Current Papers in Liver Disease - September, 1995

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

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

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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 reults, combined with the results of several other recent studies (see below), show that sustained response to treatment with alpha-interferons in patients with chronic hepatitis C is affected by dose and duration of therapy.

Gretch, D. R., dela Rosa, C., Carithers, R. L., Willson, R. A., Williams, B., and Corey, L. 1995. Assessment of hepatitis C viremia using molecular amplification technologies: correlations and clinical implications. Annals of Internal Medicine. 123:321-329.

Two techniques are sometimes used to quantify the levels of hepatitis C virus (HCV) RNA in the serum of patients with chronic hepatitis C. One of these techniques in quantitative polymerase chain reaction (PCR) after reverse transcription of HCV RNA to DNA. The other technique is a branched-chain DNA (bDNA) assay in which viral RNA is captured by nucleic acid hybridization on a plastic well, the captured DNA is hybridized again with complementary DNA which are then reacted with synthetic oligonucleotides that are attached to a chemiluminescent compound for detection. In this study, the authors compared these two tests in 299 patients with HCV viremia (detected by non-quantitative reverse transcription-PCR), 101 controls and 19 patients receiving interferon treatment. Quantitative PCR was able to detect HCV RNA four log orders lower in concentration than the bDNA assay. Nonetheless, the bDNA assay was 87.6 % sensitive and 97 % specific in the detection of HCV RNA. This assay did not detect HCV RNA in about 15 % of samples with concentrations below its lower limit detection cut-off that were detectable by quantitative PCR. The bDNA assay also gave lower and more variable values of HCV RNA concentrations than quantitative PCR in subgroups of patients with high amounts of serum RNA who had either end-stage liver disease or had undergone orthotopic liver transplantation. In 19 patients treated with interferon, 14 had detectable HCV RNA by quantitative PCR during and/or after treatment but 4 of these did not have detectable HCV RNA on the bDNA assay. These results show that the bDNA assay is generally sensitive and specific for the detection of serum HCV RNA but that it may not detect low levels of RNA in some patients. The bDNA assay also gives falsely low and variable concentration measurements in patients with end-stage liver disease or who have have undergone liver transplantation. Although quantitative PCR appears to be a superior assay, it is labor intensive and, in general, is only properly performed in research laboratories. Quantitative PCR may therefore be best suited as the "gold standard" to test newer technologies but may not be appropriate for routine clinical use.

Shakil, A. O., Conry-Cantilena, C., Alter, H. J., Hayashi, P., Kleiner, D. E., Tedeschi, V., Krawczynski, K., Conjeevaram, H. S., Sallie, R., Di Bisceglie, A. M., and the Hepatitis C Study Group. 1995. Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features. Annals of Internal Medicine. 123:330-337.

Many patients have antibodies against the hepatitis C virus (HCV) but have no symptoms and even normal serum ALT and AST activities. In this study, the significance of antibody to HCV was assessed in volunteer blood donors. Three groups, each with 20 subjects were examined. Group I had normal serum ALT activities, group II activities less than twice normal and group III activities more than twice normal. Of subjects with abnormal ALT activities, 95 % had detectable serum HCV RNA by reverse transcription-polymerase chain reacation (RT-PCR). Of subjects with normal ALT activities, 65 % had detectable serum HCV RNA. Of the patients with normal ALT activities, 3 had normal liver biopsies and 3 had only non-specific changes; the other 14 had evidence of chronic hepatitis on their biopsies. All of the patients with abnormal ALT activities had hepatitis on liver biopsy but only one of these asymptomatic patients had cirrhosis. Of the subjects that did not have detectable HCV RNA, 7 of 9 had normal ALT activities, 3 of 9 had normal liver biopsies and 2 of 9 had only non-specific changes on biopsy; only 4 had evidence of chronic hepatitis. These results show that most blood donors with antibodies against HCV have chronic hepatitis regardless of their serum ALT activities. Donors with normal ALT activities and no detectable HCV RNA generally have normal liver biopsies or minimal non-specific changes and may have recovered from hepatitis C. The clinical characteristics of these asymptomatic blood donors can also be cautiously compared to patients with hepatitis C who were referred to a liver center in another study (Tong, M. J., El-Farra, N. S., Reikes, A. R., and Co, R. L. 1995. Clinical outcomes after transfusion associated hepatitis C. New England Journal of Medicine. 332:1463-1466; see below) in which more than 50 % of patients had cirrhosis. This suggests that asymptomatic patients found to have chronic hepatitis C may have a better prognosis than symptomatic patients.

