The characteristics and clinical outcome of drug-induced liver injury: a single-center experience.

BACKGROUND AND GOALS: The aim of this cohort study was to determine the characteristics and clinical outcome of 170 patients with drug-induced liver injury (DILI) in a single center. STUDY: Between January 2001 and June 2007, a total of 170 individuals who were diagnosed with DILI were retrospectively analyzed. The median follow-up period was 110.0 days. RESULTS: During the study period, a total of 5471 new patients were assessed for liver test abnormalities. Of those, 170 patients (3.1%) fulfilled the criteria of DILI. A total of 83 different drugs were considered to be related to the hepatotoxicity; a single drug was suspected in 57.6% of individuals. The median interval between the suspicious drug intake and DILI recognition was 15.0 days. Hepatocellular pattern was observed in 50.0% of patients with a mean alanine aminotransferase level of 952.2+/-907.0 U/L. The main causative group of drugs was antibiotics. Sixty-two patients required hospitalization; acute liver failure developed in 14 (8.2%), chronicity was observed in 19 (11.2%), and 7 died (4.1%). Overall, complete recovery occurred in 82% of patients. The presence of jaundice on admission and shorter interval period between drug intake and DILI recognition were identified as risk factors for the development of acute liver failure. CONCLUSIONS: DILI is an important cause of liver test abnormalities in outpatient clinics, and antibiotics represent the most common drug group. Overall, complete recovery after the withdrawal of the suspicious drug occurred in the majority of patients, but DILI may progress to acute liver failure, chronicity, and death.

Endoscopic management of biliary parasitic diseases.

UNLABELLED: AIM/MATERIALS AND METHODS: Between January 2000 and June 2007, 3,548 endoscopic retrograde cholangiopancreatography (ERCP) were performed for extrahepatic cholestasis, cholangitis, and choledocholithiasis. The results of ERCPs were evaluated retrospectively and examined carefully to investigate the management and endoscopic therapy of biliary parasites. RESULTS: Of the 3,548 patients who underwent ERCP, 24 (0.66%) were found to have biliary parasitosis. The mean age of the biliary parasitosis patients (16 women) was 48.6 (15-77) years. Of these 24 cases, 16 patients had hydatid cystic disease (eight with partial obstruction of the biliary tract, and eight with ruptured cysts), four patients had Fasciola hepatica, and four patients had Ascaris lumbricoides infestation. Endoscopic sphincterotomy was performed, after which the choledochus was examined carefully by balloon catheter and basket procedure. CONCLUSION: The ERCP procedure is very useful in the therapy of biliary parasitic infestations.

Successful living-related liver transplantation in a child with familial yellow nail syndrome and fulminant hepatic failure: report of a case.

An 11-yr-old boy with familial YNS and FHF and who underwent LRLT is presented. LRLT was performed from his father with YNS. The findings of hepatic failure resolved immediately after LRLT, but severe respiratory complications and chylous ascites were observed during the follow-up. At 12 months after successful LT, the patient has good graft function, but findings of YNS including chronic cough, lymphedema and yellow nails are still present. To the best of our knowledge, this is the first case of YNS who underwent LRLT for FHF.

A novel mutation pattern emerging during lamivudine treatment shows cross-resistance to adefovir dipivoxil treatment.

