ATA Index: A novel score for predicting fibrosis stage in chronic viral hepatitis.

Background and Aim: This study was designed to predict the fibrosis stage with a clinical scoring system that may reduce the need for liver biopsy. Materials and Methods: The study cohort included the treatment of 430 chronic hepatitis B (CHB) and 170 chronic hepatitis C (CHC) of naive patients. The patients were divided into two groups as mild to moderate and severe fibrosis. After an index obtained in the study cohort, the index was tested in a validation cohort and compared with the FIB-4 Index. Results: The AUC of CHC index was found of 0.89 the sensitivity of 0.91 the specificity of 0.74, the positive predictive value (PPV) of 0.54 and the negative predictive value (NPV) of 0.96. The FIB-4 Index was applied to the CHC study cohort and the ATA Index Hepatitis C was found to be superior in terms of AUC (0.89-0.82), sensitivity (0.91-0.76) and NPV (0.96-0.86). The AUC of CHB Index was determined of 0.92, the sensitivity of 0.90, the specificity of 0.84, the PPV of 0.53 and the NPV of 0.98. Compared to the FIB-4 Index in CHB study cohort, the ATA Index Hepatitis B was predominant in terms of AUC (0.92-0.88), sensitivity (0.90-0.75), NPV (0.98-0.94) and PPV (0.53-0.49). Conclusion: ATA Indexes can predict the non-existence of severe fibrosis with an accuracy similar to FIB-4 Index and may reduce the need for liver biopsy.

Interferon Treatment Duration in Patients With Chronic Delta Hepatitis and its Effect on the Natural Course of the Disease.

Background: Interferon is the only treatment option in chronic delta hepatitis (CDH). A CDH database (333 patients, 161 with interferon treatment history) was analyzed for effects of treatment duration on virologic response and clinical outcomes. Methods: Ninety-nine CDH patients who received at least 6 months of interferon were selected. Maintained virologic response (MVR) was defined as hepatitis D virus RNA negative for 2 years after treatment discontinuation. Cumulative median interferon treatment duration was 24 months (range 6-126 months), with a median of 2 courses (range 1-8). Post-treatment median follow-up was 55 months (24-225 months). Results: Thirty-five patients achieved MVR. Cumulative probability of MVR increased with treatment duration and reached 50% at 5 years. Patients with MVR were less likely to die from liver disease or develop complications compared to patients without MVR (P = .032, P = .006, respectively). Cirrhosis at baseline and no response to therapy (odds ratio 16.1 and 5.23, respectively) predicted an adverse endpoint. Hepatitis B surface antigen clearance occurred in 37% of patients with MVR. Conclusion: Viral response to interferon increases with treatment duration and favorably affects the natural course of disease. Interferon treatment duration has to be individualized with careful post-treatment assessment.

Association Between Level of Hepatitis D Virus RNA at Week 24 of Pegylated Interferon Therapy and Outcome.

BACKGROUND & AIMS: Interferon is the only effective treatment for chronic hepatitis D virus (HDV) infection. No rules have been set for stopping treatment based on viral kinetics. We analyzed data from an international study of hepatitis D treatment to identify factors associated with outcomes of pegylated interferon treatment, with and without adefovir. METHODS: We analyzed data from the Hep-Net-International Delta Hepatitis Intervention Trial on 50 patients with compensated liver disease who tested positive for anti-HDV and HDV RNA. Subjects received pegylated interferon α 2a, with adefovir or placebo, or only adefovir, for 48 weeks. Twenty-four weeks after treatment ended, 41 patients were evaluated for levels of HDV RNA and DNA, liver enzymes, and hepatitis B surface antigen (HBsAg); liver biopsy specimens were analyzed for fibrosis. Response to therapy was defined as end-of-treatment response or post-treatment week 24 virologic response. In both cases virologic response was associated with undetectable HDV RNA levels. Patients with less than a 1 log decrease in HDV RNA at the end of treatment were considered null responders. RESULTS: Based on univariate and multivariate analysis, the level of HDV RNA at week 24 of treatment was associated more strongly with response to therapy than other factors analyzed. The level of HBsAg at week 24 of treatment was associated with a response to therapy only in univariate analysis. Lack of HDV RNA at week 24 of treatment, or end of treatment, identified responders with positive predicted values of 71% and 100%, respectively. At 24 weeks after treatment, a decrease in HDV RNA level of less than 1 log, combined with no decrease in HBsAg level, identified null responders with a positive predictive value of 83%. A decrease in HDV RNA level of more than 2 log at week 24 of treatment identified null responders with a negative predictive value of 95%. CONCLUSIONS: Based on an analysis of data from a large clinical trial, the level of HDV RNA at week 24 of treatment with pegylated interferon, with or without adefovir for 48 weeks, can identify patients who will test negative for HDV RNA 24 weeks after the end of treatment. This information can be used to help physicians manage patients receiving therapy for chronic hepatitis D.

