Current Papers in Liver Disease - December, 2000

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

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

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Cheng, S. J., Bonis, P. A., Lau, J., Pham, N. Q., and Wong, J. B. 2001. Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy: a meta-analysis of controlled and uncontrolled trials. Hepatology. 33:231-240.

Interferon alpha plus ribavirin induced a virological "sustained response" in about 40% of individuals with chronic hepatitis C who were never previously treated or treated with interferon alpha alone and "relapsed" after treatment. ("sustained response" is defined as absence of detectable viral RNA six or more months after stopping treatment; "relapse" is defined as having no detectable viral RNA in blood during treatment but detectable RNA after stopping treatment). Some patients do not response ("non-responders") during treatment with interferon in that viral RNA is detectable during treatment. This study presents a meta-analysis (analysis of the combined results of several published studies) of interferon alpha plus ribavirin for the treatment of patients who were "non-responders" to interferon alpha alone. The results show that treatment with interferon alpha plus ribavirin in "non-responders" is better than retreatment with interferon alpha alone. However, the overall rate of achieving "sustained responses" with interferon alpha plus ribavirin in previous interferon "non-responders" was low and an estimated 14 such patients would have to be treated to achieve one virological "sustained response." This meta-analysis shows some of the problems with the currently available therapies for chronic hepatitis C.

Parikh-Patel, A., Gold, E. B., Worman, H., Krivy, K. E. and Gershwin, M. E. 2001. Risk factors for primary biliary cirrhosis in a cohort of patients from the United States. 33:16-21.

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Kim, W. R., Lindor, K. D., Locke, G. R., Therneau, T. M., Homburger, H. A., Batts, K. P., Yawn, B. P., Petz, J. L., Melton, L. J., and Dickson, E. R. 2000. Epidemiology and natural history of primary biliary cirrhosis in a U. S. community. Gastroenterology. 199:1631-1636.

The incidence and prevalence of primary biliary cirrhosis (PBC) in the United States is not clear. Risk factor for the development of PBC have also not been clearly established and genetic as well as environmental factors have been proposed to both be involved. Kim et al. used The Rochester Epidemiology Project which entails a computerized index of diagnoses from the health care encounters of residents of Olmstead County, Minnesota assess the incidence and prevalence of PBC. The age-adjusted incidence of PBC per 100,000 person-years for 1975 through 1995 was 4.5 for women, 0.7 for men and 2.7 overall. The age- and sex-adjusted prevalence per 100,000 as of 1995 was 65.4 for women, 12.1 for men and 40.2 overall. These prevalences are among the highest reported in any previous study (mostly from Europe). A possible confounding factor is that the Mayo Clinic, a referral center for many patients, is located in Olmstead County. Parikh-Patel et al. conducted a survey of of 241 patients with PBC in the United States, 261 of their siblings and 141 friends without PBC. The patients were identified from an electronic mail list server for an Internet support group for individuals with PBC. The mean age of the participants was 53 years, 97% were Caucasion and the ratio of women to men was 10:1. Compared to friend controls, individuals with PBC were more likely to have an associated autoimmune disease (odds ratio = 4.92), smoke cigarettes (odds ratio 2.04), have had a tosillectormy (odds ratio 1.86) or have had a vaginal or urinary tract infetion if a woman (odds ratio 4.07). These odds ratios were also elevated when cases were compared to their siblings. The autoimmune conditions most commonly associated with PBC were Sjogren syndrome, Raynaud syndrome and thyroiditis. These two studies provide some of the first insights into the epidemiology of PBC in the United States. Larger epidemiological studies will likely result in more interesting findings.

Ross, R. S., Viazov, S., Gross, T., Hofmann, F., Seipp, H.-M., and Roggendorf, M. 2000. Transmission of hepatitis C virus from a patient to an anesthesiology assistant to five patients. New England Journal of Medicine. 343:1851-1854.

Transmission of the hepatitis C virus (HCV) from medical personnel, mostly surgeons, to patients is rare but has been reported (for an example see the paper by Esteban et al. New England Journal of Medicine. 1996;550-560; reviewed in April, 1996 Current Papers in Liver Disease). In this paper, Ross et al. report on an outbreak of hepatitis C in a municipal hospital in Germany. Their analysis strongly suggests that HCV was transmitted from a patient with chronic hepatitis C undergoing surgery to an anesthesiology technician who cared for her in the operating room. The anesthesiology technician in turn infected five other patients over the next several weeks. Sequencing of the genetic material of the HCV isolates from the infected subjects strongly suggested that they all arose from the initial patient. This report provides evidence that HCV can be transmitted from medical personnel other than surgeons to patients. The authors note that the anesthesiology technician did not use gloves while starting intravenous lines in patients and emphasize that these infections could have been prevented if so-called "universal precautions for infection control" practices in most hospitals had been taken.

