Current Papers in Liver Disease - February, 1997

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

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

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Falagas, M. E., Snydman, D. R., Griffith, J., Ruthazer, R., Werner, B. G, and the Boston Center for Liver Transplantation CMVIG Study Group. 1997. Effect of cytomegalovirus infection status on first-year mortality rates among orthotopic liver transplant recipients. Annals of Internal Medicine. 126:275-279.

Infection with cytomegalovirus (CMV) may be a risk factor for mortality after orthotopic liver transplantation. In this study, the authors examined 146 liver transplant recipients to determine if CMV infection status is a risk factor for mortality. One year mortality rates were as follows: CMV seronegative donor to seronegative recipient 11%, seronegative donor to seropositive recipient 22%, seropositive donor to seropositive recipient 30% and seropositive donor to seronegative recipient 44% (P = 0.0091). The relative risk of death up to one year after transplantation was 2.7 for recipients who received livers from seropositive donors compared to recipients who received livers from seronegative donors. Multivariate analysis showed that retransplantation, total number of units of blood products administered during transplantation, the presence of CMV disease, invasive fungal disease and bacteremia were independently associated with higher mortality rates. Donor and recipient CMV serological status is a significant determinant for death in orthotopic liver transplant recipients. Matching donors and recipients for CMV serological status or more intensive antiviral prophylaxis may improve survival.

The Incident Investigation Teams and Others. 1997. Transmission of hepatitis B to patients from four infected surgeons without hepatitis Be antigen. New England Journal of Medicine. 336:178-184.

Transmission of hepatitis B virus (HBV) from infected surgeons to patients has been well documented. Most surgeons who transmit HBV have serum hepatitis BeAg which is associated with high levels of viral replication and circulating virus. In the United States and United Kingdom, most recommendations of restricting the practices of health care workers depend upon the presence of BeAg. In this study, four unconnected cases of acute hepatitis B were identified in the United Kingdom in patients whose only apparent risk was recent surgery. In each case, a surgeon was found to be infected with HBV by the presence of serum HBsAg. None of the four surgeons had detectable BeAg measured by at least two different immunoassays in two different laboratories. Three of the four surgeons did not have detectable concentrations of HBV DNA ins serum measured by standard liquid hybridization assays. Sequencing of HBV DNAs amplified from sera by the polymerase chain reaction revealed that the isolates were identical in the doctors and corresponding patients. Each isolate had a mutation in the pre-core gene that created a premature stop codon that abolished the synthesis of BeAg impossible. This study demonstrates that surgeons who are infected with HBV (HBsAg positive), without detectable serum BeAg or viral DNA measured by routine clinical assays, can transmit hepatitis B to patients during procedures. It is not clear if HBV isolates with mutations in the pre-core gene are uniquely responsible for this phenomenon.

Benvegnu, L., Pontisso, P., Cavalletto, D., Noventa, F., Chemello, L., and Alberti, A. 1997. Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis. Hepatology. 25:211-215.

Hepatitis C virus (HCV) is classified into different genotypes based on sequence differences in the viral genome. Several previous studies have suggested that some genotypes, generally type 1a and 1b, are associated with more advanced liver disease. For example, Zein et al. (1996) [see November 1996 Current Papers in Liver Disease] recently showed that genotypes 1a and 1b, the most prevalent in the United States, are associated with more severe liver disease. In this study, the authors studied 429 patients in Italy with chronic hepatitis C including 109 with cirrhosis. The patients with cirrhosis were followed prospectively to assess the role of HCV genotype on disease outcome. Genotype 1 (mainly 1b) was detected in 46% of patients without cirrhosis and 43% with cirrhosis (P not significant). Genotype 2 (mainly 2a) was detected in 32% of individuals without cirrhosis and 27.5% with cirrhosis (P not significant). Genotype 3 was detected in 10% of patients without cirrhosis and 2% with cirrhosis (P < 0.005). Mixed genotype infections were found in 5.5% of individuals, all of whom had cirrhosis. During a mean follow-up of the patients with cirrhosis for 67 months, 38.5% had either worsening of Child's stage, underwent liver transplantation, developed hepatocellular carcinoma or died. The probability of developing each or at least one of these events did not differ in relation to the genotype of infecting HCV, except for a higher incidence of death in individuals with mixed genotype infections. These results, which are in contrast to those of several other studies, suggest that HCV genotype does not have a significant effect on the severity and progression of liver disease in patients with chronic hepatitis.

Bulaj, Z. J., Griffen, L. M., Jorde, L. B., Edwards, C. Q., and Kushner, J. P. 1996. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. New England Journal of Medicine. 335:1799-1805.