Lo, G.-H., Lai, K.-H., Cheng, J.-S., Hwu, J.-H., Chang, C.-F., Chen, S.-M., and Chiang, H.-T. 1995. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology. 22:466-471.

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Laine, L., and Cook, D. 1995. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding a meta-analysis. Annals of Internal Medicine. 123:280-287.

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 thearpy called sclerotherapy, has been used as a successful treatment to stop acute bleeding from varices and to obliterate them. More recently, endoscopic ligation, similar to the widely used technique of rubber band ligation of hemorrhoids, has also been used in the treatment of bleeding esophageal varices. In the study by Lo et al. from Taiwan, a randomized, prospective trial of these two treatments showed that both can effectively stop bleeding from esophageal varices but that ligation produced fewer complications and obliterated varices more rapidly. Most importantly, survival was better in the patients treated with ligation. Lane and Cook performed a meta-analysis of seven relevant randomized trials that compared endoscopic ligation to sclerotherapy for the treatment of patients with bleeding esophageal varices. This analysis showed that ligation compared with sclerotherapy reduced the rebleeding rate, the mortality rate and the rate of death due to bleeding. Based on the prospective study of Lo et al. and the meta-analysis of Laine and Cook, it appears that endoscopic ligation may be superior to sclerotherapy in the treatment of bleeding esophageal varices.

Bergasa, N. V., Alling, D. W., Talbot, T. L., Swain, M. G., Yurdaydin, C., Turner, M. L., Schmitt, J. M., Walker, E. C., and Jones, E. A. 1995. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Annals of Internal Medicine. 123:161-167.

Patients with cholestatic liver diseases often have severe pruritus (itching) refractory to available treatments such as bile acid binding resins. Past studies have suggested that endogenous opioid agonists contribute to the pruritus of cholestasis. In this double-blind, randomized, controlled trial of 29 patients with pruritus and liver disease, the authors showed that infusions of the opiate receptor antagonist naloxone was associated with amelioration of the perception of pruritus and a reduction of scratching activity. These results support the hypothesis that endogenous opioids play a role in the pathophysiology of pruritus of cholestasis and that opiate receptor antagonists may be useful in the clinical management of patients with this condition.

Marcellin, P., Routeau, M., Martinot-Peignoux, M., Degos, F., Duchatelle, V., Boyer, N, Lemonnier, C., Degott, C., Erlinger, S, and Benhamou, J.-P. 1995. Lack of benefit of escalating dosage of interferon alfa in patients with chronic hepatitis C. Gastroenterology. 109:156-165.

Many patients that receive the standard dose of interferon alfa for chronic hepatitis C do not show a long-term response and relapse after stopping treatment. Other patients do not respond to the standard dose. In this study, 25 patients were treated with the standard dose of 3,000,000 units of interferon alfa three times a week for 24 weeks. Another 50 were treated on a protocol in which the dose was increased to 5,000,000 units at 8 weeks in non-responders and to 10,000,000 8 weeks later in persistent non-responders. In both grouups, a sustained response rate of around 20 % was observed. Low pre-treatment viral RNA levels and genotype other than type 1b predicted a sustained response. This study showed that escalating dosage of interon alfa did not improve the overall rate of response. However, it is possible that other dosing schedules, or a combination of escalating dosage and a longer duration of treatment (see Poynard et al. and Olle et al. discussed below) will improve response.

Poynard, T., and the Multicenter Study Group. 1995. A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. New England Journal of Medicine. 332:1457-1462.