Blight, K. J., Kolykhalov, A. A., and Rice, C. M. 2000. Efficient initiation of HCV RNA replication in cell culture. Science. 290:1972-1974.

A robust cell culture system for the hepatitis C virus (HCV) has not been established. For this reason, it is extremely difficult to study how HCV infects cells and to test anti-viral drugs in a model system (the only animals that can be infected are humans and chimpanzees). Last year, Lohmann et al. (Science. 1999;285:110-113; see July, 1999 Current Papers in Liver Disease) made a major initial step in devising a culture system for HCV by obtaining replication of subgenomic HCV RNAs in cultured cells. These subgenomic replicons are composed of only the part of the HCV genome that encodes the non-structural proteins but are competent to be replicated in cells and synthesize viral proteins. In this paper, Blight et al. follow-up on the work of Lohmann et al. and develop similar HCV subgenomic replicons that show enhanced replication in cells. The identified multiple independent adaptive mutations that cluster in the protein NS5A and confer increased replicative ability in cultured cells. Several of these mutations were single amino acid changes in the NS5A protein and another was a deletion of 47 amino acids encompassing the part of NS5A that has been associated with sensitivity to interferon-alpha in infected humans. The replicons described in this paper, along with those previously described by Lohmann et al., will allow for future studies of HCV replication, pathogenesis and evolution in cell culture. They may also allow for cell-based testing of certain types of anti-viral drugs (in this study, for example, Blight et al. showed that interferon alpha inhibited replication).

Zeuzem, S., Feinmann, S. V., Rasenack, J., Heathcote, E. J., Lai, M.-Y., Gane, E., O'Grady, J., Reichen, J., Diago, M., Lin, A., Hoffman, J., and Brunda, M. J. 2000. Peginterferon alfa-2a in patients with chronic hepatitis C. New England Journal of Medicine. 343:1666-1172.

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Heathcote, E. J., Shiffman, M. L., Cooksley, G. E., Dusheiko, G. M., Lee, S. S., Balart, L., Reindollar, R., Reddy, R. K., Wright, T. L., Lin, A., Hoffman, J., and De Pamphilis, J. 2000. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. New England Journal of Medicine. 343:1673-1680.

Interferon-alpha is effective in the treatment of chronic hepatitis C in a minority of patients. Treatment with recombinant interferon alpha, administered by injection three times a week for a year leads to a "sustained virological response" (undetectable virus in blood using reverse-transcription polymerase chain reaction six months after stopping treatment) in less than 20% of subjects. Addition of daily oral ribavirin to interferon alpha for 48 weeks of treatment leads to increased "sustained virological response" rates of approximately 40%. Patients with cirrhosis are less likely to achieve a "sustained virological response" after treatment with interferon alpha. Recently, preparations of interferon alpha have been produced in which the molecule in covalently attached to a branched-chain of polyethylene glycol (peginterferon). Peginteferon alpha has sustained absorption, a longer half-life and slower rate of clearance than unmodified interferon alpha. In the first of these two studies that appeared in the December 7 issue of the New England Journal of Medicine, Zeuzem et al. treated randomly assigned 531 patients with chronic hepatitis C to treatment with either 180 micrograms of peginterferon alpha-2a (267 patients) or unmodified interferon alpha-2a for 36 weeks. Peginterferon alpha-2a was given once a week and unmodified interferon alpha-2a three times a week by injection. In the peginterferon alpha-2a group, 39% of subjects achieved a "sustained virological response" as compare to 19% in the group treated with unmodified interferon alpha-2a. The two groups were similar with respect to adverse events. In the second of these studies, Heathcote et al. treated 271 patients with cirrhosis (or bridging fibrosis) and chronic hepatitis C with either unmodified interferon alpha-2a or two different doses (90 or 180 micrograms) of peginterferon alpha-2a. Unmodified interferon alpha-2a was administered three times a week and peginterferon once a week by injection. Treatment with 180 micrograms of peginterferon alpha-2a led to a "sustained virological response" rate of 30% as compared to 8% in the unmodified interferon alpha-2a group and 15% in the 90 microgram peginterferon alpha-2a group. In a subgroup of patients, there was also more improvement on liver biopsies after treatment in the 180 microgram peginterferon alpha-2a group. All three treatment were similarly tolerated. These two studies show that peginterferon alpha-2a is superior to unmodified interferon alpha in the treatment of chronic hepatitis C, including in difficult-to-treat subjects with cirrhosis. The response rates to peginterferon alpha-2a alone in non-cirrhotic subjects approach those in similar subjects treatment with interferon alpha plus ribavirin in other studies, although a head-to-head comparison in the same study has yet to be reported.