AIMS: This study was conducted to clarify the resistance profile of a novel mutation pattern emerging during lamivudine (3TC) therapy and showing cross-resistance to adefovir dipivoxil (ADV) in a patient with chronic hepatitis B. METHODS AND RESULTS: Successful suppression of hepatitis B virus (HBV) replication by sequential therapy of 9 MU thrice weekly interferon (IFN) and 3TC was followed by genotypical resistance detected at month 28 of therapy (month 19 of lamivudine treatment). ADV was added to 3TC therapy on month 44 of antiviral treatment. Neither alanine aminotransferase normalization nor a stable decrease in HBV viral load was observed, although ADV was used for more than 40 months. The HBV pol region was amplified from serum samples obtained before and after ADV treatment. The complete genome was cloned into a TA vector. PCR products and 7-10 clones from each cloned vector were sequenced. A novel mutation, A181S, in the reverse transcriptase gene leading to a conversion of W172C in the overlapping surface antigen gene was detected along with a M2041 mutation. The complete genome comprising the A181S+M2041 pattern was cloned into an expression vector and its in vitro susceptibility to 3TC, ADV, tenofovir (PMPA), clevudine (L-FMAU) and emtricitabine (FTC) were determined in transiently transfected Huh7 cells. This mutation pattern displayed more than 1000-fold resistance to the nucleoside analogues 3TC and FTC and approximately sixfold resistance to L-FMAU, while it confers 28.23- and 5.57-fold resistance for the nucleotide analogues ADV and PMPA, respectively. CONCLUSION: A new mutation pattern, A181S+M2041, arising under lamivudine treatment confers cross-resistance to ADV both in vivo and in vitro.

Modelling of early viral kinetics and pegylated interferon-alpha2b pharmacokinetics in patients with HBeag-positive chronic hepatitis B.

BACKGROUND: Pegylated interferon alpha2b (PEG-IFN-alpha(2b) is effective for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, although its mechanism of action remains unclear. HBeAg loss is achieved in 36% of patients after one year of PEG-IFN-alpha2b treatment and combination therapy with lamivudine is not superior to PEG-IFN-alpha2b monotherapy. METHODS: Early pharmacokinetics and viral kinetics were analysed in patients treated for 52 weeks with PEG-IFN-alpha2b with or without lamivudine. RESULTS: After 4 weeks of treatment, there was a median viral decline of 2.94 log10 copies/ml in those treated with PEG-IFN-alpha2b and lamivudine and only 0.45 log10 copies/ml in the PEG-IFN-alpha2b monotherapy group. Peak PEG-IFN-alpha2b levels were reached approximately one day after administration and subsequently declined exponentially, consistent with a viral load rebound near to baseline levels at the end of the dosing period in most patients receiving PEG-IFN-alpha2b monotherapy. Modelling of pharmacokinetics and viral kinetics data in this group revealed that viral load was minimal 3.6 days after PEG-IFN-alpha2b administration, the mean maximal and mean antiviral effectiveness was 70% and 48% with a mean infected cell loss rate of 0.07 per day, while no significant biphasic decline was observed. CONCLUSIONS: PEG-IFN-alpha2b induces a sustained response in a considerable number of patients despite limited direct antiviral activity during the first weeks of antiviral therapy.

Trefoil factor expression in biliary epithelium of graft-versus-host disease of the liver after allogeneic hematopoietic cell transplantation.

BACKGROUND: The aims of this study were to determine the presence of trefoil factor family-3 (TFF3) expression in biliary epithelial cells (BECs) of chronic graft-versus-host disease (cGVHD) of the liver after allogeneic hematopoietic cell transplantation, to compare such expression in chronic liver diseases (CLD) with/without predominantly biliary disease, and to assess the effect of bile duct injury on the degree of TFF3 expression in BECs of cGVHD. METHODS: A total of 82 paraffin-embedded liver biopsy samples were reviewed. These samples were basically divided into two distinct groups according to the presence of ductal injury: group 1 with CLD and predominantly biliary disease (n=26: 17 cGVHD and 9 primary biliary cirrhosis [PBC]) and group 2 with CLD and predominantly parenchymal liver disease (n=56: 20 steatohepatitis and 36 chronic viral hepatitis). Group 2 was used as the controls. Immunohistochemistry was performed using a polyclonal anti-TFF3 antibody. Real-time quantitative PCR was used for the detection of TFF3 mRNA expression. RESULTS: Positive TFF3 immunohistochemical staining and the presence of TFF3 messenger RNA gene expression was demonstrably higher in group 1 than that in group 2 (P<0.0001 and P<0.05, respectively). No significant difference in terms of positive TFF3 stained BECs between GVHD and PBC samples was observed (P>0.05). The extent of TFF3 expression in GVHD samples with severe ductal injury were significantly more common than that of GVHD samples with mild/moderate ductal injury (P<0.0001). CONCLUSIONS: The expression of TFF3 in cGVHD of the liver is increased in response to bile duct damage and repair. Such expression seems to be related the severity of ductal injury.

