Soluble tumor necrosis factor receptors in patients with recurrent hepatitis C virus infection after liver transplantation.
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Biomedical subjects
Publications and source records attributed to L Theilmann.
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Primary sclerosing cholangitis is a cholestatic disease of the liver characterized by progressive fibrotic inflammation and obliteration of the extra- and/or intrahepatic bile ducts. There is no effective therapy. We, therefore, studied the safety and efficacy of ursodeoxycholic acid in patients with primary sclerosing cholangitis with or without additional ulcerative colitis. In a 1-year ursodeoxycholic acid treatment period, which preceded the controlled study period, ursodeoxycholic acid was well tolerated in 22 of 24 patients with ulcerative colitis and in all three patients without ulcerative colitis. In two patients with ulcerative colitis the dose of 750 mg ursodeoxycholic acid/day led to diarrhea, but following reduction of the dose to 500 and 250 mg/day ursodeoxycholic acid was well tolerated. After 1 year of ursodeoxycholic acid treatment, 20 patients were randomly assigned to receive either ursodeoxycholic acid 750 mg/day or placebo. All of them finished a double-blind, placebo-controlled study period. During ursodeoxycholic acid treatment, the liver enzymes improved markedly. The difference in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyltransferase between the placebo and ursodeoxycholic acid group was significant (p < 0.05). Following ursodeoxycholic acid treatment, pruritus and fatigue improved in half of the patients but the difference between the placebo and ursodeoxycholic acid group was not significant. According to the ethical guidelines, after 3 months of placebo treatment, the controlled study had to be discontinued because of a more than twofold increase of serum transaminases in 8/10 patients on placebo. After the end of the controlled study, all patients were continuously treated with ursodeoxycholic acid for up to 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)
Biliary tract complications in 105 patients who had undergone orthotopic liver transplantation were reviewed in order to determine their incidence and localization. In addition, the possible endoscopic and percutaneous management of such complications was evaluated. Signs of cholestasis appeared in 32 of 105 (30.5%) transplant recipients after a mean of 6.5 months (range 1-19 months), and visualization of the biliary system was performed in all. Twenty biliary tract complications were observed in these 32 patients (62.5%). There were multiple strictures, both intrahepatic and extrahepatic, in 11 grafts. Five of the nine extrahepatic strictures were not confined to the site of the bile duct anastomosis, and involved the whole common bile duct of the donor liver, while the remaining four were confined. The multiple intrahepatic and extrahepatic strictures were related either to occlusion of the hepatic artery or to the fact that the graft had been in a cold ischemic state for a prolonged time. In contrast, multiple strictures and necrosis of the whole extrahepatic bile duct were attributed to local ischemia due to the harvesting procedure. Stenoses strictly confined to the site of anastomosis were thought to be due to surgical technique. Ten extrahepatic bile duct stenoses with considerably impaired bile flow were corrected endoscopically (four), percutaneously (three) and by surgery (three). In four patients with complications in the whole intrahepatic and extrahepatic system, retransplantation was necessary. Biliary tract complications in our patients occurred in up to 19% after liver transplantation on long-term follow-up. Complications of only the extrahepatic system can be treated successfully, whereas complications involving multiple stenoses of the intrahepatic bile duct system frequently require retransplantation.
Interferon is currently the only established therapeutical option for chronic viral hepatitis. Sustained response can be achieved in approximately 25% of patients with chronic HBV or HCV infection. Results in chronic HDV infection are disappointing. Whether combination of interferon with other lymphokines or antiviral drugs will lead to higher response rates, remains to be established. The argument that interferon will only place spontaneous seroconversion on an earlier date has not been disproved yet. Long-term follow-ups are necessary to show that therapy with interferon will improve survival and reduce the incidence of hepatocellular carcinoma in patients with chronic viral hepatitis.
