Current Papers in Liver Disease - September, 1996

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

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

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Ling, R., Mutimer, D., Ahmed, M., Boxall, E. H., Elias, E., Dusheiko, G. M., and Harrison, T. J. 1996. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine. Hepatology. 24:711-713.

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Tipples, G. A., Ma, M. M., Fischer, K. P., Bain, V. G., Kneteman, N. M., and Tyrrell, D. L. J. 1996. Mutation in the HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology. 24:714-717.

Lamivudine (2'-deoxy-3'-thiacytidine, 3TC) is effective in reducing the viral loads of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) in infected individuals. It has been known that mutations in the HIV polymerase (pol) gene can induce resistance to lamivudine. In these two studies, the authors show that similar mutations in the HBV pol gene can also cause resistance to this compound. Resistance was characterized by the development of acute viral hepatitis and HBV replication while receiving lamivudine after orthotopic liver transplantation. In the study by Ling et al., two patients are identified who developed resistance to lamivudine after transplantation. Amplification of the pol gene and sequencing showed mutations in a tyrosine-methionine-aspartate-aspartate (YMDD) motif that is also conserved in the HIV polymerase. In one patient, the methionine (M) was mutated to a valine (V), and in the other, to an isoleucine (I). In the study by Tipples et al., one patient is described who similarly developed acute hepatitis and HBV replication 33 weeks after orthotopic liver transplantation while receiving lamivudine. In this patient, a M to I mutation in the YMDD motif was detected at 28 weeks and 33 weeks after transplantation. It should be cautioned that mutations in the pol gene also cause changes in surface antigen which is encoded by an overlapping reading frame. These two reports demonstrate that HBV can develop resistance to lamivudine by a mechanism that may be similar to that observed for HIV.

Farci, P., Alter, H. J., Shimoda, A., Govindarajan S., Cheung, L. C., Melpolder, J. C., Sacher, R. A., Shih, J. W., and Purcell, R. H. 1996. Hepatitis C virus-associated fulminant hepatic failure. New England Journal of Medicine. 335:631-634.

Fulminant hepatic failure is characterized by encephalopathy occurring within a short duration after the first symptoms of liver disease. The condition is most often caused by infection with hepatitis A and hepatitis B viruses. It has not yet been conclusively demonstrated that acute hepatitis C virus (HCV) infection can cause fulminant hepatic failure. In this brief report, the authors describe a patient who developed fulminant hepatic failure several weeks after receiving blood transfusions while undergoing coronary artery bypass grafting surgery. Prior to transfusion, antibodies against HCV were not present in the patient's serum and HCV RNA could not be detected by the polymerase chain reaction. Five weeks after transfusion, when the serum alanine aminotransferase activity was greater than 3000 U/L and fulminant hepatic failure developed, HCV RNA was detected in serum and remained detectable until the patient's death 11 days later. Anti-HCV antibodies were detected in serum one day prior to death. HCV antigen was also present in the liver at autopsy. Hepatitis G and hepatitis B virus RNA and IgM antibodies against hepatitis A virus were also not detected in serum samples. Although only a single case report, this study strongly suggests that acute HCV infection can cause fulminant hepatic failure.

Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo,,R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., Kimmel, B. E., Kronmal, G. S., Lauer, P., Lee, V. K., Loeb, D. B., Mapa, F. A., McClelland, E., Meyer, N. C., Mintier, G. A., Moeller, N., Moore, T., Morikang, E., Prass, C. E., Quintana, L., Starnes, S. M., Schatzman, R. C., Brunke, K. J., Drayna, D. T., Risch, N. J., Bacon, B. R., and Wolff, R. K. 1996. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics. 13:399-408.

Hereditary hemochromatosis is one of the most common genetic diseases and affects approximately 1 in 400 individuals of Northern European descent. It is inherited in an autosomal recessive manner and is characterized by the deposition of iron in various tissues including the liver. Liver iron overload leads to cirrhosis and hepatocellular carcinoma. Phlebotomy is highly effective in preventing the complications of hemochromatosis, including cirrhosis, however, the disease is frequently not diagnosed until complications develop. It has been known for some time that the gene for hemochromatosis is on chromosome 6 near the major histocompatibility complex (MHC). In this paper, investigators at Mercator Genetics, Inc. report the identification of a novel gene on chromosome 6 which is related to the MHC class I family. They termed this gene HLA-H and showed that it contained a particular mutation in 83% of 178 patients with hereditary hemochromatosis. Based on their comprehensive analysis of most, if not all, of the genes in this region of chromosome 6, the conclusion that HLA-H is the gene responsible for hereditary hemochromatosis is very likely true. However, the slight possibility that another closely linked gene may be responsible for the disease cannot be definitively excluded. The identification of HLA-H, which appears to contain a specific type of mutation in at least 80% of patients with hereditary hemochromatosis, should lead to a test for this common but widely under-diagnosed disease for which there is effective available therapy.

Current Papers in Liver Disease/Howard J. Worman, M. D./hjw@columbia.edu