Current Papers in Liver Disease - February, 1996

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

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

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Linnen, J., Wages, J., Jr., Zhang-Keck, Z.-Y., Fry, K. E., Krawczynski, K. Z., Alter, H., Koonin, E., Gallagher, M., Alter, M., Hadziyannis, S., Karayiannis, P., Fung, K., Nakatsuji, Y., Shih, W.-K., Young, L., Piatak, M., Jr., Hoover, C., Fernandez, J., Chen, S., Zou, J.-C., Morris, T., Hyams, K. C., Ismay, S., Lifson, J. D., Hess, G., Foung, S. K. H., Thomas, H., Bradley, D., Margolis, H., and Kim, J. P. 1996. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science. 271:505-508.

In this paper, the authors identify a RNA virus associated with acute and chronic hepatitis similar to the previously identified GB-C virus and distantly related to the hepatitis C, GB-B and GB-A viruses. A cDNA expression library was constructed from the plasma of a patient with chronic hepatitis C. Immunoscreening of the expression library with the patient's serum identified several hepatitis C virus sequences and several other sequences that were unique. From these unique sequences, an anchored polymerase chain reaction method was used to amplify overlapping clones for the entire viral genome. The virus was termed the hepatitis G virus (HGV). Using these sequences, overlapping cDNAs for HGV were also isolated from the plasma of another patient. The polyprotein sequence identities between HGV and GB-A, GB-B and a hepatitis C virus (HCV) isolate were 43.8%, 28.4% and 26.8%, respectively. HGV was 85.5% identical in nucleotide sequence and 100% identical in amino acid sequence to the corresponding portion of GB-C that has been characterized. Using reverse transcription-polymerase chain reaction, HGV sequences were identified in 13% of 38 patients with non-A-E hepatitis in the U. S. It was also identified in about 18% of patients with hepatitis C. HGV was detected in serum samples from patients in the U. S., Australia, South America and Europe. HGV was also implicated in two prospectively studied patients with post-transfusion hepatitis who were negative for HGV prior to transfusion. These findings demonstrate that HGV, a virus the same as or very similar to GB-C, is associated with acute and chronic hepatitis worldwide.

Enomoto, N., Sakuma, I., Asahina, Y., Kurosaki, M., Murakami, T., Yamamoto, C., Ogura, Y., Izumi, N., Marumo, F., and Sato, C. 1996. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. New England Journal of Medicine. 334:77-81.

Different genotypes of the hepatitis C virus (HCV) can produce different clinical outcomes. Infection with HCV genotype 1b generally causes more active liver disease and progression to cirrhosis and hepatocellular carcinoma. This genotype is also more resistant to treatment with interferon. These investigators previously identified a region from amino acid 2209 to amino acid 2248 in the nonstructural protein 5A (NS5A) of HCV genotype 1b strain HCV-J that is associated with interferon sensitivity. In this study, 84 patients chronically infected with HCV genotype 1b, who had received interferon-alpha for six months, were retrospectively analyzed for response. The amino acid sequences of NS5A between amino acids 2209 and 2248 were also determined in the patients. Response to interferon-alpha, as indicated by the absence of HCV RNA after six months of therapy, did not occur in any of the 30 patients whose NS5A sequences were identical to wild type strain HCV-J. Of 38 patients with 1 to 3 amino acid substitutions in this region, 5 (13%) had a response to interferon-alpha treatment, as did all 16 patients with 4 to 11 amino acid substitutions in this region. In patients with chronic HCV genotype 1b infection, there is a correlation between response to interferon-alpha therapy and mutations in the NS5A gene. How mutations in this gene lead to interferon sensitivity remain to be determined, however, if they are deciphered, important therapeutic advancements may be realized.

Vakil, N. B., Schwartz, S. M., Buggy, B. P., Brummitt, C. F., Kherellah, M., Letzer, D. M., Gilson, I. H., and Jones, P. G. 1996. Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee. New England Journal of Medicine. 334:19-23.