In this large, prospective study from France, over 300 patients with chronic non-A, non-B hepatitis, approximately 88 % of whom were shown to be infected with the hepatitis C virus, were treated with various interferon alfa-2b regimens for 18 months. All 329 patients received the standard dose of 3,000,000 units three times a week for the first six months. For the next 12 months, approximately a third of the patients continued to receive 3,000,000 units three times a week (Group 1), another third 1,000,000 units three times a week (Group 2) and another third no interferon alfa-2b (Group 3). After a total of 18 months, 44.7 % of patients in Group 1, 26.7 % of patients in Group 2 and 30.3 % of patients in Group 3 had normal serum aminotransferase activities, respectively. At times between 19 and 42 months, 22.3 % of patients in Group 1, 9.9 % in Group 2 and 8.1 % in Group 3 had normal serum aminotransferase activities, respectively. Of patients who had follow-up liver biopsies at 18 months, a greater number in Group 1 showed improvement compared to Groups 2 and 3. These results suggest that longer treatment with interferon alfa-2b may improve the long-term response in patients with chronic hepatitis C. This study did not take into account the additional cost of longer treatment. It also is not known if the improved response at times up to 42 months will persist or prolong overall survival.

Tong, M. J., El-Farra, N. S., Reikes, A. R., and Co, R. L. 1995. Clinical outcomes after transfusion associated hepatitis C. New England Journal of Medicine. 332:1463-1466.

This study followed 131 patients with chronic hepatitis C acquired by blood transfusion that presented to the Liver Center at Huntington Memorial Hospital in Pasadena, California between 1980 and 1994. Of the 131 patients , 101 had liver biopsies and 30 did not because of cirrhosis complicated by blood coagulation abnormalities. The average patient age was 57 years and 35 years at the time of blood transfusion. At initial presentation, 67.2 % of patients suffered from fatigue, 67.9 % had enlarged livers, 20.6 % had active hepatitis on biopsy, 51.1 % had cirrhosis and 5.3 % had hepatocellular carcinomas (liver cancer). After a mean follow-up of 36 months, there were 7 new cases of hepatocellular carcinoma and 15.3 % of patients died, mostly from complications of cirrhosis. These results show that hepatitis C can be a progressive disease. The patient population followed was at a hospital referral center and as a result, may represent patients with the most severe cases of chronic hepatitis C. A previous natural history study of a more general population suggests that the overall mortality of patient who acquired hepatitis C from blood transfusion may not be greater than that for a matched group that did not develop chronic hepatitis C.

Garcia-Buey, L., Garcia-Monzon, C., Rodriguez, S., Borque, M. J., Garcia-Sanchez, A., Iglesias, R., DeCastro M., Mateos, F. G., Vicaro, J. L., Balas, A., and Moreno-Otero, R. 1995. Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology. 108:1770-1777.

Interferon is known to stimulate the immune response, and for this reason, is effective in the treatment of viral hepatitis B and C. In this study from Spain, 144 patients with chronic hepatitis C, diagnosed by the detection of viral RNA and a liver biopsy, were treated with interferon. During treatment, 7 women showed clinically worsening hepatitis with increases in serum aminotransferase activities. Analysis of these seven patients showed that they developed autoimmune hepatitis as diagnosed by elevated serum gamma-globulin concentrations, elevated serum IgG concentrations and the development of various autoantibodies. These patients improved when interferon therapy was discontinued, but some needed further treatment with immunosuppressive agents. These results show that some patients with chronic hepatitis C, particularly younger woman, may develop autoimmune diseases, such as autoimmune hepatitis, during treatment with interferon.

Meisel, H., Reip, A., Faltus, B., Lu, M., Porst, H., Wiese, M., Roggendorf, M., and Kruger, D. H. 1995. Transmission of hepatitis C virus to children and husbands by women infected with contaminated anti-D immunoglobulin. Lancet. 345:1209-1211.

In 1978-1979, 2533 women in Germany received hepatitis C virus-contaminated anti-D immunoglobulin after delivery to prevent rhesus incompatibility. Of these women, 74 developed self-limited hepatitis and 86 chronic hepatitis C. The present study reports on the 10-15 year follow-up of these women's families. In 3 of 231 investigated children (1.3%), antibodies against the hepatitis C virus were detected, however, none of the children developed clinically apparent hepatitis. Antibodies against the hepatitis C virus, or hepatitis viral RNA, were not detected in any of the husbands. These data show that the risk of intrauterine and perinatal transmission of the hepatitis C virus, as well as the risk of transmission among close household contacts, is low. The risk of sexual transmission from women to men appears to be zero. It should be pointed out that this study examined the transmission of only one hepatitis C virus genotype (Ib, which is the most common genotype associated with cirrhosis and hepatocellular carcinoma in Europe) and that it did not address sexual transmission from men to women and between persons known to be sexually promiscuous.

