A major problem, however, is the inability to isolate an adequate number of human hepatocytes as they generally die after several rounds of division in culture. In this study, Kobayashi et al. genetically modified normal human hepatocytes to express the simian virus 40 T gene, a cancer gene that immortalizes cells. These genetically modified cells grew rapidly in culture, however, they could not be transplanted into animals as they are essentially cancer. To overcome this problem, Kobayashi and collaborators inserted the simian virus 40 T gene in hepatocytes using the Cre/Lox site specific recombination methods that allows for excision of the inserted gene by expressing Cre recombinase. After growing the modified hepatocytes in culture and then excising the simian virus 40 T gene, the authors transplanted the hepatocytes into the spleens of rats who had 90% of their livers removed. The transplanted hepatocytes supported many of these rats until their own livers could regenerate. In contrast, the rats not receiving hepatocyte transplants died. This method provides a way to grow adequate amounts of non-cancerous hepatocytes in culture for transplantation into subjects with failing livers.

Jin, D.-Y., Wang, H.-L., Zhou, Y., Chun, A. C. S., Kibler, K. V., Hou, Y.-D., Kung, H., and Jeang, K.-T. 2000. Hepatitis C virus core protein-induced loss of LZIP function correlates with cellular transformation. EMBO Journal. 19:729-740.

Hepatitis C virus infection can lead to the development of hepatocellular carcinoma (primary liver cancer). The core protein of the hepatitis C virus interacts with several cellular components when expressed in the liver. In this study, Jin et al. show that hepatitis C virus core protein interacts with LZIP, a transcription factor that regulates cell proliferation. Loss of LZIP function leads to changes in cultured cells similar to those of cancer cells. Hepatitis C virus core protein prevents LZIP from reaching the nucleus, where it normally functions, in turn potentiating cell proliferation. These results suggest that the interaction between hepatitis C virus core protein and LZIP may play a role in the development of liver cancer.

Macejak, D. G., Jensen, K. L., Jamison, S. F., Domenico, K., Roberts, E. C., Chaudhary, N., Von Carlowitz, I., Bellon, L., Tong, M. J., Conrad, A., Pavco, P. A., and Blatt, L. M. 2000. Inhibition of hepatitis C virus (HCV)-RNA-dependent translation and replication of a chimeric HCV poliovirus using synthetic stabilized ribozymes. Hepatology. 31:769-776.

Ribozymes are catalytic RNA molecules that can be designed to cleave specific RNA sequences. Ribozymes therefore have potential utility as drugs against RNA viruses, including the hepatitis C virus. In this study, Macejak et al. developed ribozymes that target hepatitis C virus RNA. Several of the ribozymes were able to inhibit hepatitis C virus-dependent protein synthesis and RNA replication in experimental systems. These experiments results demonstrate that synthetic ribozymes have potential for the treatment of human subjects with chronic hepatitis C.

Conte, D., Fraquelli, M., Prati, D., Colucci, A., and Minola, E. 2000. Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology. 31:751-755.

Previous studies have suggested that the rate of transmission of hepatitis C virus from infected mothers to their new born babies is less than 10%. This large study of 15,200 pregnant women in Italy evaluated the rate of hepatitis C virus transmission from pregnant mothers to their children. The overall rate of transmission 5.1% . Transmission was not apparently affected by the type of delivery or feeding or the HIV infection status of the mother. These results confirm previous studies showing that the rate of hepatitis C virus transmission from pregnant mothers to their babies is less than 1 in 10.

Copyright, 2000, Howard J. Worman, M. D. All rights reserved. Printing or other reproduction is prohibited without the written authorization of Howard J. Worman.