In patients with human immundeficiency virus (HIV) infection, cryptosporidial infections of the biliary tree can occur. In March 1993, the municipal water supply in Milwaukee became contaminated with cryptosporidium and an outbreak of cryptosporidiosis occurred. This study retrospectively examined 82 patients infected with HIV in whom cryptosporidiosis occurred during the outbreak as documented by the detection of cryptosporidium in stool. Twenty-four subjects had biliary symptoms. Four of these 24 patients were alive one year after the outbreak as compared to 30 of 58 without biliary symptoms (P = 0.003). Of the patients with biliary symptoms, 21 had CD4 counts less than 50 per cubic millimeter as compared to 36 of 57 patients tested without biliary symptoms (P = 0.03). Within one year, there were significantly more deaths in patients with CD4 counts less than 50 per cubic millimeter than in those with higher counts. The results showed that when HIV-infected individuals are exposed to cryptosporidium, those with CD4 counts of less than 50 per cubic millimeter are at increased risk for biliary symptoms and death within one year of infection. However, death may not be directly related to cryptosporidial disease.

Zignego, A. L., Ferri, C., Giannini, C., Monti, M., La Civita, L., Careccia, G., Longombardo, G., Lombardini, F., Bombardieri, S., and Gentilini, P. 1996. Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia. Annals of Internal Medicine. 124:31-34.

Hepatitis C virus infection can cause mixed cryoglobulinemia. This study was designed to test the possible role of different hepatitis C genotypes in mixed cryoglobulinemia. Ninety patients with antibodies against hepatitis C were identified: 29 with and 61 without mixed cryoglobulinemia. Serum aminotransferase activity elevations were present in 55 % of patients with mixed cryoglobulinemia. Hepatitis C virus genotype 2a/III was detected in 41 % of patients with mixed cryoglobulinemia as compared to 15 % of patients without it. Among patients with mixed cryoglobulinemia, infection with genotype 2a/III was more frequent (85 %) in those without clinical and biochemical signs of liver disease. These results suggest that certain hepatitis C virus genotypes (2a/III) may be associated with mixed cryoglobulinemia, while others (e. g. 1b/II) are associated with more severe liver disease.

Bortolotti, F., Giacchino, R., Vajro, P., Barbera, C., Crivellaro, C., Alberti, A., Nebbia, G., Zancan, L., De Moliner, L., Bertolini, A., Balli, F., and Callea, F. 1995. Recombinant interferon-alfa therapy in children with chronic hepatitis C. Hepatology. 22:1623-1627.

Hepatitis C is relatively rare in children and its natural history is poorly understood. In this controlled pilot study, 27 children between the ages of 2 and 14 year with chronic hepatitis C were studied. On entry, all patients had abnormal serum alanine aminotransferase (ALT) activities, 22 had hepatitis C viral RNA detected by the polymerase chain reaction and all had evidence of chronic hepatitis on liver biopsies. Fourteen children received 5,000,000 units per square meter of recombinant interferon-alpha2b three times a week for four months. If serum ALT activities decreased by 50 % or more at 4 months, treatment was continued up to 12 months. Interferon-alpha was stopped at four months in 3 cases because ALT did not sufficiently decrease and in 1 case because of febrile convulsions. Of the 10 patients treated for 12 months, all had normal serum ALT activities at the end of treatment and 9 did not have detectable hepatitis C viral RNA. Four children relapsed as soon as therapy was withdrawn but 5 had sustained biochemical and virological responses at 24 months. Only one untreated patient had a sustained normalization of serum ALT activity and none cleared serum hepatitis C viral RNA. These preliminary results show that treatment with recombinant interferon-alpha may be of benefit to children with chronic hepatitis C.

Yoshiba, M., Okamoto, H., and Mishiro, S. 1995. Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown etiology. Lancet. 346:1131-1132.