Hereditary hemochromatosis is an autosomal recessive disease. The responsible gene is located on chromosome 6 and tightly linked to HLA class I genes. A candidate gene has recently been identified (Feder et al. 1996. Nature Genetics. 13:399-408.). Homozygous individuals develop complications of iron overload including, among others, cirrhosis of the liver. It has been estimated that about 10% of whites are heterozygous for the hemochromatosis mutation, and although heterozygotes generally do not develop complications of iron overload, the degree of morbidity in this population is not completely clear. In this study, 1058 genotyped heterozygotes (defined by HLA haplotypes) were examined, 505 of which were male and 533 female from 202 pedigrees. The comparison group was 321 genetically normal individuals from the same families. Mean serum iron concentrations and transferrin-saturation values were higher in the heterozygotes than in the normal subjects but did not increase with age. For percent of male and 8% of female heterozygotes had transferrin-saturation values generally associated with homozygotes (50% for females and 62% for males). Mean serum ferritin concentrations were also higher in hemochromatosis heterozygotes than in normal subjects. Liver biopsies were performed in 39 heterozygotes, 17 of whom had normal transferrin-saturation and ferritin levels. Liver biopsy abnormalities were associated with other diseases and not with iron overload. These results show that the phenotype of individuals heterozygous for hemochromatosis differs from that of normal persons but that complications caused by iron overload in heterozygotes are extremely rare or absent.

Cressman, D. E., Greenbaum L. E., DeAngelis, R. A., Ciliberto, G., Furth, E. E., Poli, V., and Taub, R. 1996. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 274:1379-1383.

Normal mouse and human liver has an amazing capacity for regeneration. After 70% of the liver is removed, the remaining normally quiescent hepatocytes proliferate and the liver mass is restored in several days. The same can occur after toxic injury. Abnormal proliferation also occurs in cirrhosis. The factors that stimulate resting hepatocytes to proliferate are only poorly understood. In this paper, the authors show that knockout mice deficient in the cytokine interleukin-6 (IL-6) have defective hepatocyte regeneration after partial hepatectomy that results in liver failure. After partial hepatectomy, STAT3, a protein involved in IL-6 signal transduction, was not activated as it was in controls. Decreased expression of AP-1, Myc, cyclin D1, and various other genes was also observed in IL-6 knockout mice after partial hepatectomy. There was also decreased DNA synthesis in hepatocytes but not in non-parenchymal liver cells. Mortality and morbidity was significantly increased in the IL-6-deficient mice compared to controls after partial hepatectomy. A single dose of IL-6 prior to surgery returned STAT3 activation, gene expression and hepatocyte proliferation to near normal and prevented liver damage. This study demonstrates that IL-6 is a critical factor in liver regeneration.

Lindsay, K. L., Davis, G. L, Schiff, E. R., Bodenheimer H. C., Balart L. A., Dienstag, J. L., Perrillo, R. P., Tamburro C. H., Goff, J. S., Everson, G. T., Silva, M., Katkov, W. N., Goodman, Z., Lau, J. Y. N., Maertens, G., Gogate, J., Sanghvi, B., Albrecht, J., and the Hepatitis Interventional Therapy Group. 1996. Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatology. 24:1034-1040.

Interferon alpha-2b is effective in reducing serum aminotransferase activities and viral loads in patients with chronic hepatitis C. The currently approved dose and treatment course is 3 million units three times a week for six months. However, a significant number of patients do not respond to this dose and most, after stopping treatment, have recurrent elevations in serum aminotransferase activities and viral concentrations. This study was designed to determine if higher doses of interferon alpha-2b would improve response rates and the durability of response. Two hundred forty-eight patients with chronic hepatitis C, not previously treated with interferon, were enrolled at nine centers and started on either 3, 5, or 10 million units of interferon alpha-2b three times a week for 12 weeks. Based on alanine aminotransferase activities after 12 weeks of treatment, patients were randomized to either continuation of the same dose or an increased dose for another 12 to 36 weeks. The overall complete response rates at 12 weeks were not significantly different in the individuals receiving either 3, 5 or 10 millions units of interferon (31% vs. 42% vs. 40%). Twelve percent of patients who did not respond to the 3 million unit dose at 12 weeks responded when the dose was increased to 5 million or 10 million units three times a week, but none responded to continued therapy with 3 million units three times a week. There was a marginal increase in long-term, sustained responses in individuals receiving doses greater than 3 million units three times a week, however, side effects were more intolerable. In summary, only about 10% of patients who do not respond to 3 million units three times a week of interferon alpha-2b will respond to dose increases to up to 10 million units three times a week. There appears to be little added benefit and increased toxicity if initial doses greater 3 million units are used.