Current Papers in Liver Disease - March, 1998

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

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

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Lebron, J. A., Bennett, M. J., Vaughn, D. E., Chirino, A. J., Snow, P. M., Mintier, G. A., Feder, J. N., and Bjorkman, P. J. 1998. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 93:111-123.

In 1996, Feder et al. showed that mutations in the HFE (formerly HLA-H) gene were responsible for hereditary hemochromatosis (see Feder et al. Nature Genetics. 1996;13:399-408 in the September, 1996 Current Papers in Liver Disease). Between 70% and 100% of patients with hereditary hemochromatosis have a cysteine to tyrosine substitution at amino acid residue 260 of HFE. Until recently, it was unclear how HFE functions in iron homeostasis and how mutations in HFE cause hereditary hemochromatosis. HFE is a membrane protein with homology to HLA class I molecules. In this study, Lebron et al. used X-ray crystallographic methods to determine the three-dimensional structure of the extracellular domain of HFE. They also carefully examined the interactions of the extracellular domain of HFE with the extracellular domain of transferrin receptor. Transferrin receptor binds to iron bound transferrin to mediate the uptake of iron into cells and the binding of HFE to transferrin receptor inhibits the binding of transferrin and the uptake of iron. The mutant HFE in individuals with hereditary hemochromatosis cannot bind to transferrin receptor, suggesting that this may be responsible for the enhanced uptake of iron in such patients. These results explain how mutations in HFE can result in the iron overload characteristic of hereditary hemochromatosis. Knowledge of the structure of HFE could also lead to the development of drugs to mimic its functions in individuals with the disease.

Heathcote, E. J., Keefe, E. B., Lee, S. S., Feinman, S. V., Tong, M. J., Reddy, K. R., Albert, D. G., Witt, K., Blatt, L. M., and the Consensus Interferon Study Group. 1998. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology. 27:1136-1143.

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Chow, W.-C., Boyer, N., Pouteau, M., Castelnau, C., Martinot-Peignoux, M., Martins-Amado, V., Degos, F., Maghinici, C., Sinegre, M., Benhamou, J.-P., Degott, C., Erlinger, S., and Marcellin, P. 1998. Re-treatment with interferon alfa of patients with chronic hepatitis C. Hepatology. 27:1144-1148.

Most patients with chronic hepatitis C who receive a 24 week course of interferon alpha "relapse" after treatment is discontinued (so-called "relapsers"). In addition, about a third of patients never respond to treatment (so-called "non-responders"). Response to treatment is best evaluated by the loss of detectable hepatitis C virus (HCV) RNA from the blood and also by normalization of serum alanine aminotransferase (ALT) activities. These two studies published in Hepatology in April, 1998 addressed re-treatment of such individuals. In the open-label study by Heathcote et al., 337 patients with chronic hepatitis C who had not responded to or relapsed after treatment with either interferon alpha-2b (3,000,000 units three times a week) or interferon alfacon-1 (9 micrograms three times a week) were re-treated with interferon alfacon-1 at a dose of 15 micrograms three times a week for either 24 or 48 weeks. Twenty-four weeks after re-treatment was discontinued, 58% of so-called "relapsers" treated for 48 weeks and 28% treated for 24 weeks did not have detectable serum HCV RNA (so-called long-term response). Only 13% of prior non-responders treated for 48 weeks and 5% treated for 24 weeks had long-term responses with re-treatment. The study by Chow et al. was a retrospective analysis of 111 patients who either were "relapsers" or "non-responders" to 24 weeks of treatment with one of several different preparations of alpha-interferon at a dose of 3,000,000 units three times a week. Most were re-treated with interferon alpha-2b at doses of either 3,000,000 or 5,000,000 units three times a week for either 24 or 48 weeks. Of the re-treated patients, 19% of "relapsers" and 3% of "non-responders" had a long-term response and all were treated with higher doses (5,000,000 units three times a week) and longer duration (48 weeks). The results of these two studies suggest that so-called "relapsers" have a chance of achieving a long-term response after re-treatment with interferon-alpha. Although some "non-responders" may benefit from re-treatment, the chances of obtaining a long-term response are lower. The different response rates to re-treatment in the two studies cannot be directly compared because of differences in the patient populations. Only a randomized, double-blind trial to compare interferon alfacon-1 to interferon alpha-2b can establish if re-treatment with either one of these preparations is superior.

Corrao, G., and Arico, S. 1998. Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis. Hepatology. 27:914-919.

Alcohol abuse and hepatitis C virus (HCV) infection are the two major risk factors for the development of cirrhosis in the Western Hemisphere. This report examined these two risk factors in two case-control studies from Italy. The cases were 285 patients with cirrhosis admitted for the first time to a hospital for worsening liver disease. The controls were 417 patients admitted during the same time period for acute diseases not related to alcohol. The odds ratio of developing symptomatic cirrhosis was 9.2 in subjects who drank no alcohol and had HCV infection compared to subjects who had zero lifetime daily alcohol consumption and no evidence of HCV infection. For heavy lifetime alcohol users (greater than 175 g/day), the odds ratio for developing symptomatic cirrhosis was 15 in those without HCV infection and 147 in those with HCV infection. An additive relative risk for developing symptomatic cirrhosis was also seen with lower levels of daily alcohol consumption in individuals with chronic HCV infection. These results show that alcohol abuse and chronic HCV infection are independent risk factors for developing cirrhosis. These two risk factors together greatly compound the odds of developing cirrhosis, especially at high levels of alcohol use.

