Current Papers in Liver Disease - February, 2000

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

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

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Seeff, L. B., Miller, R. N., Rabkin, C. S., Buskell-Bales, Z., Straley-Eason, K. D., Smoak, B. L., Johnson, L. D., Lee, S. R., and Kaplan, E. L. 2000. 45-year follow-up of hepatitis C virus infection in healthy young adults. Annals of Internal Medicine. 132:105-111.

The long-term outcomes of individuals infected with the hepatitis C virus (HCV) is unknown. In this study, blood samples from 8,568 military recruits obtained between 1948 and 1954 were examined for infection with HCV. Of these, 17 (0.2%) were found to have evidence of HCV infection. Seven of the 17 (41%) individuals with evidence of HCV infection had died by the end of 1996. One of these (5.9%) died of liver disease 37 years after his blood was originally drawn. Of the individuals without evidence of HCV infection, 119 (1.4%) died of liver disease. These results suggest that there is a relatively low incidence of death from liver disease in individuals infected with HCV followed for 45 years. However, because of the small numbers of infected individuals and the retrospective (backward-looking) design of this study, the conclusions must be interpreted with caution.

Bellentani, S., Saccoccio, G., Masutti, F., Croce, L. S., Brandi, G., Sasso, F., Cristanini, G., and Tiribelli, C. 2000. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Annals of Internal Medicine.132:112-117.

Steatosis or fatty liver occurs in obese individuals. Steatosis is also a manifestation of alcoholic liver disease. Although these associations are well-accepted, few details are known about the prevalence of and risk factors for steatosis. In this study, 257 individuals were examined for suggestive evidence of fatty liver by ultrasound. The individuals were divided into four groups: controls (67), obese (66), heavy drinkers (69) and obese heavy drinkers (55). Subjects were examined and alcohol intake was estimated using a semi-quantitative questionnaire. The relative risks for steatosis compared to controls were 2.8 fold in heavy drinkers, 4.6 fold in obese persons and 5.8 fold in obese persons who drank heavily. The authors conclude that steatosis is almost always present (94.5% of the time) in obese people who drink more than 60 g of alcohol (about 6 drinks) a day. They also conclude that steatosis is more strongly associated with obesity than with heavy drinking. A major weakness of this study is that only ultrasound was used to obtain evidence of steatosis. Although information obtained by ultrasound is suggestive, liver biopsy is a far more sensitive and specific test for the diagnosis.

Forman, L. M., Simmons, D. A., and Diamond, R. H. 2000. Hepatic failure in a patient taking rosiglitazone. Annals of Internal Medicine.132:118-121.

and

Al-Salman, J., Arjomand, H., Kemp, D. G., and Mittal, M. 2000. Hepatocellular injury in a patient receiving rosiglitazone. Annals of Internal Medicine.132:121-124.

Previous reports have suggested that troglitazone, an oral agent approved for the treatment of type 2 diabetes mellitus, may be associated with liver damage (see for examples papers by Gitlin et al. and Neuschwander-Tetri et al. reviewed in July 1998 issue of Current Papers in Liver Disease). Rosiglitazone is a recently approved compound of the same class (thiazolidinediones) for the treatment of diabetes mellitus. In clinical trials, there was no evidence that rosiglitazone caused liver damage. These two case reports describe liver failure and/or severe liver damage in two individuals, both in their 60's, while receiving rosiglitazone. The subject reported by Forman et al. was suffering from congestive heart failure, which could also lead to liver damage. The subject reported by Al-Salman et al. was taking another medication (repaglinide) and also had "a remote history of alcoholism." These reports describe two subjects who developed liver damage while receiving rosiglitazone. Isolated case reports such as these, however, do not establish cause and effect.

Bennett, M. J., Lebron, J. A., and Bjorkman, P. J. 2000. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 403:46-53.

Hereditary hemochromatosis is a relatively common inherited disease characterized by body iron overload. A consequence of iron overload in the liver is cirrhosis. About 90% of individuals with hereditary hemochromatosis have a particular mutation in HFE, a protein similar in structure to major histocompatability complex class I proteins. Some studies have suggested that HFE binds to transferrin receptor. Transferrin receptor is a cell surface protein that mediates the uptake of iron into cells. Binding of HFE to transferrin receptor may somehow inhibit the uptake of iron. In this study, Bennett et al. use X-ray crystallography to describe in detail the structure of HFE bound to transferrin receptor. The binding of HFE significantly alters the structure of transferrin receptor and may somehow alter its function in iron uptake. This elegant work strongly implicates HFE, via its binding to transferrin receptor, as a regulator of iron uptake into cells. Although not directly demonstrated in this work, mutations in HFE in individuals with hereditary hemochromatosis may weaken this interaction, or other protein-protein interactions, and prevent HFE from regulating iron uptake. In the long-term, knowledge of the HFE-transferrin receptor complex structure could lead to the development of drugs to decrease cellular iron uptake in individuals with hemochromatosis.

Theise, N. D., Badve, S., Saxena, R., Henegariu, O., Sell, S., Crawford, J. M., and Krause, D. S. 2000. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 31:235-240.

Some data suggest that the liver has "stem cells" which are undifferentiated cells that can divide and differentiate into hepatocytes (the primary liver cell type) and bile duct cells. A recent report by Petersen et al. (Science. 1999;284:1168-1170, see July, 1999 issue of Current Papers in Liver Disease) strongly supported the hypothesis that hepatic stems cells originate in the bone marrow. In the current paper, Theise et al. provide further evidence that hepatocytes derive from bone marrow cells. The authors lethally irradiated female mice, whose cells have two X chromosomes, and then gave them bone marrow transplants from male mice, whose cells have one X and one Y chromosome. After bone marrow transplantation, some liver hepatocytes in the recipient female mice contained a Y chromosome, strongly suggesting that they arose from the transplanted male bone marrow. The authors performed addition experiments which suggested that a particular type of bone marrow cell may develop into hepatocytes. These results, along with those of Petersen et al., strongly suggest that cells originating in the bone marrow differentiate into hepatocytes. In the long-term, this knowledge may be used to devise ways to regenerate damaged livers.

Soussan, P., Garreau, F., Zylberberg, H., Ferray, C., Brechot, C., and Kremsdorf, D. 2000. In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA. Journal of Clinical Investigation. 105:55-60.

It has been known for some time that hepatitis B virus encodes four proteins: precore, surface, polymerase and X. Precore protein becomes the viral capsid and surface protein is the hepatitis B surface antigen. Polymerase replicates the viral DNA and X is a protein of unclear function. The current report demonstrates that the hepatitis B virus encodes another protein the authors call HBSP for hepatitis B virus splice-generated protein. The protein arises by alternative splicing of the virus's RNA and includes the first 46 amino acids of the polymerase followed by 47 amino acids corresponding to a novel sequence. HBSP was detected in liver tissue infected with the hepatitis B virus and antibodies against HBSP were found in sera from one-third of chronic hepatitis B virus carriers. Expression of HBSP in vitro did not alter viral replication but induced apoptosis (programmed cell death). These results show that the hepatitis B virus encodes a novel protein by alternative RNA splicing and suggest that it may be involved in modulating the virus-cell interaction.

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