Utility of endoscopy for diagnosis of barrett in a non-Western society: endoscopic and histopathologic correlation.

Barrett esophagus is metaplastic transformation of esophageal squamous epithelium to columnar cells. A total of 1370 patients who had undergone upper endoscopy because of dyspeptic complaints were enrolled in the study. Age, sex, alcohol and smoking habits, body mass index, type and duration of symptoms (heartburn, epigastric pain, nausea, vomiting), and use of proton pump inhibitors were evaluated in all patients and recorded on standardized forms. Patients were grouped as normal esophagogastric junction, long-segment Barrett esophagus, and short-segment Barrett. Biopsies were taken from at least 6 points and examined histopathologically. Of the 1370 patients involved in the study, 748 (54.6%) were female and 622 (45.4%) were male. Mean age was 47.2 ± 15.30 years. Short-segment Barrett esophagus was detected in 16 patients, and long-segment Barrett was detected in 11 patients. Although Barrett esophagus was detected in 11 cases that were suspected to have Barrett during endoscopy, histopathology was negative in all cases that were not suspected to have Barrett. Barrett esophagus prevalence was significantly higher in people who used alcohol and tobacco and who had hiatal hernia. Although Barrett esophagus was detected in 40% of cases that were suspected to have Barrett during endoscopy, histopathology was negative in all cases that were not suspected to have Barrett. Barrett was detected in 40.7% of cases that were suspected to have Barrett during endoscopy; histopathology was negative in all cases that were not suspected to have Barrett. Senstivity of endoscopy is questionable in detection of short-segment Barrett.

Manometric assessment of esophageal motor function in patients with primary biliary cirrhosis.

INTRODUCTION/AIM: Primary biliary cirrhosis is associated with other autoimmune diseases including Sjögren's syndrome, and scleroderma. Esophageal dysmotility is well known in scleroderma, and Sjögren's syndrome. The aim of this study is to investigate whether any esophageal motor dysfunction exists in patients with primary biliary cirrhosis. METHOD: The study was performed in 37 patients (36 women, mean age: 56.29 ± 10.01 years) who met diagnostic criteria for primary biliary cirrhosis. Thirty-seven functional dyspepsia patients, were also included as a control group. Patients entering the study were asked to complete a symptom questionnaire. Distal esophageal contraction amplitude, and lower esophageal sphincter resting pressure were assessed. RESULTS: Manometric findings in primary biliary cirrhosis patients vs. controls were as follows: Median lower esophageal sphincter resting pressure (mmHg): (24 vs 20, p=0.033); median esophageal contraction amplitude (mmHg): (71 vs 56, p=0.050); mean lower esophageal sphincter relaxation duration (sc, x ± SD): (6.10 ± 1.18 vs 8.29 ± 1.92, p<0.001); and median lower esophageal sphincter relaxation (%) (96 vs 98, p=0.019); respectively. No significant differences were evident in median peak velocity (sc) (3.20 vs 3.02, p=0.778) between patients with primary biliary cirrhosis and the functional dyspepsia patients. Esophageal dysmotility was found in 17 (45.9%) primary biliary cirrhosis patients (non-specific esophageal motor disorder in ten patients, hypomotility of esophagus in five patients, nutcracker esophagus in one patient and hypertensive lower esophageal sphincter in one patient). CONCLUSION: Esophageal dysmotility was detected in 45.9% of patients. The study suggests that subclinic esophageal dysmotility is frequent in patients with primary biliary cirrhosis.

Role of immunohistochemistry for hepatitis D and hepatitis B virus in hepatitis delta.