Thrombophilic gene mutations in cirrhotic patients with portal vein thrombosis.

OBJECTIVE: Thrombophilic gene mutations have been reported to be associated with the formation of portal vein thrombosis (PVT). This study aimed to investigate the role of thrombophilic gene mutations in cirrhotic patients with PVT. PATIENTS AND METHODS: A total of 74 cirrhotic patients (17 with PVT, 57 without PVT), and 19 non-cirrhotic patients with PVT and 80 healthy controls were included. Factor V Leiden G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase C677T mutations were analysed by restriction fragment length polymorphism. RESULTS: Aetiologies and Child-Pugh distribution of cirrhotic patients with and without PVT were similar. Five of 17 (29%) of cirrhotic patients with PVT but only two of 57 (3.5%) of cirrhotics without PVT, five of 80 (6%) of controls and none of the 19 non-cirrhotic patients with PVT had factor V Leiden G1691A mutation (P<0.05). Prothrombin G20210A mutation was found in five (29%) cirrhotic patients with PVT while only two (3.5%) cirrhotic patients without PVT, one (5%) non-cirrhotic patient with PVT and two (2.5%) controls had this mutation (P<0.05). The frequency of the homozygote methylenetetrahydrofolate reductase 677C-T mutation was similar in all four groups. CONCLUSIONS: Inherited thrombophilic gene mutations appear to increase the risk of PVT formation in cirrhotic patients but not in patients without liver disease in a cohort of Turkish patients.

Primary sclerosing cholangitis: MR cholangiopancreatography and T2-weighted MR imaging findings.

PURPOSE: To present MR cholangiopancreatography (MRCP) findings and to determine the hepatic morphological changes of primary sclerosing cholangitis (PSC) seen on T2-weighted fast spin echo (FSE) images. MATERIALS AND METHODS: Twenty-three patients (15 women, 8 men) with ages ranging from 17 to 80 years (median, 45.1 years) were included in the study. MR imaging was performed on a 1 Tesla MR unit using a phased-array coil. Heavily T2-weighted images were obtained with single-shot fast spin echo technique for MRCP. Morphological changes encountered in livers were evaluated with coronal and axial T2-weighted fast spin echo images. RESULTS: Irregularities, multifocal strictures, and dilatations in different levels of the biliary channels were seen in all patients. T2-weighted images showed lobulated hepatic contours in 21.73%, atrophy in both anterior and posterior segments of the right lobe in 21.73%, atrophy in the anterior segment in 13.04%, atrophy in both medial and lateral segments of the left lobe in 17.39%, atrophy in the medial segment in 8.69%, atrophy in the lateral segment in 4.34%, hypertrophy in the posterior segment of the right lobe in 4.34%, global hypertrophy in the left lobe in 4.34%, hypertrophy in the lateral segment of the left lobe in 4.34%, and caudate lobe hypertrophy in 21.73% of the patients. In addition, periportal edema was noted in 39.13%, increased parenchymal signal on T2-weighted images in 26.08%, periportal and/or portocaval lymphadenopathy in 34.78%, and portal hypertension in 34.78% of our patients. In one patient (4.34%), the liver had a round shape characteristic of PSC. CONCLUSION: MR imaging is a useful method for establishing the changes in biliary ducts specific to PSC, and for identifying long-standing cases complicated with cirrhosis.

Oral ganciclovir for treatment of lamivudine-resistant hepatitis B virus infection: a pilot study.

Although liver disease seems to be stable in most patients who are infected with lamivudine-resistant mutant hepatitis B virus (HBV) in the short term, it may progress to more-advanced disease in some patients. In our pilot study, we investigated the efficacy of oral ganciclovir for the treatment of lamivudine-resistant HBV infection. Six patients infected with lamivudine-resistant HBV (3 patients had decompensated cirrhosis and 3 had chronic active hepatitis without cirrhosis) were included. Ganciclovir was administered at a dosage of 3 g daily for 6 months. Four of 6 patients completed the 6-month treatment period. Two patients with cirrhosis completed only 2 months of ganciclovir treatment because they died of cirrhosis complications. None of the patients had a > or =2-log(10) reduction of HBV DNA and complete alanine aminotransferase normalization at the end of their treatment regimens. In conclusion, 6 months of ganciclovir treatment is not effective for suppression of lamivudine-resistant HBV infection.