Shimoda, S., Nakamura, M., Ishibash, H., Hayashida, K., and Niho, Y. 1995. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. Journal of Experimental Medicine. 181:1835-1845.

Most patients with primary biliary cirrhosis (PBC) have autoantibodies that recognize the inner lipoyl domain of the E2 subunit of the mitochondrial pyruvate dehydrogenase complex (PDC-E2). Over the years, these autoantibodies, and the autoepitope of the protein, have been well-characterized. Much less is known, however, about the domain of PDC-E2 that is the epitope recognized by T cells. In this study, the authors isolated six T cell clones from four patients with PBC and showed that the minimal epitope of PDC-E2 recognized by these T cells is contained within the inner lipoyl domain of the enzyme. They further showed that the HLA restriction molecules for all of these T cells was DRB 0101. These T cells also cross reacted with a portion of the outer lipoyl domain of the enzyme, and one of these T cell clones also reacted with a polypeptide derived from the sequence of Escherichia coli PDC-E2. These results suggest, but do not prove, that anti-self T cells may arise from mimicry of bacterial antigens. Additional studies of this sort may also provide the basis for trials of immunotherapy for PBC.

Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire. 1995. A comparison of Lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. New England Journal of Medicine. 332:1256-1261.

Patients with hepatocellular carcinoma (primary liver cancer) generally have an extremely poor prognosis. Because hepatocellular carcinomas are vascular tumors, injection with drugs followed by intra-arterial embolization with foam or other agents has received considerable attention as a therapeutic modality. Past studies have suggested that such therapy may prolong survival. Combining anti-cancer drugs with Lipiodol, an iodized oily agent that remains in the tumor, and embolization is considered the most effective of these treatments. This prospective, randomized study showed that such treatment did not significantly improve survival in a group of patients with unresectable hepatocellular carcinoma without severe liver disease. A similar group of patients, receiving conservative therapy involving only treatment of complications and pain, had no significant difference in survival.

Wong, J. B., Koff, R. S., Tine, F., and Pauker, S. G. 1995. Cost-effectiveness of interferon-alpha2b treatment for hepatitis B e antigen-positive chronic hepatitis B. Annals of Internal Medicine. 122:664-675.

A meta-analysis (analysis of data from several separate studies) demonstrating that treatment with interferon-alpha2b is cost-effective in the treatment of patients with chronic hepatitis B and replicative viral infection demonstrated by the presence of hepatitis B e antigen. The authors conclude that interferon-alpha2b should prolong life and lower costs for patients with chronic hepatitis B who are hepatitis B e antigen positive.

Olle, R., Glaumann, H., Fryden, A., Norkrans, G., Schvarcz, R., Sonnerborg, A., Yun, Z.-B., and Weiland, O. 1995. Two-year biochemical, virological, and histological follow-up in patients with chronic hepatitis C responding in a sustained fashion to interferon-alpha2b treatment. Hepatology. 21:918-922.

A small study (only fourteen patients) showing that patients with chronic hepatitis C who had a sustained response to a 60-week treatment course with interferon-alpha2b continued to have a good response two years after the completion of treatment. [The present US FDA-approved dose and duration of treatment with interferon-alpha2b is 3,000,000 units three times a week for 24 weeks.] Patients who had a good response six months after treatment continued to do so after two years without any evidence of liver inflammation or detectable virus. Hopefully, these findings will be confirmed in studies with more patients and in subsequent studies following patients for longer periods of time.

Simons, J. N., Pilot-Matias, T. J., Leary, T. P., Dawson, G. J., Desai, S. M., Schlauder, G. G., Muerhoff, A. S., Erker, J. C., Buijk, S. L., Chalmers, M. L., Van Sant, C. L., and Mushahwar, I. K. 1995. Identification of two flavivirus-like genomes in the GB hepatitis agent. Proceedings of the National Academy of Sciences, U. S. A. 92:3401-3405.