BACKGROUND & AIMS: Immunohistochemical assessment of liver tissue in chronic delta hepatitis (CDH) is underinvestigated. Aim of the study was (i) to assess variables associated with hepatitis D antigen (HDAg), hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) staining in the liver. METHODS: Demographic, biochemical and virologic data collected from the HIDIT 1 study were used. HBsAg, HBcAg and HDAg immunohistochemical (IHC) staining was semiquantitatively assessed. RESULTS: Hepatitis D antigen immunohistochemical staining displayed positive correlations with age and alanine aminotransferase (ALT) and negative correlations with serum HBsAg (P = 0.01 for all). HBsAg IHC displayed a negative correlation with gamma glutamyl transferase and positive correlations with serum HBV DNA, serum HBsAg levels and HBeAg serology (P < 0.001, P = 0.02 and P = 0.007 respectively). HBcAg staining was mainly nuclear and displayed negative correlations with serum HBsAg and histologic activity (P = 0.002 and P = 0.02 respectively). Pegylated IFN based treatment led to a decline of all IHC markers, however, these markers had no impact on treatment outcome. CONCLUSIONS: These data suggest an association of liver injury with HDAg expression in CDH whereas the negative correlation between HBcAg expression and liver injury and the overall nuclear localization of HBcAg suggest that HBcAg does not contribute to liver injury in CDH. HDV cases with high level of HBV replication, high serum HBsAg levels, HBeAg positivity, that are probably in the earlier stages of disease (low gamma-glutamyl transferase), had a more intense HBsAg staining profile. Overall, the data enforce the importance of HDAg and HBsAg in different phases of CDH infection.

Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.

Pegylated interferon-based treatment in patients with advanced liver disease due to chronic delta hepatitis.

BACKGROUND/AIMS: The safety and efficacy of interferons in advanced delta hepatitis have not been explored. The aim of this subanalysis of a multicenter clinical trial was to compare the efficacy and safety of 48 weeks of pegylated interferon alpha-2a (180 µg weekly) with or without adefovir (10 mg daily) in patients with chronic delta hepatitis-induced advanced liver disease and in those with non-advanced liver disease. MATERIALS AND METHODS: Thirty-one patients with advanced and 27 patients with non-advanced liver disease were assessed. Patients were considered to have advanced liver disease when biopsy disclosed a fibrosis score of ≥4 according to Ishak or when imaging studies were indicative of cirrhosis. Virologic response, defined as achievement of undetectable hepatitis D virus RNA, was assessed at the end of treatment and end of 24 weeks of treatment-free follow-up. RESULTS: Patients with advanced disease had lower hepatitis D virus RNA levels and platelet counts (p=0.014 and p=0.0015, respectively). End of treatment and end of follow-up virologic responses in patients with advanced vs. non-advanced liver disease were similar (29% vs. 19% and 32% vs 23%). Proportion of adverse events did not differ between groups except that thrombocytopenia was noted more often in the advanced liver disease group. Further, four cases of clinically important adverse events including two cases of hepatic decompensation and one case of tuberculosis reactivation occurred in the advanced liver disease group. CONCLUSIONS: Pegylated interferon is as effective in patients with advanced liver disease due to chronic delta hepatitis as in patients with non-advanced liver disease, but patients should be monitored closely for clinically important side effects.

HBeAg-positive hepatitis delta: virological patterns and clinical long-term outcome.

BACKGROUND AND AIMS: The presence of the hepatitis B virus (HBV)-eAg in patients with hepatitis B is associated with higher HBV replication and with an increased risk to develop liver-related clinical endpoints defined as liver related death, liver transplantation, development of hepatocellular carcinoma and hepatic decompensation. The aim of this study was to investigate the role of HBeAg in patients co-infected with the hepatitis D virus (HDV). METHODS: We studied virological markers of HBV and HDV infection and as well as biochemical and clinical features of liver disease in a cohort of 534 anti-HDV-positive patients. In addition, we compared the clinical long-term outcome of HBeAg-positive HDV-infected patients with HBeAg-negative control patients matched for age, gender and baseline-MELD score. RESULTS: HBeAg-positive hepatitis delta was detected in 71 of 534 patients (13.3%). HBeAg positivity was associated with a higher biochemical disease activity and higher HBsAg levels in HDV co-infected patients. Sixty one per cent of the HBeAg-positive HDV-infected patients presented with HBV DNA levels below 2000 IU/ml, at least once during follow-up. Both HBeAg-positive and -negative patients showed a similar severe clinical long-term course with about half of the patients developing a liver-related clinical complication after a median follow-up period of 51 months (range: 9-193 months). CONCLUSIONS: HBV DNA levels are low in both HBeAg-negative and HBeAg-positive patients suggesting suppressive effects of HDV on HBV irrespective of the phase of HBV infection. The clinical long-term outcome of HBeAg-positive patients is not different to HBeAg-negative patients infected with the HDV.