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Complications of portal hypertension, e.g. bleeding from esophageal or gastric varices or ascites, can be efficiently treated by transjugular intrahepatic portosystemic stent shunting. The most important and most frequently encountered contra-indications to this procedure are malignant liver tumors, systemic infections or hepatic decompensation, and encephalopathy. Before and after the shunt procedure, treatment of these patients must be selected and administered with due consideration for the fact that they extremely prone to bacterial infections and have many concomitant diseases, e.g. impaired renal function. To prevent early occlusion of the stent, patients receive anticoagulants in the first few days after the procedure.
Use of a transjugular intrahepatic portosystemic stent shunt (TIPSS) is a highly efficient method of controlling bleeding from esophageal or gastric varices in patients with portal hypertension. Early mortality is between 2% and 13%. Stenosis and occlusion of the stent are reported in 6-56% and 7-9%, respectively, within the first year. Stenoses occur more often in patients with good liver function. In 17-27% de novo encephalopathy is observed. The rate correlates with the extent of liver cirrhosis, which is the main factor that determines prognosis of the patients in the long run. All patients with liver cirrhosis classified as Child A were alive after 1 year, in contrast to only 51% of patients with Child C cirrhosis.
The goal of this study was to assess the influence of prior treatment of bleeding esophageal varices on liver transplantation. After sclerotherapy the results of liver transplantation were identical to those achieved in patients without previous variceal hemorrhage (74% 1-year survival). The results of liver transplantation to patients who already had surgical shunts were dismal. Four of nine patients with portocaval or Warren shunts were long-term survivors. In comparison, the intraoperative course in five patients with transjugular intrahepatic portosystemic stent shunts (TIPSS) was uneventful and four of these were long-term survivors. This has led us to adopt TIPSS as the treatment modality of choice for patients with bleeding varices awaiting liver transplantation.
We undertook a retrospective study to determine the prevalence of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection in 81 Caucasian patients with confirmed hepatocellular carcinoma (HCC). Besides HBV and HCV serological markers, HCV RNA and HBV DNA were detected in serum and liver tissue by polymerase chain reaction. Overall, HCV RNA was found in 20 cases (25%), HBV DNA in 21 patients (26%), and coinfection in 3 patients (3%). HCV RNA in liver tissue was not found without virus in serum, whereas HBV DNA was found in the liver tissue of one patient without viremia. In an additional analysis, 32 patients with HCC and alcoholic cirrhosis (HCC-AC) were compared to 35 cases with AC without HCC and 35 cases with alcoholic hepatitis. The prevalence of HCV RNA in HCC-AC (19%) was significantly higher than in the other groups (AC, 3%; alcoholic hepatitis, 0%). HBV DNA was present in 19% of HCC-AC as compared to 3% of AC and 0% of alcoholic hepatitis. We conclude that the form of HCC in 50% of the patients in a Western European country is related to chronic viral hepatitis. Our data obtained from a group of patients having alcoholic liver disease with or without HCC suggest that the prevalence of HCV RNA or HBV DNA in these populations increases with the severity of hepatic injury.
Stenosis or occlusion of the transjugular intrahepatic portal-systemic stent shunt may be initiated by aggregation and activation of thrombocytes on the surface of the metallic stent material. To find effective prevention of this event, we conducted a controlled trial administering acetylsalicylic acid for 3 mo. Forty-four patients (8 women and 36 men) with portal hypertension were included in this study. The patients were randomized into a group receiving 100 mg acetylsalicylic acid/day (n = 21) or into a control group (n = 23). Treatment was started immediately after transjugular intrahepatic portal-systemic stent shunt. Three months after transjugular intrahepatic portal-systemic stent shunt, 15 patients in the acetylsalicylic acid group and 19 patients in the control group underwent clinical reevaluation, gastroscopy and recatheterization with determination of the portal-systemic pressure gradient. No variceal bleeding occurred in any patients. In four patients in the acetylsalicylic acid group, erosive gastritis was observed in gastroscopy in contrast to only one patient in the control group. Complete patency of the stent was noted in 10 of 15 patients in the acetylsalicylic acid group and in 14 of 19 patients in the control group. Transjugular intrahepatic portal-systemic stent shunt restenosis associated with a significant increase of the portal-systemic