Current Papers in Liver Disease - April, 1999

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

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

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Showstack, J.,Katz, P. P., Lake, J. R., Brown, R. S., Jr., Dudley, R. A., Belle, S., Wiesner, R. H., Zetterman, R. K., Everhart, J., for the NIDDK Liver Transplantation Database Group. 1999. Resource utilization in liver transplantation. Effects of patient characteristics and clinical practice. Journal of the American Medical Association. 281:1381-1386.

Liver transplantation is one of the most costly medical procedures. This study examined 711 patients over the ages of 16 years who received orthotopic liver transplants from 1991 to 1994 at three U. S. medical centers (University of California San Francisco, Mayo Clinic and University of Nebraska) to determine the patient characteristics and clinical practice patterns that influenced cost. Patients were those with end-stage cirrhosis and not those with fulminant hepatic failure. The average first-year costs at these three centers was $203,434. Recipient and donor ages of 60 years or more were associated with higher overall costs. Also associated with higher cost was transplantation for alcoholic liver disease (26% higher), more advanced cirrhosis (Child-Pugh class C 41% higher), death in the hospital (35% higher and having multiple liver transplants during the hospitalization (154% higher). There were also differences in cost between the three participating centers. This study shows that identifiable patient characteristics and clinical practice activities influence the cost of liver transplantation. Based on these findings, certain clinical guidelines may be able to be established to lower costs and maintain quality of care.

Kenny-Walsh, E., for the Irish Hepatology Research Group. 1999. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. New England Journal of Medicine.340:1228-1233.

Batches of anti-D immune globulin used to prevent Rh immunization in 1977 and 1978 in Ireland were later found to be contaminated with the hepatitis C virus (HCV). In 1994, a national screening program was initiated for women who received anti-D immune globulin between 1970 and 1994. Of 62,667 women screened, 1.1% had antibodies against HCV and 55% of these had HCV RNA detected by reverse transcription-polymerase chain reaction in their sera. In this study, the authors evaluated 376 women (96% of those screened with detectable serum HCV RNA). The mean age of these women was 45 years and they had been infected for about 17 years at the time of screening. A total of 81% reported symptoms with fatigue being most common (66%). Serum alanine aminotransferase activities were mildly elevated in 47% of subjects and more highly elevated (> 100 IU/L) in 8%. Liver biopsies showed inflammation in 98% of cases with fibrosis in 51%. Only 7 (2%) of these women had cirrhosis and 2 of these 7 reported excessive alcohol consumption. These somewhat encouraging results show that only about 2% of women had cirrhosis 17 years after infection with HCV. However, about 50% had fibrosis on biopsy which may progress to cirrhosis with longer follow-up.

Li, Q., Van Antwerp, D., Mercurio, F., Lee, K.-F., and Verma, I. M. 1999. Severe liver degeneration in mice lacking the I-kappa-B kinase 2 gene. Science. 284:321-325.

NF-kB is a transcription factor protein complex that is a regulator of genes involved in responses to infection, inflammation, and stress. To be active, NF-kB must be translocated from the cytoplasm to the cell nucleus where it affects gene expression. NF-kB is "trapped" in the cytoplasm of cells by binding to inhibitors known as IkB's. When cells are activated by certain cytokines or other factors that signal through NF-kB, IkB's are phosphorylated by enzymes known as IkB kinases. Phosphorylation of IkB's by IkB kinases leads to the degradation of IkB's which then allows NF-kB to reach the nucleus. [Sounds complex but hang in there.] In this study, the authors make a "knockout" mouse that lacks a IkB kinase known as IkB kinase 2 or IkB kinase beta. These mice have extensive liver damage from apoptosis (programmed cell death) and die as embryos. If these mice are crossed with mice that lack tumor necrosis factor receptor 1, the severe liver damage is prevented. These results suggest that liver cell death induced by tumor necrosis factor (a cytokine) is prevented or attenuated by its activating NF-kB. They also suggest that IkB kinase 2 plays an important role in normal liver development. The phenotype of the IkB kinase 2 knockout mouse is similar to that of mice that lack a component of NF-kB itself (Beg et al. Nature. 1995;376:167-170; see September, 1995 Current Papers in Liver Disease. As liver cells die by apoptosis in some acquired diseases (hepatitis C being an example), these results also have long-term implications for the development of drugs to prevent tissue damage in liver diseases.

Sarin, S. K., Lamba, G. S., Kumar, M., Misra, A., and Murthy, N. S. 1999. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. New England Journal of Medicine. 340:988-993.