Akriviadis, E., Botla, R., Briggs, W., Han, S., Reynolds, T., and Shakil, O. 2000. Pentoxifylline improves short-term survival in severeacute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology. 119:1637-1648.

Acute alcoholic hepatitis is inflammation of the liver of sudden onset caused by excessive ethyl alcohol consumption. Severe alcoholic hepatitis is a life-threatening illness with a high mortality rate. Some studies have suggested that steroids may improve the outcome in severe alcoholic hepatitis, however, neither steroid nor any other drugs are approved by the United States Food and Drug Administration for treatment of this disease. Based on preliminary data showing its ability to inhibit tumor necrosis factor, a cytokine that may mediate liver injury in alcoholic hepatitis, and a pilot study, Akriviadis et al. conducted a well-designed study of pentoxifylline in 101 patients with severe alcoholic hepatitis. The study was randomized (subject were given drug or placebo in a random fashion) and doubled-blind (neither the doctors nor the patients knew if they were getting pentoxifylline or placebo). The results were impressive in that 24.5% of patients who received pentoxifylline died compared to 46.1% who received placebo. These results clearly warrant further clinical trials of pentoxifylline for severe alcoholic hepatitis.

Cope, K., Risby, T., and Diehl, A. M. 2000. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology. 199:1340-1347

Both excessive ethyl alcohol (ethanol) consumption and obesity can cause accumulation of fat in hepatocytes, the primary liver cell type. In some cases, fat accumulation (steatosis) is accompanied by a type of inflammation known as steatohepatitis. As intestinal bacteria can produce ethanol, Cope et al. decided to test the hypothesis that intestinal production of ethanol is increased in genetically obese mice (known as ob/ob mice that have mutations in the leptin gene). Breath analysis of mice showed that 24-week-old obese mice had a significantly higher ethanol content than their lean littermates. Breath ethanol content increased with age in obese, but not lean, mice. Treatment with neomycin, an antibiotic that kills bacteria in the large intestine, caused a decrease in breath ethanol content in obese mice. These studies show that ethanol can be detected in the breath of in the absence of drinking it and that obese mice have higher breath ethanol than lean mice. As the ob/ob obese mice usually have fatty livers (steatosis), the authors make the intriguing speculation that this increase in ethanol production may contribute to the development of fatty liver. This intriguing hypothesis, based upon the findings in this study, remains to be tested.

Richter, L. J., Thanavala, Y., Arntzen, C. J., and Mason, H. S. 2000. Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nature Biotechnology. 18:1167-1171.

As many as 500 million people worldwide are infected with the hepatitis B virus. Vaccination with hepatitis B virus surface antigen (HBsAg) produces protective immunity in most subjects. Vaccination generally requires a course of three injections over a one year period. As hepatitis B virus infection is endemic in many poorer parts of the world, an inexpensive and conveniently administered vaccine is necessary. In this study, the authors expressed HBsAg in transgenic potato tubers. Feeding of mice with the transgenic HBsAg potato tubers showed a primary immune response (increased in antibody against HBsAg) that could be boosted by injection of commercially-available hepatitis B vaccine. This preliminary study is an important initial step that may ultimately lead to the development of an inexpensive, oral vaccine for hepatitis B.

Schwarz, M., Wright, A. C., Davis, D. L., Nazer, H., Bjorkhem, I., and Russell D. W. 2000. The bile acid synthetic gene 3-beta-hydrozy-delta-5-C27-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis. Journal of Clinical Investigation. 106:1175-1184.

Progressive intrahepatic cholestasis is actually a group of inherited diseases caused by errors of metabolism that affect the production and secretion of bile. The condition is marked by jaundice, inability to absorb fat-soluble vitamins and the development of cirrhosis. Mutations in one of several genes encoding enzymes that synthesize bile acids or that active transport them from the liver cells into the bile often underlie familial cases of intrahepatic cholestasis manifested in childhood. In this study, Schwarz et al. demonstrate that mutation in 3-beta-hydrozy-delta-5-C27-sterod oxidoreductase, an enzyme that participates in bile acid synthesis, also cause progressive intrahepatic cholestasis. They found a mutation in the gene encoding this enzyme in a patient with this disease. The results show that the enzyme plays an important role in the synthesis of bile acids and also provide the tools for the diagnosis of another form of progressive intrahepatic cholestasis.

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