gradient occurred in five patients in the acetylsalicylic acid group, which required redilation in all and additional stent placement for expansion of the stented tract in two patients. In the control group, redilation was necessary in five patients with additional stent extension in two patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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Heterogeneity of hepatitis C viral (HCV) genomes of several isolates from different countries has been reported, but there is little information on HCV isolates for the Federal Republic of Germany. Therefore, the nucleotide (nt) and deduced amino acid (aa) sequences of interesting parts of the viral genome derived from different human isolates in Germany were compared with each other and with the nt and predicted aa sequences of recently published isolates. HCV sequences were obtained by reverse transcription of viral RNA extracted from serum followed by polymerase chain reaction (PCR) amplification. Within the 5' nontranslated region we found only 3 single nucleotide exchanges among 2 of our isolates, and in comparison to sequences of Japanese isolates 2 to 3 exchanges, and to U.S. isolates 1 to 5 exchanges (homologies 98% to > 99%). Determination of a 249-bp core sequence from two German isolates exhibited 3% sequence divergence. The sequence of the core region (nt 342-911) showed a homology of about 88-91% on nt level and 96-97% on aa level as compared to U.S. isolates and other German isolates, and a homology of 95-96% (nt) and 96-98% (aa), respectively, to Japanese isolates. Less homologies were noticed for the E1 and E2/NS1 genes, especially in the N-terminal E2/NS1 hypervariable domain. Our isolates HD1 and HD2 showed nt sequence homologies of about 72-81% and aa homologies of 76-88% to U.S., German, and French isolates, and 89-91% (nt) and 88-96% (aa), respectively, to Japanese isolates. These results indicate that various German isolates are more closely related to Japanese isolates and differ from other European isolates as reported so far. Because of a nucleotide sequence heterogeneity of up to 10% among the tested isolates, we conclude that more than one closely related but distinct viral genotype of HCV exists in Germany. Furthermore, heterogeneous sequences of HCV can be detected in a single patient suggesting multiple infection with different genomic variants or, alternatively, a genetic drift forced by mutational events as a consequence of host immune selection.
To study possible extrahepatic sites for the replication of hepatitis C virus (HCV), we examined fresh and cultured peripheral blood mononuclear leukocytes (PBML), as well as different subpopulations of PBML of HCV-infected patients, for the presence of viral genomic and antigenomic RNA. Sense and antisense oligonucleotide primers derived from HCV sequences were used for reverse transcription (RT) followed by an amplification with the polymerase chain reaction assay (PCR). Using antisense primers for RT, genomic viral RNA could be detected in serum, liver, total PBML and B lymphocytes of chronically infected patients. However, only liver tissue and PBML specimens were positive when a sense primer was used. To demonstrate further the specificity of these findings, total PBML were stimulated using pokeweed mitogen and synthesis of HCV RNA was determined by incorporation of [3H]uridine into nascent viral RNA molecules using a hybrid release assay. Additionally, total PBML from an uninfected person could be infected in vitro using an HCV RNA-positive serum. The PCR products obtained from serum, liver and PBML specimens of an HCV-positive individual were found to have nearly identical sequences. Our findings suggest that PBML could be a site for viral replication of HCV during the natural course of infection and may represent a reservoir for hepatitis C virions.
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Social-psychological aspects and rehabilitation after liver transplantation were examined in 21 patients. One-year survival was not different in patients with alcoholic liver disease compared with patients with other end-stage liver disease (65% vs 71%). After liver transplantation a temporary return to alcohol drinking was observed in 3 patients (14%). 52% of patients transplanted for alcoholic liver disease are occupationally rehabilitated. Social-psychological conflicts were reported by 46%. Patients with alcoholic liver disease are potential candidates for hepatic transplantation.
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Of 32 patients with non-A, non-B hepatitis, 10 (31%) were still anti-HCV-positive 12.8 years after the acute phase of the disease. Seven of the patients (21.9%) still had elevated ALT levels, and among these, 5 out of 5 patients who had been subject to parenteral risk were anti-HCV-positive. In contrast, none of the patients who had not been subject to parenteral risks were positive.