Esophageal varices (varicose veins in the esophagus) are a potential complication of cirrhosis. If these varices rupture, serious hemorrhage and death can result. Several studies have supported the fact that beta-blocker drugs such as propranolol and nadolol decrease the chance of bleeding from esophageal varices. If bleeding from esophageal varices does occur, it can be treated by either endoscopic sclerotherapy (injection of a chemical to obliterate the varicose vein) or endoscopic rubber band ligation (placing a rubber band around the varicose vein). These treatments also prevent the chance of subsequent bleeding. However, several studies have shown the endoscopic sclerotherapy is not a safe method to prevent first-time bleeding from esophageal varices that have not previously bleed. This study from New Delhi, India, compared endoscopic rubber band ligation to medical treatment with propranolol for the prevention of first-time bleeding from large esophageal varices. Of a total of 89 patients (82 with cirrhosis), 44 were treated with propranolol and 45 with rubber band ligation. After 18 moths, the risk of bleeding from varices was 43% in the patients who received propranolol and 15% in those who underwent ligation (P < 0.05). However, the death rates in both groups were the same with 5 individuals dying in each. The number of deaths from bleeding was also similar in both groups. One problem with this study is that the bleeding rate (43%) in the patients treated with propranolol was higher than that in most previous studies. Another problem is that the study was not double-blinded (that is the patients and doctors their knew which treatments they received). Although this study suggests that rubber band ligation may be safe and effective in preventing first-time bleeding from esophageal varices in individuals with cirrhosis, the limitations of the study do not make the results strong enough to support changing the currently accepted practice of treatment with beta-blockers.

Frieden, T. R., Ozick, L., McCord, C., Nainan, O. V., Workman, S., Comer, G., Lee, T. P., Byun, K.-S., Patel, D., and Henning, K. J. 1999. Chronic liver disease in central Harlem: the role of alcohol and viral hepatitis. Hepatology. 29:883-888.

Individuals living in poorer, inner city communities experience a disproportionate burden of the morbidity and mortality due to chronic liver disease. This observational study looked at 52 individuals with chronic liver disease in central Harlem, New York City. The most common cause of chronic liver was a combination of chronic hepatitis C virus infection and alcohol (46%). Alcohol abuse alone appeared to be responsible for chronic liver disease in 29% of cases and hepatitis C alone in 12%. A combination of chronic hepatitis B virus infection and alcohol was responsible for 6% of cases. In a case-control analysis, the combination of alcohol plus hepatitis B or hepatitis C virus infection put individuals at an increased risk of having chronic liver disease. Although only a small observational study, the results emphasize the significance of excessive alcohol consumption combined with chronic viral hepatitis as the major cause of chronic liver disease in an inner city community.

Rollier, C., Sunyach, C., Barraud, L., Madani, N., Jamard, C., Trepo, C., and Cova, L. 1999. Protective and therapeutic effect of DNA-based immunization against hepadnavirus large envelope protein. Gastroenterology. 116:658-665.

Chronic infection with the hepatitis B virus is the number one cause of cirrhosis and liver cancer in the world. Although some available drugs such as alpha-interferon and lamivudine inhibit viral replication and improve prognosis, there are no effective agents to completely eliminate the virus form the body, especially when the virus is in a slowly replicating state (patients without HBeAg in their serum). This study looked at DNA-based vaccination in an animal model of human hepatitis B virus infection. The animal model used was infection of Peking ducklings with the duck hepatitis B virus, a hepadnavirus very similar to the human hepatitis B virus. A DNA plasmid expressing a duck hepatitis B virus protein was injected into ducklings. Ducks not infected with the virus were protected against infection. Perhaps more interestingly, ducklings already infected with the duck hepatitis B virus showed decreases in viral DNA in blood and liver compared to controls after DNA vaccination. These results in a model system suggest that DNA vaccination may someday be useful the treatment of chronic hepatitis B in humans.

El-Serag, H. B., and Mason, A. C. 1999. Rising incidence of hepatocellular carcinoma in the United States. New England Journal of Medicine. 340:745-750.

Hepatocellular carcinoma (a primary liver cancer) is one of the leading causes of cancer death in the world. Although relatively rare in the United States and other developed countries, hepatocellular carcinoma is extremely common in parts of Southeast Asia and sub-Saharan Africa. In these parts of the world, infection with the hepatitis B virus is endemic and the carcinogenic aflatoxins contaminate several different foods. Most individuals with hepatocellular carcinoma also have cirrhosis. In this study, El-Serag and Mason determined the incidence of hepatocellular carcinoma in the United States by analyzing several different databases of medical diagnoses. The authors determined that the incidence of hepatocellular carcinoma increased in the United States from 1.4 per 100,000 population for the period from 1976 to 1980 to 2.4 per 100,000 fro the period from 1991 to 1995. During the 1991 to 1995 period, the incidence was about twice as high in black men as compared to white men. During these time periods, the incidence also increased in younger (ages 40 to 60 years) persons. This analysis suggests that the number of cases of hepatocellular carcinoma increased in the United States over the past two decades and the age-specific incidence has shifted to younger people. The authors speculate (but do not prove) that this may due to an increase in the number of new hepatitis B and hepatitis C virus infections during the 1960's and 1970's when intravenous drug use, needle sharing, transfusion of unscreened blood and unsafe sexual practices were widespread.

Hutin, Y. J. F., Pool, V., Cramer, E. H., Nainan, O. M., Weth, J., Williams, I. T., Goldstein, S. T., Gernsheimer, K. F., Bell, B. P., Shapiro, C. N., Alter, M. J., and Margolis, H. S., and the National Hepatitis A Investigation Team. 1999. A multistate, foodborne outbreak of hepatitis A. New England Journal of Medicine. 340:595-602.