Spath, G. F., and Weiss, M. C. 1998. Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells. Journal of Cell Biology. 140:935-946.

The basic mechanisms of how the primary liver cell or hepatocyte develops are only poorly understood. It is generally accepted that hepatic differentiation results from the actions of several different transcription factors (proteins that bind to DNA and turn specific genes on or off). This paper addresses the role of one such hepatic transcription factor known as hepatocyte nuclear factor 4 (HNF4). When the authors expressed HNF4 in dedifferentiated liver cancer cells in vitro, re-expression of a set of hepatocyte genes was observed. In particular, expression of HNF4 resulted in expression of cytokeratins and E-cadhedrin, proteins of the cytoskeleton. These cells were able to respond to the steroid dexamethasone which induced the formation of junctional complexes (connections between cells) and a polarized cell phenotype (cells with two distinct plasma membrane domains, for example, one that faces the blood and another that faces the bile ducts). A primarily important step in this in vitro differentiation process appeared to be the expression of E-cadhedrin by HNF4. The results have implications for understanding how the normal liver develops during embryogenesis and for identifying defects in primary liver cancer.

Mathurin, P., Moussalli, J., Cadranel, J.-F., Thibault, V., Charlotte, F., Dumouchel, P., Cazier, A., Huraux, J.-M., Devergie, B., Vidaud, M., Opolon, P., and Poynard, T. 1998. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity. Hepatology. 27:868-872.

Many individuals infected with the hepatitis C virus (HCV) have normal serum biochemical tests of liver inflammation, in particular normal serum alanine aminotransferase (ALT) activities. It is not clear if subjects with persistently normal serum ALT activities and HCV infection have a relatively benign clinical course as serum ALT activity does not always correlate with actual liver inflammation. This study compared 102 subjects with HCV infection and persistently normal serum ALT activities (mean 25 IU/L) to 102 subjects with HCV infection and elevated values (mean 127 IU/L). HCV RNA was detected less frequently in serum from subjects with normal serum ALT activities (66% vs. 97%, P < 0.001). Histological activity and the degree of fibrosis on biopsy were also significantly less in the group with normal ALT activities. In subjects for whom the times of infection were known, estimated progression rate of liver fibrosis was twice as slow in those with persistently normal ALT activities than in those with abnormal values. All subjects with cirrhosis and normal ALT activities were also heavy alcohol users and severe fibrosis was also associated with high alcohol consumption. This study suggests that liver disease progresses more slowly in individuals with chronic HCV infection and persistently normal serum ALT activities than in those with abnormal values.

Keeffe, E. B., Iwarson, S., McMahon, B. J., Lindsay, K. L., Koff, R. S., Manns, M., Baumgarten, R., Wiese, M., Fourneau, M., Safary, A., Clemens, R., and Drause, D. S. 1998. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology. 27:881-886.

Acute hepatitis A infection in individuals with pre-existing chronic liver disease may cause severe illness and fulminant hepatic failure. This multicenter study compared the safety and immunogenicity of inactivated hepatitis A vaccine in patients with chronic liver disease and healthy subjects. A total of 475 subjects older than 18 years received two doses of inactivated hepatitis A vaccine. Local injection site symptoms were the only common adverse events. After one dose, 93% of healthy subjects developed antibodies against hepatitis A virus compared to 73% of subjects with chronic hepatitis C and 83% of subjects with chronic liver disease form non-viral causes. However, greater than 94% of all subjects had antibodies against hepatitis A virus after receiving two doses of vaccine. In conclusion, hepatitis A vaccine is safe and most likely effective in individuals with chronic liver diseases.

Bull, L. N., van Eijk, M. J. T., Pawlikowska, L., DeYoung, J. A., Juijn, J. A., Liao, M., Klomp, L. W. J., Lomri, N., Berger, R., Scharschmidt, B. F., Knisely, A. S., Houwen, R. H. J., and Freimer, N. B. 1998. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nature Genetics. 18:219-224.

Cholestasis means impaired bile flow and presents in patients as jaundice, itching and fat malabsorption. Two autosomal recessive inherited disorders of bile flow are benign recurrent intrahepatic cholestasis or Summerskill syndrome and progressive familial intrahepatic cholestasis type 1 or Byler disease. The former is not associated with signficant liver damage whereas the later is characterized by end-stage liver disease in childhood. The gene(s) for both of these disorders had been mapped previously to chromosome 18q21. In this study, the authors identify a gene in this chromosomal region that encodes a P-type ATPase. P-type ATPases are involved in transport across cell membranes, presumably bile salts in this case. By DNA sequencing, these investigators determined the primary structure of this new protein and identified different mutations in subjects with benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis type 1. These results show that mutations in the same gene encoding a P-type ATPase cause two different forms of hereditary cholestasis. Depending upon the specific mutation, a disorder with a relatively benign or severe phenotype can result.