The recently isolated GB-C virus (GBV-C), also called hepatitis G virus (HGV), is homologous to known flaviviruses and pestiviruses. It is similar to the hepatitis C virus but clearly a distinct species. This virus, along with two other recently identified viruses called GBV-A and GBV-B, have been implicated in acute and chronic hepatitis. In this study, six Japanese patients with fulminant non-A, non-B, non-C, non-D, non-E hepatitis were investigated for the presence of GBV-C genomic RNA sequences in their serum. GBV-C sequences were amplified from three of these six patients, implicating this virus as the cause of fulminant hepatitis. GBV-C/HGV may therefore be a cause of fulminant hepatitis in Japan and possibly in other parts of the world.

Dienstag, J. L., Perrillo, R. P., Schiff, E. R., Bartholomew, M., Vicary, C., and Rubin, M. 1995. A preliminary trial of lamivudine for chronic hepatitis B infection. New England Journal of Medicine. 333:1657-1661.

Lamivudine [(-)-2'-deoxy-3'-thiacytidine] is a nucleoside analog that inhibits the reverse-transcriptase activities of the human immunodeficiency virus (HIV) and hepatitis B virus (HBV). In this double-blind trial, 32 patients with chronic hepatitis B, including 17 who had not responded to previous treatment with interferon, were treated with 25, 100 or 300 mg daily oral doses of lamivudine for 12 weeks. Levels of serum HBV DNA became undetectable in 70 % of the patients treated with 25 mg/day and 100 % of the patients treated with 100 or 300 mg/day. However, in only 6 patients (19 %), did HBV DNA remain undetectable and serum aminotransferase activities normalize 24 weeks after treatment was discontinued. Serum hepatitis Be antigen disappeared in four patients. Serum aminotransferase activities increased in 41 % of treated patients concurrent with the lose of detectable serum HBV RNA. Only minor adverse reactions occurred during treatment, most commonly fatigue and headache. The results of this preliminary study indicate that larger, controlled trials of lamivudine are warranted for the treatment of chronic hepatitis B. In another article in the same volume (Eron et al. 1995. New England Journal of Medicine. 333:1662-1662), lamivudine was also shown to be of possible benefit in combination with zidovudine in the treatment of patients with HIV infection.

Di Bisceglie, A. M., Conjeevaram, H. S., Fried, M. W., Sallie, R., Park, Y., Yurdaydin, C., Swain, M., Kleiner, D. E., Mahaney, K., Wright, D., and Hoofnagle, J. H. 1995. Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine. 123:897-903.

This randomized, double-blind trial of ribavirin versus placebo for chronic hepatitis C was conducted at the National Institutes of Health. Twenty-nine patients received oral ribavirin (600 mg twice a day) and 29 placebo for 12 months. Only 5 % of the patients treated with placebo had decreases in their serum aminotransferase activities compared to 54 % of patients who received ribavirin. Serum aminotransferase activities became normal in 35 % of patients treated with ribavirin but none who received placebo. However, serum aminotransferase activities remained normal in only 2 of 29 patients after ribavirin therapy was discontinued. Serum hepatitis C virus RNA concentrations did not changes during or after therapy. Liver biopsy specimens showed decreased inflammation and necrosis in some of the treated patients who had decreases in serum aminotransferase activities. These results show that ribavirin has some beneficial effects on serum aminotransferase activities and liver histology in patients with chronic hepatitis C, however, these effects are not accompanied by decreases in hepatitis C viral RNA and do not persist when therapy is discontinued. Therefore, ribavirin alone does not appear to be efficacious as sole therapy for chronic hepatitis C. Because it has some beneficial effects, clinical trials are underway to see if ribavirin will improve the response rates when used in combination with interferon-alpha.

Ku, N.-O., Michie, S., Oshima, R. G., and Omary, M. B. 1995. Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant. Journal of Cell Biology. 131:1301-1314

Mutations in keratins, cytoplasmic intermediate filament proteins, cause several different skin diseases. In about 40% of these skin diseases, a highly conserved arginine residue near the beginning of the central rod domain is mutated. In liver, the two major keratins expressed are keratin 8 and keratin 18. Abnormalities in hepatocyte keratin filaments are also observed in alcoholic hepatitis and Mallory body formation. In this study, the authors developed a strain of transgenic mice that overexpressed keratin 18 with arginine 89 mutated to a cysteine. These mice developed chronic hepatitis and liver necrosis associated with fragile hepatocytes but no Mallory body formation. Mice overexpressing wild type keratin 18 did not develop liver abnormalities. The mutation was also associated with a relative increase in the phosphorylation and glycosylation of keratins 8 and 18 and abnormal formation of intermediate filaments in transfected cells. Mice expressing mutant keratin 18 provide a novel animal model for human chronic hepatitis. These finding also raise an intriguing possibility that some forms of human familial or autoimmune chronic hepatitis may be caused by mutations in keratins.

