Current Papers in Liver Disease - November, 1997

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

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

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Koehler, J. E., Sanchez, M. A., Garrido, C. S., Whitfeld, M. J., Chen, F. M., Berger, T. G., Rodriguez-Barradas, M. D., LeBoit, P. E., and Tappero, J. W. 1997. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. New England Journal of Medicine. 337:1876-1883.

Peliosis hepatis is an unusual vascular proliferative lesion of the liver and sometimes spleen. It is similar to bacillary angiomatosis which usually involves the skin and bones. These conditions are most often described in patients infected with the human immunodeficiency virus (HIV). Both of these lesions are associated with gram-negative bacteria of the genus Bartonella, specifically B. henselae and B. quintana. B. henselae also causes cat scratch disease, an inflammation of the regional lymph nodes after being scratched by a cat, in immunocompetent individuals. In this study, the authors used the polymerase chain reaction to determine the infecting Bartonella species in 49 patients with either bacillary angiomatosis or peliosis hepatis. Of these patients, 53% were infected with B. henselae and 47% with B. quintana. Peliosis hepatis was exclusively associated with B. henselae (6 of 6 cases) whereas B. quintana was strongly associated with lytic bone lesions (8 of 8 cases). Skin involvement was seen in infections with both species but B. henselae infection was significantly associated with lymph node involvement. B. henselae infection was epidemiologically linked to cat and flea exposure whereas B. quintana infection was associated with low incomes, homelessness and exposure to lice. These results show that B. henselae infection causes peliosis hepatitis in HIV-infected individuals whereas the related species B. quintana causes lytic bone lesions. The results also demonstrate that infections with these two Bartonella species are associated with different epidemiological risk factors.

Williams, I., Smith, M. G., Sinha, D., Kernan, D., Minor-Babin, G., Garcia, E., Robertson, B. H., Di Pentima, R., and Shapiro, C. N. 1997. Hepatitis B virus transmission in an elementary school setting. Journal of the American Medical Association. 278:2167-2169.

This study documents transmission of hepatitis B virus (HBV) from a student to a teacher in an elementary school. The teacher's household and sexual contacts did not have HBV infection. One student in the classroom was identified with HBV infection ( HBeAg positive) and the virus sequence from this student and the teacher were identical. Of 102 of 104 other children in the same grade who were tested at the same school, none had serological evidence of HBV infection. The risk of HBV transmission in schools is very low, however, this study shows that it can rarely occur. The authors conclude that this isolated, unusual case does not suggest that current guidelines advocating the inclusion of HBV-infected children in day care centers or schools should be changed. They also point out that the current strategy of vaccinating all newborns and 11 to 12 year-old children against HBV in the United States will make the already very low risk of transmission in school settings virtually zero.

Kafri, T., Blomer, U., Peterson, D. A., Gage, F. H., and Verma, I. M. 1997. Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors. Nature Genetics. 17:314-317.

The major problem confronting gene tharapists, including those interested in liver-directed gene therapy, is to produce efficient delivery systems that provide sustained expression of the transgene. In this paper, the authors describe sustained expression of a reporter gene in liver and muscle by using a recombinant human lentivirus (HIV)-based vector that can transduce non-dividing cells. The authors used green fluorescent protein as a surrogate for a putative therapeutic protein encoded by the transgene. Direct injection of livers in living mice with the recombinant HIV-based vector encoding green fluorescent protein resulted in mice with fluorescent liver cells. The fluorescent protein was expressed in the livers for more than 22 weeks. Similar long-term expression was observed in directly injected muscle. Additional work may lead to the development of highly efficient lentiviral-based gene delivery vectors that give sustained gene expression and are suitable for use in liver-directed gene therapy.

Bennett, W. G., Inoue, Y., Beck, R., Wong, J. B., Pauker, S. G., and Davis, G. L. 1997. Estimates of the cost-effectiveness of a single course of interferon alpha-2b in patients with histologically mild chronic hepatitis C. Annals of Internal Medicine. 127:855-865

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Kim, W. R., Poterucha, J. J., Hermans, J. E., Therneau, T. M., Dickson, E. R., Evans, R. W., and Gross, J. B., Jr. 1997. Cost-effectiveness of 6 and 12 months of interferon-alpha therapy for chronic hepatitis C. Annals of Internal Medicine. 127:866-874.