The hepatitis A virus is transmitted by contaminated foods and water. Outbreaks of hepatitis A associated with contaminated foods have been known to occur in the United States. In this paper, Hutin et al. investigated a large outbreak of hepatitis A that occurred in Michigan in 1997 that was associated with the consumption of frozen strawberries. A total of 213 cases of hepatitis A were reported in children from 23 schools in Michigan and 29 cases from 13 schools in Maine. In both case-control and cohort studies, hepatitis A was significantly associated with the consumption of frozen strawberries in both Michigan and Maine. The genetic sequences of the viruses from 126 patients in Michigan and Maine were identical to one another and to those from several patients in Wisconsin, Arizona and Louisiana, all of whom had consumed frozen strawberries from the same processor. These results describe a large outbreak of hepatitis A in Michigan associated with the consumption of contaminated frozen strawberries. They also show that apparently sporadic cases in other states could be linked to the same source by genetic analysis.

Ueki, T., Kaneda, Y., Tsutsui, H., Nakanishi, K., Sawa, Y., Morishita, R., Matsumoto, K., Nakamura, T., Takahashi, H., Okamoto, E., and Fujimoto, J. 1999. Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nature Medicine. 5:226-230.

Cirrhosis is an irreversible process of widespread nodules in the liver combined with fibrosis (scarring). The factors responsible for the development of cirrhosis are only poorly understood and there are no treatments that can reverse the condition. Hepatocyte growth factor (HGF) is a protein that stimulates liver cells to divide, prevents them from dying by apoptosis (programmed cell death) and has many other effects. In this study, Ueki et al. examined the effects of HGF in rats treated with dimethylnitrosamine (DMN), a compound that induces liver damage resembling cirrhosis. After four weeks of taking DMN, rats developed histological changes in their livers similar to cirrhosis in humans. All rats died after the seventh week of DMN administration. Repeated administration of the human HGF gene into rat skeletal muscle using a plasmid vector and a liposome delivery system led to high levels of human HGF in the circulation. This inhibited the increased expression of transforming growth factor-beta-1 which plays a role in the development of cirrhosis. It also inhibited liver fibrosis and cell death by apoptosis. Administration of the human HGF gene 4 weeks after DMN, a time a which severe liver damage presumably occurred, led to the resolution of fibrosis in the cirrhotic livers and increased the survival rates of DMN-treated rats (median survival 43 days versus 34 days, P<0.01). These results suggest that high levels of HGF expression may lead to the resolution or the fibrosis associated with cirrhosis. Caution must be used in extrapolating these results to humans in that the pathobiology of cirrhosis formation in DMN-treated rats may be different than that in human conditions. Nonetheless, based on these results, HGF gene therapy may someday be tried as an experimental treatment for cirrhosis in humans.

Tahara, M., Matsumoto, K., Nukiwa, T., and Nakamura, T. 1999. Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver. Journal of Clinical Investigation. 103:313-320.

Alcohol intake can lead to the accumulation of fat (steatosis) in hepatocytes (see Alcoholic Liver Disease on the Diseases of the Liver Website). In addition, obesity and diabetes mellitus are also associated with fatty liver. Hepatocyte growth factor (HGF) stimulates the division of hepatocytes and also has other effects on the liver (see Ueki et al, 1999, above). In this study, Tahara et al. studied the effects of HGF on the development of fatty liver in rats fed an alcohol-containing diet. Intravenous administration of human recombinant HGF decreased the accumulation of fat in liver cells in alcohol-fed rats. There were concurrent increases in the concentrations of fats and lipoproteins in the blood and increased synthesis of apoprotein B, a factor involved in the secretion of fats from hepatocytes. These results suggest that HGF may reverse fatty liver by stimulating the secretion of fats from liver cells.

Tanaka, S., Mori, M., Sakamoto, Y., Makuuchi, M., Sugimachi, K., and Wands, J. R. 1999. Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. Journal of Clinical Investigation. 103:341-345.

Hepatocellular carcinoma is a primary liver tumor that is one of the leading causes of cancer death in the world. Hepatocellular carcinomas are usually highly vascular (have a lot of blood vessels feeding them) which supports their growth. Recently, a family of proteins known as angiopoietins have been identified that are involved in the generation of new blood vessels. These investigators show that angiopoietin-1 is equally expressed in hepatocellular carcinomas and adjacent normal tissue but that angiopoietin-2 is highly expressed only in tumor tissue in high vascular hepatocellular carcinomas. High expression of angiopoietin-2 may therefore be responsible the formation of new blood vessels that supply hepatocellular carcinomas and enable them to grow. These results also suggest that drugs directed against angiopoietin-2 may be of clinical utility in the treatment of hepatocellular carcinomas.

Copyright, 1999, Howard J. Worman, M. D. All rights reserved. Printing or other reproduction is prohibited without the written authorization of Howard J. Worman.