Nishiguchi, S., Kuroki, T., Nakatani, S., Morimoto, H., Takeda, T., Nakajima, S., Shiomi, S., Seki, S., Kobayashi, K., and Otani, S. 1995. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 346:1051-1055.

Patients with cirrhosis and chronic hepatitis C have an increased risk for the development of hepatocellular carcinoma. In this prospective study, 90 patients with chronic hepatitis C and compensated cirrhosis were randomly assigned to receive either 6,000,000 units of interferon-alpha three times a week for 12-24 weeks (n=45) or symptomatic treatment (n=45). The patients were followed for 2 to 7 years. Patients in the treatment group had lower serum alpha-fetoprotein concentrations and were more likely to have improvement on follow-up liver biopsy. Serum albumin concentrations were also greater in the treated patients. Hepatitis C viral RNA disappeared in 16% of the treated patients and none of the controls. Hepatocellular carcinoma was detected in two (4%) of patients treated with interferon-alpha and 17 (38%) of control subjects. In this study, interferon-alpha treatment of 12 to 24 weeks improved liver function in patients with compensated cirrhosis and hepatitis C. The use of interferon-alpha was also associated with a decreased incidence of hepatocellular carcinoma.

Shiffman, M. L., Jeffers, L., Hoofnagle, J. H., and Tralka. T. S. 1995. The role of transjugular intrahepatic portosystemic shunt for treatment of portal hypertension and its complications: a conference sponsored by the National Digestive Diseases Advisory Board. Hepatology. 22:1591-1597.

Transjugular intrahepatic portosystemic shunting (TIPS) is increasing in popularity for the treatment of portal hypertension and its complications. On February 28 and March 1, 1995, the National Digestive Diseases Advisory Board convened a scientific conference to review the current data available on TIPS and to make recommendations regarding the safety, efficacy and indications for the procedure. This "Special Article" in Hepatology is compiled by the organizers of the conference. The Advisory Board stated two conditions as accepted indications for TIPS: 1) acute variceal bleeding that cannot be successfully controlled with medical treatment including sclerotherapy and 2) recurrent variceal bleeding in patients who are refractory or intolerant to conventional medical management including sclerotherapy and pharmocological therapy. Uses considered as unproven but promising for TIPS were treatment of refractory ascites and treatment of Budd-Chiari syndrome. Several conditions were also described in which TIPS is not indicated or contraindicated. The adverse effects and complications of the procedure were also outlined, as were current research needs and recommended qualifications for physicians to perform the procedure. In summary, the Advisory Board stated that "TIPS is a new and exciting modality for treatment of portal hypertension and its complications. Indications for TIPS remain to be better defined in terms of efficacy and cost-benefit relationship to other established modes of therapy for portal hypertension. Prospective, randomized controlled trials are needed for these comparisons. Until the role of TIPS in the routine management of the complications of portal hypertension is better defined, TIPS should be used only in situations in which conventional medical and endoscopic therapies have failed."

Bosma, P. J. Chowdhury, J. R., Bakker, C., Gantla, S., De Boer, A., Oostra, B. A., Lindhout, D., Tytgat, G. N. J., Jansen, P. L. M., Oude Elferink, R. P. J., and Chowdhury, N. R. 1995. The genetic basis of the reduced expression of bililrubin UDP-glucuronosyltransferase I in Gilbert's syndrome. New England Journal of Medicine 333:1171-1175.