Recipient-derived hepatocytes in sex-mismatched liver allografts after liver transplantation: early versus late transplant biopsies.

BACKGROUND: The presence of microchimerism in transplanted tissues is well defined; however, the timeframe of appearance and disappearance of engraftment in liver allograft is unknown. The aims of this study were to analyze for the presence of "recipient-derived cells" in sex-mismatched individuals after liver transplantation, comparing the frequency of "recipient-derived cell repopulation" in early versus late transplant biopsies and to evaluate the relationship between "recipient-derived cell repopulation" and the severity of graft injury. METHODS: Paraffin-embedded liver biopsy samples of 18 recipients were reviewed. Sixteen of them were obtained from recipients with sex-mismatched donors. The remaining two were obtained from recipients with sex-matched donors and were used as controls. Immunohistochemistry and fluorescence in situ hybridization double-labeling method were performed on pretreated slides using anti-human hepatocyte antibody to identify hepatocytes, a mouse anti-human cytokeratin-7 to identify ductal epithelial cells, and using CEPX/Y DNA probes for visualizing X and Y chromosomes. The double-labeled slides were examined systematically using an image analyzer system. RESULTS: The mean time from transplantation to biopsy was 8.1 months. Eleven of the 16 samples obtained from recipients with sex-mismatched grafts demonstrated "recipient-derived hepatocyte repopulation," comprising a mean of 2.1% of the hepatocytes. In the control biopsies, none of the cells demonstrated different nuclear signals from the donor's sex origin. The presence and proportion of "recipient-derived hepatocyte repopulation" rate were significantly higher in early transplant biopsies than in late transplant biopsies (P < 0.05). CONCLUSION: Some hepatocytes of sex-mismatched liver grafts were replaced by "recipient-derived cells" during injury. Such repopulation is more common in the early liver-graft biopsies. The severity of acute cellular rejection appears to have no effect on the rate of recipient-derived repopulation.

Hepatic outflow obstruction: enhancement patterns of the liver on MR angiography.

Our purpose was to present the enhancement patterns of the liver on MR angiography in patients with hepatic outflow obstruction. Twenty-three patients with Budd-Chiari syndrome (4 in acute stage and 19 in chronic stage of the disease) were examined with 3D contrast-enhanced MR angiography. During early and late portal venous phase of MR angiography the pattern of parenchymal enhancement was assessed on source images. The enhancement patterns were evaluated under 4 groups as following: (a) central (b) peripheral (c) patchy and (d) homogeneous enhancement. The morphologic changes in the liver (lobar hypertrophy or atrophy, hepatic surface irregularities) were also recorded. In the acute stage global liver enlargement (75%) with caudate hypertrophy (100%) and central enhancement of the liver (75%) were suggestive findings of the hepatic outflow obstruction. The left lobe hypertrophy (53%) associated with the caudate lobe hypertrophy (72%) and irregular surface (26%) were predominant in the chronic stage of the disease. The enhancement patterns seen in chronic disease were variable and reflected the persistent stasis of the portal blood flow (patchy enhancement in 32% of the patients) or the altered hemodynamics of the liver due to the development of subcapsular collaterals (peripheral enhancement in 21% of the patients). Homogeneous enhancement of the liver in Budd-Chiari syndrome may indicate the chronicity of the outflow obstruction (37%) and shows a more stable hepatic perfusion that occurs after the formation of intra and extrahepatic collateral veins. The morphological and perfusional features on multiphase contrast-enhanced MR angiography are valuable in understanding the effects of the hepatic outflow obstruction on the liver parenchyma.

Portal venous system: evaluation with contrast-enhanced 3D MR portography.

