Current Papers in Liver Disease - May, 1997

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

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

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Martinot, M., Marcellin, P., Boyer, N., Detmer, J., Pouteau, M., Castelnau, C., Degott, C., Auperin, A., Collins, M., Kolberg, J., Wilber, J., Benhamou, J.-P., and Erlinger, S. 1997. Influence of hepatitis G virus infection on the severity of liver disease and response to interferon-alpha in patients with chronic hepatitis C. Annals of Internal Medicine. 126:874-881.

In a previous retrospective study, Tanaka et al., 1996 (see November, 1996 Current Papers in Liver Disease) studied 189 patients in Japan and showed that those with chronic hepatitis C virus (HCV) and hepatitis G virus (HGV) co-infection do not differ from patients with only HCV infection. They also showed that a small sample of co-infected individuals do not appear to responsd differently to interferon therapy. [For more information on hepatitis G click here.] In this larger but similar study, Martinot et al. report on 228 patients in France with chronic hepatitis C who were retrospectively examined for HGV co-infection. HGV co-infection was detected in 21% of all patients and 32% of those who were intravenous drug users. Serum HCV RNA levels, liver histology and response to treatment with interferon-alpha did not differ between patients with and without HGV co-infection. Loss of serum HGV RNA did not correlate with a biochemical response whereas loss of serum HCV RNA did. These results show that HGV co-infection frequently occurs in individuals infected with HCV and that HGV does not influence the severity of liver disease or response to treatment with interferon-alpha in patients with chronic hepatitis C.

Lopez-Alcorocho, J. M., Millan, A., Garcia-Trevijano, E. R., Bartolome, J., Ruiz-Moreno, M., Otero, M., and Carreno, V. 1997. Detection of hepatitis GB virus type C RNA in serum and liver from children with chronic viral hepatitis B and C. Hepatology. 25:1258-1260.

and

Kanda, T., Yokosuka, O., Ehata, T., Maru, Y., Imazeki, F., Saisho, H., Shiratori, Y., and Omata, M. 1997. Detection of GBV-C RNA in patients with non-A-E fulminant hepatitis by reverse-transcription polymerase chain reaction. Hepatology. 25:1261-1265.

and

Pessoa, M. G., Terrault, N. A., Ferrell, L. D., Kim, J. P., Kolberg, J., Detmer, J., Collins, M. L., Yun, A. J., Viele, M., Lake, J. R., Roberts, J. P., Ascher, N. L., and Wright, T. L. 1997. Hepatitis G virus in patients with cryptogenic liver disease undergoing liver transplantation. Hepatology. 25:1266-1270.

and

Fried, M. W., Khudyakov, Y. E., Smallwood, G. A., Cong, M.-E., Nichols, B., Diaz, E., Siefert, P., Gutekunst, K., Gordon, R. D., Boyer, T. D., and Fields, H. A. 1997. Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease. Hepatology. 25:1271-1275.

The hepatitis G virus (HGV, also known as GB-C) is a member of the Flaviviridae family and is approximately 25% identical in its genomic sequence to the hepatitis C virus [for more information on hepatitis G click here]. The role of this recently identified virus in human hepatitis remains unclear. These four papers provide further evidence that HGV may not be a significant cause of acute or chronic liver disease. Lopez-Alcoroch et al. show that 15% of children with chronic hepatitis C or hepatitis B are infected with HGV, however, HGV co-infection does not appear to cause more severe liver disease. Kanda et al. and Pessoa et al. both show that HGV is frequently transmitted by blood transfusions to patients who either have fulminant hepatic failure or undergo orthotopic liver transplantation. However, Kanda et al. show that HGV is usually absent on initial presentation in persons with fulminant hepatic failure and Pessoa et al. showed no differences in the frequencies of post-transplantation hepatitis or graft survival in individuals with or without HGV infection. Fried et al. also show no differences in graft or patient survival in individuals who undergo liver transplantation for hepatitis C. These four papers, along with other recent publications suggest that HGV, although common in the blood supply, may not be major cause of hepatitis in humans.

Ray, R. B., Steele, R., Meyer, K., and Ray, R. 1997. Transcriptional repression of p53 promoter by hepatitis C virus core protein. Journal of Biological Chemistry. 272:10983-10986.