Gilbert syndrome is characterized by benign, mild, chronic, unconjugated hyperbilirubinemia in the absence of structural liver disease or overt hemolysis. The syndrome is inherited but its genetic basis is not known. In patients with Gilbert syndrome, hepatic glucuronidating activity is decreased by 30%. In this study, the authors examined the sequences of the UDP-glucuronosyltransferase 1 genes in 10 unrelated individuals with Gilbert syndrome, 16 members of a kindred with a history of Crigler-Najjar syndrome type II and 55 normal subjects. The coding region of the gene was found to be normal in 4 of the 10 patients with Gilbert syndrome (although in the Abstract to the article the authors claim this to be the case for all 10 subjects, in the results section they state that the coding regions were only sequenced in 4). All 10 subjects with Gilbert syndrome were homozygous for having two extra bases (TA) in the TATAA element of the gene's promoter. The sequence was ATATATATATATATATAA in subjects as compared to ATATATATATATAA in most normal individuals. When attached to a reporter gene and transfected into cultured hepatocyte cell lines, expression from the promoter with the extra TA was reduced compared to the promoter with the shorter element. Nonetheless, the frequency of the longer promoter element was fairly high in normal subjects and 8 of the 55 were homozygous for this allele but did not have Gilbert syndrome. Homozygosity for this allele therefore did not necessarily lead to Gilbert syndrome. Six subjects form the kindred with a history of Crigler-Najjar syndrome type II were heterozygous for the longer promoter element and had mild hyperbilirubinemia. The authors conclude that the longer promoter element in the UDP-glucuronosyltransferase 1 gene is necessary but not sufficient for the complete manifestations of Gilbert syndrome. The likely possibility still exists that Gilbert syndrome is a heterogeneous disorder with multiple different genotypes. This study did not correlate the two different promoter alleles with RNA levels or enzyme activities in subjects and did not state the ethnic origins of the 10 unrelated subjects. (Might different mutations occur in subjects with Gilbert syndrome from different ethnic groups?). Although the identified allele certainly plays a role in the development of Gilbert syndrome, at least in some cases, additional work is still required to better characterize this common syndrome at the genetic level.

McKenzie, R., Fried, M. W., Sallie, R., Conjeevaram, H., Di Bisceglie, A. M., Park, Y., Savarese, B., Kleiner, D., Tsokos, M., Luciano, C., Pruett, T., Stotka, J. L., Straus, S. E., and Hoofnagle, J. H. 1995. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue form chronic hepatitis B. New England Journal of Medicine. 333:1099-1105.

At the present time, only interferon alpha is approved for the treatment of chronic hepatitis B and only about one third of treated patients have a response. As for other agents, nucleoside analogues have been evaluated for patients with chronic hepatitis B. In this paper, the authors report on their experience at the National Institutes of Health with the nucleoside analogue fialuridine (FIAU) in patients with chronic hepatitis B. In their protocol, liver failure and lactic acidosis occurred rapidly in one patient who died. Seven patients of fifteen were found to have hepatotoxicity and lactic acidosis despite stopping the drug. Three other patients had mild hepatotoxicity. Some patients also developed pancreatitis, myopathy and neuropathy. Five of the seven patients with severe hepatotoxicity died and two survived only after liver transplantation. Histological and electron microscopic analysis of liver tissue showed microvesicular and macrovesiclular steatosis and abnormal mitochondria, suggesting that widespread mitochondrial damage was the primary cause of the toxicity. The unfortunate outcome of this trial should alert investigators to the possibility of mitochondrial toxicity with other drungs. Fortunately, this toxicity may be rare with other nucleoside analogues.

Margolis, H. S., Coleman, P. J., Brown, R. E., Mast, E. E., Sheingold, S. H., and Arevalo, J. A. 1995. Prevention of hepatitis B virus transmission by immunization. An economic analysis of current recommendations. Journal of the American Medical Association. 274:1201-1208.

and

Dobson, S., Scheifele, D., and Bell, A. 1995. Assessment of a universal, school-based hepatitis B vaccination program. Journal of the American Medical Association. 274:1209-1213.