Type I interferons are effective in the treatment of chronic hepatitis C, however, their cost-effectiveness has not been critically analyzed. These two paper address this issue. Both studies used Markov simulations of outcomes in hypothetical cohorts of patients. In the study by Bennett et al. (supported in part by a grant from the pharmaceutical company that sells interferon alpha-2b), the authors concluded that treating patients with "histologically mild" hepatitis C with interferon alpha-2b should "prolong life expectancy at a reasonable marginal cost per year of life gained, particularly in younger patients." In the study by Kim et al. (supported in part by a grant from the US government), the authors concluded that "from the standpoint of cost-effectiveness, interferon-alpha therapy for 6 to 12 months may be justified in patients with chronic hepatitis C" with the "possible exception" of patients older than 60 years. These simulated models suggest that alpha interferons are cost-effective treatments for younger patients with non-advanced chronic hepatitis C.

Marcellin, P., Boyer, N., Gervais, A., Martinot, M., Pouteau, M., Castelnau, C., Kilani, A., Areias, J., Auperin, A., Benhamou, J. P., Degott, C., and Erlinger, S. 1997. Long-term histological improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Annals of Internal Medicine. 127:875-881.

Less than 20% of patients with chronic hepatitis C treated with interferon alpha have a "sustained response" generally defined as normal serum alanine aminotransferase activity and undetectable viral RNA in serum six months after stopping therapy. This study examined the longer-term biochemical, virological and histologic outcomes in 80 such patients. The patients were followed for 1 to 7.6 years (mean ± SD of 4.0 ± 2.0 years). During the follow-up period, 93% of patients had persistently normal serum alanine aminotransferase activities and 96% continued to have undetectable serum viral RNA. A comparison of liver histology before and 1 to 6.2 years after treatment showed improvement in 94% of cases. In 62% of patients, the last liver biopsy showed normal or nearly normal histologic finding. In 27 of 80 patients tested, liver virus RNA was undetectable by reverse transcription-polymerase chain reaction 1 to 5 years after treatment. These results demonstrate that patients with chronic hepatitis who have a sustained responses to interferon-alpha have excellent longer-term responses and improvements in liver histology.

Gavier, B., Martinez-Gonzalez, M.-A., Riezu-Boj, J.-I., Lasarte, J.-J., Garcia, N., Civeira, M.-P., and Prieto, J. 1997. Viremia after one month of interferon therapy predicts treatment outcome in patients with chronic hepatitis C. Gastroenterology. 113:1647-1653.

It is not clear which patients with chronic hepatitis C will experience a sustained, viremia-free response after treatment with interferon-alpha. This study was designed to determine if undetectable serum viremia one month into treatment predicts a sustained response after treatment. One hundred eighty-one patients with chronic hepatitis C were treated with interferon-alpha for 12 months. Viremia and serum aminotransferase activities were measured at the end of one and three months of therapy. Serum viral RNA was detected by reverse transcription-polymerase chain reaction. A sustained response was considered as normal serum aminotransferase activities and non-detectable serum viral RNA for a minimum of 18 months after interferon-alpha was discontinued. Sustained responses were obtained in 28% of subjects. Detectable serum virus RNA at one month of therapy significantly predicted non-response with a predictive value of 95.3 (P < 0.0001). Independent predictors of sustained response were undetectable viremia at one month (P < 0.001), undetectable viremia at three months (P < 0.001), younger age (P = 0.006), nonsporadic infection (P = 0.012) and higher pretreatment aspartate aminotransferase activities (P = 0.032). The results suggest that patients with chronic hepatitis C are unlikely to have a sustained response to treatment with interferon alpha if hepatitis C viral RNA is detectable in serum by reverse transcription-polymerase chain reaction after one month of therapy.

Sauer, P., Theilmann, L., Stremmel, W., Benz, C., Goetz, R. M., and Stielh, A. 1997. Transjugular intrahepatic portosystemic stent shunt versus sclerotherapy plus propranolol for variceal rebleeding. Gastroenterology. 13:1623-1631.