GB was a 34 year-old surgeon who contracted hepatitis. His serum was able to infect monkeys and the "GB agent" has been passaged in monkeys over the years. It is known to be distinct from other human hepatitis viruses (A, B, C, D, E). Using a technique called representational difference analysis, which was pioneered by investigators at Columbia University who used it to indentify the virus that may cause Kaposi sarcoma in patients with AIDS, the authors of this paper isolated genetic sequences in the infectious serum of a tamarin infected with the "GB agent." Analysis shows that the "GB agent" contains two flavivirus sequences related to, but distinct from, the hepatitis C virus. These findings suggest that novel flaviviruses may cause hepatitis in man and other primates.

Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S., and Baltimore, D. 1995. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kB. Nature. 376:167-170.

NF-kB is a transcription factor protein complex that consists of a polypeptide called p50 and another called RelA. NF-kB is a regulator of genes involved in responses to infection, inflammation and stress. In this paper, the authors made mice in which the gene encoding the RelA subunit of NF-kB was knocked out. The lack of RelA led to embryonic lethality at 15-16 days of gestation. At this time, massive degeneration of the liver by apoptosis occurred. Embryonic fibroblasts from these knock-out mice also showed defective induction of certain genes normally stimulated by tumor necrosis factor. The results show that RelA is necessary for embryonic liver development.

Fernandez-Salguero, P., Pineau, T., Hilbert, D. M., McPhail, T., Lee, S. S. T., Kimura, S., Nebert, D. W., Rudikoff, S., Ward, J. M., and Gonzalez, F. J. 1995. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 268:722-726.

The aryl hydrocarbon (Ah) receptor is a transcription factor required to mediate the harmful effects of toxic environmental compounds such as dioxin and PCBs. In this laboratory study, the investigators used "gene knockout" technology to produce mice that lacked the Ah receptor gene. About 50 % of mice lacking the Ah receptor reached maturity but had abnormalities in the immune system and the liver. These mice also did not respond to dioxin-mediated induction of genes that catalyze the metabolism of foreign compounds. The livers in these mice were about half normal size and showed bile duct fibrosis that in some cases resembled sclerosing cholangitis. These exciting results demonstrate that the Ah receptor plays a role in the normal development of the liver and the immune system. Future studies with this strain of mice may also provide insights into diseases characterized by bile duct fibrosis and how environmental toxins are converted into carcinogens by metabolism in the liver.

Ochs, A., Rossle, M., Haag, K., Hauenstein, K.-H., Diebert, P., Siegerstetter, V., Huonker, M., Langer, M., and Blum, H. E. 1995. The transjugular intrahepatic portosystemic stent-shunt proceudure for refractory ascites. New England Journal of Medicine. 332:1192-1197.

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Wong, F., Sniderman, K., Liu, P., Allidina, Y., Sherman, M., and Blendis, L. 1995. Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites. Annals of Internal Medicine. 122:816-822.

Refractory ascites (fluid accumulation in the abdomen that is not relieved by low-salt diets and diuretic medications) is a common complicaton in patients with cirrhosis. Ascites results in-part from increased blood pressure in the portal vein leading to the liver (see "Cirrhosis" on the Diseases of the Liver Page). A transjugular intrahepatic portosystemic shunt (TIPS) is a device placed in the liver (without surgery, usually by a radiologist) that makes a direct connection between the portal and systemic circulations, letting some blood bypass the cirrhotic liver and lowering pressure in the portal vein. The resulting decrease in pressure is effective in stopping bleeding from esophageal and gastric varices, but some investigators have also suggested that this procedure can be used to treat refractory ascites. Ochs et al. studied 62 patients in Germany with refractory ascites who received TIPS. They claimed that TIPS was successful in decreasing ascites in many patients but that mortality in these patients was nontheless very high. In all, about half of the patients died within one year. Wong et al. inserted TIPS in 7 patients in Canada and performed physiological measurements of kindey and heart function. They concluded that response to TIPS depends upon cardiac and renal functions, that TIPS should not be inserted without paying careful attention to these functions and that TIPS is safe and effective in managing refractory ascites in carefully selected patients. These studies together suggest that TIPS has a limited role in the treatment of refractory ascites and should not be used widely for this purpose but only in carefully selected patients.