Effective vaccines are available for hepatitis B. In the United States and Canada, most new infections of hepatitis B occur in adults, however, about 10% of infections occur in infants and young children. In the first of these two papers, Margolis et al. used a decision model to show that routine hepatitis B immunization of infants is cost-effective over a wide range of assumptions. A strategy of adolescent vaccination was economically less attractive than infant vaccination but useful to protect children who were not vaccinated as infants. In the second of these papers, Dobson et al. assessed a hepatitis B vaccination program offered to all grade six students in British Columbia Canada. They showed that school-based programs for universal hepatitis B immunization can also be highly acceptable and efficient. These two studies show that vaccines to present hepatitis B can be successfully and cost-effectively delivered to infants and children.

Scheinman, R. I., Cogswell, P. C., Lofquist, A. K., and Baldwin, A. S., Jr. 1995. Role of transcriptional activation of I-kappa-B-alpha in mediation of immunosuppression by glucocorticoids. Science. 270:283-286.

and

Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A., and Karin, M. 1995. Immunosuppression by glucocorticoids: inhibition of NF-kappa-B activity through induction of I-kappa-B synthesis. Science. 270:286-290.

Glucocorticoids such as prednisone, prednisolone, hydrocortisone and dexamethasone are mainstays in the treatment of autoimmune diseases including autoimmune hepatitis (see below). Despite their widespread use, little is known about how this class of drugs suppresses the immune response. In these two papers, the authors show that glucocorticoids stimulate the production of an intracellular protein called I-kappa-B-alpha. I-kappa-B-alpha inhibits the action of the transcription factor NF-kappa-B by binding to it and sequestering it in the cytosol. Immune stimulators are known to cause the degradation of I-kappa-B-alpha enabling NF-kappa-B to reach the nucleus and turn on genes for proteins such as cytokines that stimulate the immune response. Hence, by increasing I-kappa-B-alpha production, glucocorticoids inhibit the activity of NF-kappa-B. If these exciting findings prove to be the major mechanism of action of glucocorticoids in immunosuppression, the exciting possibility exists of designing drugs with similar activities without the side-effects of glucocorticoids.

Johnson, P. J., McFarlane, I. G., and Williams, R. 1995. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. New England Journal of Medicine. 333:958-963.

Corticosteroids, usually with azathioprine, are effective in inducing remission (resolution of symptoms, normalization of serum aminotransferase activities and decreased inflammation on liver biopsy) in patients with autoimmune hepatitis. However, about 80 % of patients relapse when both drugs are withdrawn making long-term maintenance therapy necessary in most individuals. Low-dose prednisone or prednisolone (5 to 10 mg a day) keeps about 70 % of patients in continued remission but side effects including Cushingoid facies and weigh gain can make such therapy undesirable. In the present study, 72 patients with autoimmune hepatitis in remission for one year on 5 -15 mg a day of prednisolone and 1 mg/kg a day of azathioprine were gradually tapered off prednisolone and maintained on 2 mg/kg a day of azathioprine. Of these 72 patients, 62 (83 %) remained in clinical and biochemical remission for a median follow-up period of 67 months. Of 48 liver biopsies in 45 patients, 45 showed minimal disease activity and only 3 showed moderate activity. Cushingoid facies improved in 26 patients and weight loss occurred in 32. Arthralgia was the most common side effect after prednisolone taper; 4 patients had myeolosuppression. Nine patients died during the follow-up period; only one from liver failure and 4 from cancer. One patient developed lymphoma but survived. There were also 3 unplanned pregnancies in 2 patients. In 26 patients, the daily dose of azathioprine was reduced to 1 mg/kg after one year in remission at 2 mg/kg and 5 patients in whom the dose was reduced had relapses. In conclusion, maintenance therapy with azathioprine alone is effective in patients with autoimmune hepatitis after remission has been induced with corticosteroids plus azathioprine. For individual patients, the choice of maintenance therapy should be determined by the side effect profiles of corticosteroids and azathioprine. As about 20 % of patients can remain in remission without maintenance therapy, an important remaining question is how long to continue therapy in each individual.