Chronic hepatitis C infection can lead to the development of hepatocellular carcinoma (the predominant type of primary liver cancer), however, the mechanisms are not understood. Inactivation of the p53 tumor suppressor by mutation is seen in many or most hepatocellular carcinoma. In this study, the authors show that, in transfection assays using tissue culture cells, the hepatitis C virus core protein represses transcription of the p53 gene. In liver cells, this could result in decreased amounts of the p53 tumor suppressor protein that may predispose to the development of cancer. This interesting mechanism remains to be proven to be operative in humans with chronic hepatitis C.

Kaplan, M. M., DeLellis, R. A., and Wolfe, H. J. 1997. Sustained biochemical and histological remission of primary biliary cirrhosis in response to medical treatment. Annals of Internal Medicine. 126:682-688.

Several studies have examined the effectiveness of methotrexate in the treatment of primary biliary cirrhosis (PBC). A fairly recent report of 32 patients suggested that this drug may not be useful (See Lindor et al. 1995. Hepatology. 22:1158-1162; reviewed in February, 1996 Current Papers in Liver Disease). In this report by Kaplan et al., the authors describe 5 of 19 patients with PBC who were treated in a non-randomized, uncontrolled trial with methotrexate. These 5 patients, who were followed for at least 6 years, had "biochemical and histological remissions" based on the facts that "biochemical tests of liver function became normal", that "symptoms remitted" and that "serial liver biopsy specimens showed few signs of PBC and, in 3 patients, were close to normal." It must be cautioned that this paper was only an anecdotal report of 5 cases. There was no control group for comparison and a statistical analysis could not be performed. At best, the results suggest that large, randomized, controlled trials of methotrexate are warranted for patients with PBC.

Mahler, H., Pasi, A., Kramer, J. M., Schulte, P., Scoging, A. C., Bar, W., and Krahenbuhl, S. 1997. Fulminant liver failure in association with the emetic toxin of bacillus cereus. New England Journal of Medicine. 336:1142-1148.

Bacillus cereus is a foodborne pathogen known to cause self-limited gastroenteritis. Bacterial toxins are responsible for the symptoms including an enterotoxin that causes diarrhea and cereulide that is an emetic (causes vomiting). This paper reports fulminant liver failure in a 17 year-old boy that is attributed to cereulide. The boy and his father developed gastrointestinal symptoms soon after eating pasta with homemade pesto sauce. The father recovered but the boy, who ate more pasta and pesto, developed fulminant hepatic failure and died. There was no evidence of viral hepatitis, drug toxicity or other causes of liver failure. Liver biopsy showed microvesicular steatosis, a finding indicative of decreased mitochondrial fatty acid oxidation. B. cereus strains were isolated from the pesto, the patient's intestinal contents and the pan that was used to reheat the food. A large amount of cereulide was also detected in the pan residue. The authors showed that cereulide had effects on mitochondrial respiration in vitro by both inhibiting the electron transport chain and uncoupling oxidative phosphorylation. This case report implicates cereulide, the emetic toxin of B. cereus, as a cause of fulminant liver failure. The mechanism of action appears to be mitochondrial toxicity.

Vogels, A. P. M., Maas, M. A. W., Daalhuisen, J., Quack G., and Chamuleau, R. A. F. M. 1997. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology. 15:820-827.

Hepatic encephalopathy is a complication of end-stage cirrhosis and fulminant hepatic failure. Its pathogenesis is not completely understood, however, it is associated with high concentrations of circulating ammonia. In this study, the possible role of N-methyl-D-aspartate (NMDA) receptor over activity in hyperammonemia-induced encephalopathy was investigated. NMDA receptors bind to and are activated by the neurotransmitters glutamate and aspartate. Two rat models of hepatic encephalopathy were used, protacaval-shunted rats and complete liver ischemia. Encephalopathic rats treated with the noncompetitive NMDA receptor antagonist (blocker) memantine had improvements in encephalopathy and in their electroencephalograms. Memantine-treated rats also had less brain swelling which often accompanies severe encephalopathy. These results suggest that NMDA receptor over activity may play a role in hyperammonemia-induced hepatic encephalopathy and lead to the development of drugs to treat the condition. A large body of past work has also shown that benzodiazapine receptor antagonists transiently improve hepatic encephalopathy.