The purpose of this study is to compare contrast-enhanced three-dimensional (3D) magnetic resonance (MR) portograms to Doppler sonography in detection of portal venous abnormalities. Thirty-five consecutive patients, who were suspected of having portal venous system abnormalities, were examined with MR portography and Doppler sonography. Vascular abnormalities were identified in 27 of 35 patients. There was statistically significant agreement between the results of MR portography and Doppler sonography. The major limitation of contrast-enhanced 3D MR portography was its inability to provide objective hemodynamic data regarding flow direction and flow pattern.

Percutaneous transhepatic venoplasty: an alternative treatment for Budd-Chiari syndrome.

BACKGROUND/AIMS: In patients with Budd-Chiari syndrome due to short segment hepatic vein stenosis where percutaenous transluminal venoplasty is not successful, percutaneous transhepatic balloon venoplasty may be a valid treatment option. The aim of this prospective study was to evaluate the effects of this procedure for the treatment of patients with Budd-Chiari syndrome, in whom transluminal cannulation was unsuccessful. METHODS: Ten patients with short segment occlusion of the hepatic veins were treated by percutaneous transhepatic balloon venoplasty between January 1997 and January 2000. The median follow-up period of these patients was 20 months (2-33 months). RESULTS: The procedure was unsuccessful in two patients. Eight patients (five men, three women) with a median age of 28 (range, 15-61) years were treated by percutaneous transhepatic balloon venoplasty and in seven of them, clinical symptoms including abdominal distension and ascites, resolved completely. Long term anticoagulation therapy was not given to the patients. One patient with advanced stage liver disease died of variceal bleeding two months after the procedure. During follow-up, symptomatic reocclusion requiring dilatation occurred in three patients. CONCLUSIONS: Percutaneous transhepatic balloon venoplasty is an alternative treatment option for selected patients with Budd-Chiari syndrome when transluminal cannulation of the hepatic veins is not possible. Long term anticoagulation therapy seems to be necessary in these patients.

The mutations in ISDR of NS5A gene are not associated with response to interferon treatment in Turkish patients with chronic hepatitis C virus genotype 1b infection.

BACKGROUND/AIMS: A significant association between variations in amino acid sequences resides between 2209-2248 nucleotides of HCV non-structural 5A (NS5A) gene, and response to interferon treatment has been proposed. The aim of this study was to determine whether the amino acid sequence changes in ISDR could be correlated to response to alpha interferon treatment in Turkish patients infected with HCV genotypes 1b and 1a. METHODS: Thirty-nine patients with chronic C virus infection (35 and 4 patients with genotype 1b and 1a, respectively), receiving 3x3-5 MU of interferon a-2b for six months were included in the study. Following PCR amplification of the region from pre-treatment serum samples, the products were directly sequenced. The amino acid sequence of NS5A was compared with the published sequence for HCV-J (AA 2209-2248). Mutant type was defined as three or more amino acid mutations, and intermediate type as 1-3 amino acids in this region. Otherwise, they were defined as the wild type (no amino acid mutations). HCV RNA serum viremia levels were analyzed by branched DNA assay. RESULTS: Eighteen patients were responders (R; 46%), whereas 21 patients were non-responders (NR; 54%). Amino acid changes in both R and NR groups did not show significant difference. Intermediate or wild type strains were detected in both groups. CONCLUSIONS: In this study, we could not determine a significant association between number of amino acid changes in NS5A2209-2248 and response to interferon treatment. In the majority of the patients, it seems that amino acid sequences in this region are well conserved.

Endoscopic treatment of biliary complications following liver transplantation.