David, M., Petricoin, E., III, Benjamin, C., Pine, R., Weber, M. J., and Larner, A. C. 1995. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 262:1721-1723.

Interferons have anti-viral activities and are used in the treatment of chronic hepatitis B and chronic hepatitis C. Interferon alpha and beta bind to a cell membrane receptor that transduces information to the cell nucleus to stimulate the expression of several genes, some of which are necessary for the anti-viral response. Proteins called signal transducers and activators of transcription (STATs) are phosphorylated on tyrosine residues when interferon binds to its receptor by a protein kinase associated with the receptor called Jak. The STATs are then translocated to the nucleus where they, along with other factors, stimulate the transcription of certain genes. In this study, the authors show that the serine-threonine kinase MAP kinase (ERK2) also interacts with the alpha-subunit of the interferon alpha/beta receptor. In addition, interferon binding to its receptor induces an association between MAP kinase and a STAT protein. These results, along with those of previous studies showing that transcription activation by STATs requires phosphorylation on serine residues (Zhang et al. 1995. Science. 267:1990-1994; Wen et al. 1995. Cell. 82:241-250), suggest that MAP kinase regulates interferon alpha- and beta- stimulation of gene expression by modifying the Jak-STAT signaling cascade. They also demonstrate cross-talk between two signal transduction pathways previously thought to operate independently of each other.

Martinot-Peignouz, M., Marcellin, P., Pouteau, M., Castelnau, C., Boyer, N., Degott, C., Descombes, I., Le Breton, V., Milotova, V., Benhamou, J.-P., and Erlinger, S. 1995. Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotype are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C. Hepatology. 22:1050-1056.

Although interferon alpha is effective in the treatment of chronic hepatitis C, only about 20 % of patients show a long-term response. This retrospective analysis of 141 patients with chronic hepatitis C treated with different preparations of interferon alpha in different protocols was designed to determine the influence of pretreatment serum hepatitis C RNA levels and hepatitis C virus genotype on the response to interferon. A sustained response (normal serum ALT activity six months after cessation of treatment) was achieved in 28 patients (20 %), a response during treatment but with relapse after treatment (normal serum ALT activity during treatment but elevated after stopping interferon alpha) was seen in 43 patients (30 %) and no response to interferon alpha in 70 patients (50 %). Pretreatment serum RNA concentration was measured using the branched DNA assay and genotyping was performed by polymerase chain reaction (PCR) methods. All patients had detectable serum hepatitis C virus RNA by reverse transcription-PCR but only 43 % of the sustained responders, 77 % of the relapsers and 84 % of the non-responders on branched DNA assay. Mean serum viral RNA amounts were significantly lower in the patients with a sustained response. Genotype 1b was found in 7 % of the patients with a sustained response but 47 % and 46 % of the relapsers and non-responders respectively. On mutivariate analysis, only viral RNA concentration and genotype other than 1b were associated with a sustained response. Other factors such as younger age, shorter duration of infection and intravenous drug use as a source of infection were associated with sustained response on univariate analysis. The results suggest that pretreatment RNA levels and hepatitis C virus genotype are the main independent factors associated with a sustained response to treatment with interferon alpha.

Lindor, K. D., Dickson, E. R., Jorgensen, R. A., Anderson, M. L., Wiesner, R. H., Gores, G. J., Lange, S. M., Rossi, S. S., Hofmann, A. F., and Baldus, W. P. 1995. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology. 22:1158-1162.

Ursodeoxycholic acid (ursodiol) has been reported to be of benefit in most patients with primary biliary cirrhosis (PBC). Ursodiol lowers serum biochemical activities indicative of liver dysfunction and may slow the progression to cirrhosis or end-stage disease. Methotrexate is an immunosuppresive agent that has been suggested to be of benefit in patients with PBC in a few small pilot studies. In this study, 32 patients with PBC were treated for two years with a combination of ursodiol and methotrexate. Their courses were compared to those of a group of patients being treated only with ursodiol in another study during the same time period. Patients treated with both drugs did not show improvement in symptoms, biochemical parameters or liver biopsy findings compared to those treated with ursodiol alone. Seven patients in the combined treatment group had to be withdrawn because of side-effects attributed to methotrexate. The authors concluded that methotrexate should not be routinely used in the treatment of patients with PBC and that its use in this disease should be confined to prospective clinical trials.