Bleeding from esophageal varices is a life-threatening complication of cirrhosis. Treatments used to prevent rebleeding after a first variceal bleed include endoscopic sclerosis of the varices (sclerotherapy), endoscopic rubber band ligation of the varices, surgical shunt procedures, beta-blockers and transjugular intrahepatic portosystemic stent shunting (TIPS). Uncontrolled studies have demonstrated that TIPS is effective in preventing recurrent variceal bleeding, however, there have been only a few controlled studies and their conclusions have not been consistent. This randomized study compared TIPS to endoscopic sclerotherapy plus propranolol (a beta-blocker) in the treatment of patients with cirrhosis after a first variceal bleed. Eighty-three patients with cirrhosis were randomized, 42 to TIPS and 41 to sclerotherapy plus propranolol. Initial bleeding was controlled with sclerotherapy in most subjects and randomization performed 1 to 3 days after variceal bleeding was stopped. After median observation times of 1.6 years in the TIPS group and 1.45 years in the sclerotherapy group, cumulative rebleeding rates were 23% after TIPS and 57% in those subjects treated with sclerotherapy plus propranolol (P = 0.0001). However, hepatic encephalopathy was significantly more common in the subjects treated with TIPS (29% vs. 13%, P = 0.041) and overall survival rates were the same in both groups (69% vs. 67%, P = 0.62). The authors conclude that although TIPS significantly reduces rebleeding in patients with cirrhosis after a first-time variceal bleed, the increased risk of hepatic encephalopathy and lack of a survival benefit make it unsuitable to recommend as an elective treatment after the first variceal bleeding episode. TIPS, however, appears to be an effective therapy for patients in whom endoscopic sclerotherapy fails to control variceal bleeding.

Thompson, G. N., Hsu, B. Y. L., Pitt,J. J., Treacy, E., and Stanley, C. A. 1997. Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. New England Journal of Medicine. 337:1203-1207.

Many basic metabolic processes take place in the liver. During fasting, acetyl-CoA, which is produced by the breakdown of fats in liver cells, is converted to ketone bodies. The ketone bodies are used for energy production by other organs when the blood sugar level gets low. This report describes an 11 year-old boy who developed coma secondary to an inability to produce adequate ketone bodies during fasting. Histological examination of the liver showed mild fatty infiltration but no other abnormalities. Analysis of metabolic enzymes in the liver, however, showed that the patient had only 5 to 20 percent of the normal amount of HMG-CoA synthase, an enzyme (actually one of two similar enzymes located in the mitochondria) essential for the production of ketone bodies. This case report shows that deficiency of mitochondrial HMG-CoA synthase, an enzyme necessary for the production of ketone bodies in the liver during fasting, can lead to hypoketotic, hypoglycemic coma.

Poynard, T., Bedossa, P., Opolon, P., for the OBSVIRC, METAVIR, CLINIVIR, and DOSIVIRC groups. 1997. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 349:825-832.

Some individuals infected with the hepatitis C virus (HCV) have essentially normal lifespans and no complications of liver disease. Other infected individuals go on to develop cirrhosis. The natural history of HCV infection is poorly understood and it is unclear which infected individuals have an increased risk of developing cirrhosis. In this study, the authors recruited 2,235 patients from several hepatitis C study groups. All of the patients had a single liver biopsy consistent with chronic hepatitis C prior to treatment with any agent. The authors assessed the effects of the following factors on liver fibrosis: sex, age at infection, alcohol consumption, HCV genotype, HCV viremia, cause of infection and histological activity. Three of these factors were independently associated with an increased rate of fibrosis progression: age at infection greater than 40 years, male sex and consumption of 50 g or more of alcohol a day. There was no association between fibrosis progression and HCV genotype. The authors also estimated that, without treatment, 33% of patients had an expected median time to cirrhosis of <20 years and that 31% will not progress to cirrhosis in 50 or more years. Although complicated by the use of only single liver biopsies and some uncertainty about the time of HCV infection, the results indicate that male sex, older age at infection and significant alcohol consumption predict a worse prognosis for individuals with chronic hepatitis C.

Bonis, P. A. L., Ioannidis, J. P. A., Cappelleri, J. C., Kaplan, M. M., and Lau, J. 1997. Correlation of biochemical response to interferon alfa with histological improvement in hepatitis C: a meta-analysis of diagnostic test characteristics. Hepatology. 26:1035-1044.

In current practice, serum alanine aminotransferase (ALT) activity and viremia are used to follow patients with chronic hepatitis C treated with interferon-alpha. These parameters may not accurately reflect liver histology. This study was a meta-analysis of 15 previously published studies in which liver biopsies were performed before and after treatment. Two separate criteria for "histological response" were considered by the authors: an improvement in the Knodell or other scoring system of greater than or equal to 50% (strict criteria) of any improvement (less stringent criteria). When strict criteria were considered, 28% of patients showed improvement after treatment. The sensitivity and specificity of serum ALT activity normalization for determining this response were 70% and 66%, respectively. When less stringent criteria for histological response were considered, 62% of patients improved after treatment. The sensitivity and specificity of serum ALT activity normalization for this response were 55% and 77%, respectively. As many as 51% of treated patients showed some histological improvement despite failure to normalize serum ALT activity. These results show that normalization of serum ALT activity after interferon-alpha treatment does not always predict histological improvement in patients with chronic hepatitis C.