BACKGROUND/AIMS: The aims of the present study were to review biliary complications following liver transplantation in a single-center experience, to identify the factors associated with biliary complications, and to evaluate the success of endoscopic and percutaneous treatment in such patients. MATERIALS AND METHODS: Between January 1994 and June 2010, a total of 176 patients with liver disease underwent liver transplantation; 119 recipients were included in this retrospective analysis. Median posttransplant follow-up period was 49 months. RESULTS: Mean age was 43.0±12.7 years. Living donor liver transplantation (LDLT) and deceased-donor liver transplantation (DDLT) were performed in 71 and 48 patients, respectively. Duct-to-duct anastomosis and Roux-en-Y hepaticojejunostomy were performed in 68 and 51 patients, respectively. The overall incidence of posttransplant biliary complications was 36%; anastomotic biliary strictures were the most common biliary complications (42%), followed by biliary leakage (28%). On logistic regression analysis, duct-duct anastomosis was the only risk factor associated with the development of biliary complications (Odds ratio (OR), 3.346; p=0.005). Endoscopic and percutaneous treatment was successful in the majority of patients (81%), and the remaining 19% recipients underwent surgery for biliary repair. Endoscopic retrograde cholangiopancreatography (ERCP) guided drainage and balloon dilatation with stent placement were the most common treatment modalities. CONCLUSION: Biliary complications were most frequent after liver transplantation; biliary strictures were the most commonly seen. The use of duct-to-duct anastomosis for biliary reconstruction is a risk factor for the development of biliary complications. Endoscopic and percutaneous treatment was successful in the majority of these patients.

Aflatoxin exposure in viral hepatitis patients in Turkey.

BACKGROUND/AIMS: Hepatocellular carcinoma is the fifth most common cancer and a major public health problem worldwide. Differences in distribution of hepatocellular carcinoma incidence are probably due to different levels of exposure to hepatocellular carcinoma risk factors: chronic infections with hepatitis B virus (HBV) and aflatoxin exposure in developing countries, and smoking and alcohol abuse in developed countries. Aflatoxin is one of the most important of the environmental toxins that contribute to the pathogenesis of hepatocellular carcinoma, especially in the regions where dietary foodstuffs (peanuts, corn, Brazil nuts, pistachios, spices and figs) are highly contaminated. High aflatoxin levels have been shown in the foodstuffs that are produced in our country. The specific aim of this study was to assess the rate of aflatoxin exposure and to determine some clues about aflatoxin metabolism by measuring and comparing the levels of carcinogenic forms in healthy subjects, in different stages of viral disease, and in different viral hepatitis types. METHODS: This was a cross-sectional observational, single-center study. A total of 203 (male/female: 119/84) viral hepatitis patients who were consecutively admitted to Ankara University, School of Medicine, Gastroenterology Clinic, between January 2006 and June 2007 were enrolled into the study. Sixty-two healthy subjects (male/female: 33/29) with normal blood chemistry and negative viral serology served as controls. Chemical forms AFB1, AFB2, AFG1, and AFG2 were assessed in plasma of study participants by high-performance liquid chromatography. RESULTS: AFB1, AFB2, AFG1, and AFG2 were detected in 24.6%, 17.2%, 22.7%, 18.2% of the 203 patients, respectively, and were significantly higher than in the control group for all chemical forms. Percentage of AFB1-positive patients was significantly higher than in the control group irrespective of disease stage. There was no significant difference between chronic infected patients, cirrhotic patients and patients with Hepatocellular carcinoma with respect to percentage of aflatoxin-positive individuals. CONCLUSIONS: With this study, we have documented that in viral hepatitis patients, aflatoxin exposure is significantly higher than in healthy subjects in Turkey and it may play an important role in the development of hepatocellular carcinoma. Thus, large studies exploring the relation between aflatoxin exposure, viral hepatitis status, and risk of hepatocellular carcinoma development are needed.

The fate of recipient-derived hepatocytes in sex-mismatched liver allograft following liver transplantation.