Banks, A. T., Zimmerman, H. J., Ishak, K. G., and Harter, J. G. 1995. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology. 22:820-827.

Diclofenac is a nonsteroidal anti-inflammatory agent widely prescribed for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and the management of pain. This study analyzed 180 cases of hepatic toxicity associated with diclofenac use reported to the FDA between 1988 and 1991. The data indicate that diclofenac-associated hepatotoxicity is particularly likely to involve osteoarthritic women presenting with jaundice 1 to 6 months after starting the drug. Liver injury is predominantly hepatocellular and presumably caused by metabolic idiosyncrasy.

Chemello, L., Bonetti, P., Cavalletto, L., Talato, F., Donadon, V., Casarin, P., Belussi, F., Frezza, M., Noventa, F., Pontisso, P., Benvegnu, L., Casarin, C., Alberti, A., and the TriVeneto Viral Hepatitis Group. 1995. Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C. Hepatology. 22:700-706.

This paper reports another trial of different dosing schedules of alpha-interferon in the treatment of chronic hepatitis C. In this study from Italy, 174 patients with chronic hepatitis C using were randomized to three different dosing schedules: (1) 12-month treatment starting with 6 million units (MU) three times a week and decreasing the dose on the basis of serum ALT activities; (2) fixed dose of 3 MU three times a week for 12 months; (3) fixed dose of 6 MU three times a week for 6 months. Serum ALT activities became normal during therapy in between 65 % and 76 % of patients with no significant differences between groups. Twelve months after the completion of therapy, however, 49 % of the patients in the first group had normal serum ALT activities while only 31 % and 28 % respectively did in the second two groups. The majority of patients with normal serum ALT activities 12 months after treatment had no serum HCV RNA detected by the reverse transcription-polymerase chain reaction and improved liver biopsy findings at that time. Patients infected with HCV genotype 1b did worse overall but showed a better chance of having a sustained response with higher dose and longer treatment. These results, combined with the results of several other recent studies, show that sustained response to treatment with alpha-interferons in patients with chronic hepatitis C is affected by dose and duration of therapy.

Besson, I., Ingrand, P., Person, B., Boutroux, D., Heresbach, D., Bernard, P., Hochain, P., Larricq, J., Gourlaouen, A., Ribard, D., Kara, N. M., Legoux, J.-L., Pillegand, B., Becker, M.-C., Di Costanzo, J., Metreau, J.-M., Silvain, C., and Beauchant, M. 1995. Sclerotherapy with or without octreotide for acute variceal bleeding. New England Journal of Medicine. 333:555-560.

Bleeding from esophageal varices is a life-threatening complication of portal hypertension that most frequently is caused by liver cirrhosis. In recent years, endoscopic injection of varices with sclerosing agents, a therapy called sclerotherapy, has been used as a successful treatment to stop acute bleeding from varices and to obliterate them. Octreotide is a synthetic somatostatin analog that reduces collateral splanchic blood flow and is effective in controlling variceal bleeding. In this prospective, double-blind, randomized trial, the investigators studies 199 patients with cirrhosis and variceal bleeding who underwent emergency sclerotherapy. The patients were then randomly assigned to receive octreotide (98 patients) or placebo (101 patients) for five days by continuous infusion. In the octreotide group, 87 % survived without rebleeding while 71 % of patients survived without rebleeding in the placebo group (p = 0.009). Patients in the octreotide group also received fewer blood transfusions. However, the mean 15-day cumulative survival rate was the same (approximately 88 %) in both groups. In patients with cirrhosis, sclerotherapy plus octreotide is more effective than sclerotherapy alone in controlling acute variceal bleeding but the addition of octreotide does not influence overall mortality. This study also did not address the technique of rubber band ligation as an alternative to sclerotherapy in patients with bleeding esophageal varices.