BACKGROUND: ''Bone marrow-derived stem cells'' have attracted great attention as potential candidates for liver-directed gene therapy and as a tool for regenerative medicine. However, the fate of these cells is not well-known. The aim of this present study was to investigate the fate of ''recipient-derived repopulated hepatocytes'' in sex-mismatched liver allografts in individuals following liver transplantation during systematic longitudinally performed liver biopsies. METHODS: Paraffin-embedded sex-mismatched liver biopsy samples of nine recipients (male/female ratio 5/4; mean age: 39.7 yr) were reviewed. Double labeling with immunohistochemistry for hepatocytes and recipient-specific bone marrow-derived cells and fluorescence in-situ hybridization for visualizing X and Y chromosomes were performed. These slides were examined systematically using an image analyzer system (Olympus microscope; Cyto-Vision, Applied Imaging, Biosciences Centre, Newcastle, UK). Only cells with two nuclear spots were considered for interpretation. RESULTS: The mean times from transplantation to first biopsy and between the first and the second biopsies were 5.9 and 20.9 months respectively. The proportion of recipient-derived repopulated hepatocytes was significantly decreased in the late biopsies when compared with the early biopsies (p = 0.001). All nine samples of the first biopsies had demonstrated recipient-derived hepatocyte repopulation, with a mean of 2.0%, whereas only seven of nine samples of the second biopsies had demonstrated recipient-derived hepatocyte repopulation with a low mean of 0.5% (p = 0.001). CONCLUSION: Based on these results, we suggest that ''recipient-specific bone marrow-derived hepatocyte repopulation'' in liver allograft during tissue injury is a relatively early event.

Successful treatment with peginterferon alfa-2b of HBeAg-positive HBV non-responders to standard interferon or lamivudine.

OBJECTIVES: Antiviral therapy leads to HBeAg seroconversion in 10-40% of the patients with HBeAg-positive chronic hepatitis B. Nonresponse may result in progression of liver disease and increased risk of hepatocellular carcinoma. As part of a global randomized controlled trial we investigated the efficacy (i.e., loss of HBeAg at the end of follow-up) of peginterferon alfa-2b (Peg-IFN alpha2b) in patients who failed to respond to previous courses of standard interferon (IFN) or lamivudine. METHODS: We analyzed a total of 76 previous nonresponders: 37 were nonresponders to standard IFN, 17 were nonresponders to lamivudine, and 22 were nonresponders to both therapies. All patients received a 52-wks course of 100 microg Peg-IFN alpha2b weekly combined with either 100 mg lamivudine daily or a placebo. After therapy patients were followed for 26 wks. RESULTS: Thirteen (35%) nonresponders to previous IFN, five (29%) nonresponders to previous lamivudine, and four (22%) nonresponders to both IFN and lamivudine responded to treatment with Peg-IFN alpha2b. No difference in response was found for those treated with Peg-IFN alpha2b alone or in combination with lamivudine. Nonresponders to prior IFN therapy with baseline ALT (alanine aminotransferase) > 4 x ULN (upper limit of normal) responded better to Peg-IFN alpha2b than those with ALT levels

Ursodeoxycholic acid treatment in isolated chronic graft-vs.-host disease of the liver.

OBJECTIVES: Data regarding the long-term treatment of ursodeoxycholic acid (UDCA) in individuals of chronic graft-vs.-host disease (cGVHD) of the liver are limited. The aims of this prospective study were to determine whether, (i) UDCA treatment is useful as a long-term treatment for individuals with limited cGVHD of the liver following allogeneic hematopoietic cell transplantation, and (ii) the tolerability of UDCA treatment in such individuals. METHODS: Fifteen consecutive patients with de novo isolated cGVHD of the liver were included. All individuals were treated with UDCA at a dose of 13 mg/kg/d for 1 yr. Clinical evaluation and laboratory testing were assessed at 30-d intervals during UDCA therapy and every 30 d after discontinuation of UDCA for a total of 3 months. RESULTS: At the end of the treatment, 60% of patients with cGVHD of the liver had normal liver tests, the remaining 40% of patients demonstrated improvement in their abnormal liver tests (partial responders), whereas none of the patients had worsening of the liver tests. When compared with baseline, there was a significant decrease in the serum aminotransferases, alkaline phosphatase and gamma-glutamyl transpeptidase levels after completion of the UDCA treatment at 12 months (p < 0.01). No significant increase in serum liver enzyme tests was observed at the third month after the completion of therapy. Pruritus in seven of nine patients resolved after UDCA treatment. All patients completed their assigned treatment with no major adverse event. CONCLUSION: Long-term UDCA therapy appears to be effective, safe and tolerable in individuals with cGVHD presenting with isolated liver involvement.