Anti-HDV immunoglobulin M testing in hepatitis delta revisited: correlations with disease activity and response to pegylated interferon-α2a treatment.

BACKGROUND: The role of anti-HDV immunoglobulin M (IgM) testing in patients receiving pegylated interferon-α therapy for hepatitis delta is unknown. We performed anti-HDV IgM testing in a well defined cohort of HDV-infected patients who were treated with pegylated interferon-α2a plus adefovir, or either drug alone. METHODS: Sera from 33 HDV-RNA-positive patients from the international HIDIT-1 trial were available for anti-HDV IgM testing (ETI-DELTA-IGMK-2 assay, DiaSorin, Saluggia, Italy) before therapy, at treatment weeks 24 and 48, and at 24 weeks after the end of treatment. RESULTS: Anti-HDV IgM tested positive in 31 out of the 33 patients (94%) prior to treatment. HDV IgM levels correlated with histological inflammatory activity (r=0.51, P<0.01) and were higher in patients with alanine aminotransferase and γ-glutamyl transpeptidase levels above the median (P<0.05). Quantitative anti-HDV IgM values declined in patients responding to antiviral therapy, however anti-HDV IgM remained positive after treatment in the majority of virological responders. CONCLUSIONS: We suggest that anti-HDV IgM testing might give additional useful information to determine disease activity in hepatitis delta and to predict treatment response to antiviral therapy with type I interferons. However, determination of anti-HDV IgM can not substitute HDV RNA testing, which remains the primary virological marker for response to therapy.

Serum connective tissue markers as predictors of advanced fibrosis in patients with chronic hepatitis B and D.

BACKGROUND/AIMS: Liver biopsy to assess fibrosis is invasive and prone to sampling error. While algorithms of serum markers to predict fibrosis stage have been described for chronic hepatitis C, these cannot be applied equally well to hepatitis B. METHODS: We therefore determined 9 serum fibrosis markers, liver biochemical tests and ultrasound parameters in 109 consecutive adult patients with chronic hepatitis B and D. All patients had compensated liver disease. Using the METAVIR score, advanced disease was defined as fibrosis stage ≥F2, and active inflammation as grade ≥A2. A gold standard was created considering splenomegaly and/or platelets <150,000 as indicators of advanced fibrosis irrespective of histology. Area under receiver operating characteristics curves was used for assessment of single markers and odds ratio for their combinations. RESULTS: Patients with advanced disease were older, had lower albumin, higher gamma glutamyl transferase and lower platelet. Levels of 6 of the 9 fibrosis markers, tissue inhibitor of metalloproteinases-1, procollagen type III aminoterminal propeptide, matrix metalloproteinase-2, laminin, hyaluronan and collagen IV correlated with advanced fibrosis. Markers useful for fibrosis prediction also predicted marked inflammation. Using the gold standard, age, prothrombin time, gamma glutamyl transferase and albumin were independent predictors of fibrosis with odds ratio's of 3.11, 4.18, 3.35 and 5.25, respectively. Their combined use predicted fibrosis with an odds ratio of 228.8. Tissue inhibitor of metalloproteinases-1 and hyaluronan were powerful predictors of fibrosis (Odds ratio's of 8.65 and 8.38). Their combined use revealed an odds ratio of 28.6, when compared with the gold standard. CONCLUSION: In conclusion, advanced liver fibrosis in chronic hepatitis B and D may be predicted with use of these two fibrosis markers.

Peginterferon plus adefovir versus either drug alone for hepatitis delta.

BACKGROUND: Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and adefovir dipivoxil alone. METHODS: We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 µg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, 29 received 180 µg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS: The primary end point--normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48--was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P = 0.006 for the comparison of the first and third groups; P = 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log(10) IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P = 0.01 for the comparison of the first and second). CONCLUSIONS: Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection. (Current Controlled Trials number, ISRCTN83587695.).

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.

Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis.

UNLABELLED: Abstract Background: Hepatitis delta virus (HDV) causes severe liver disease. AIMS: To investigate the quantitative HDV-RNA, HBsAg and hepatitis B virus (HBV)DNA levels in correlation to histological, biochemical and demographical parameters in patients with chronic HDV infection as similar data in a large series of HDV patients are missing. METHODS: Eighty HDV patients were recruited in Germany, Turkey and Greece; quantitative determination of HDV-RNA, HBsAg and HBV-DNA was performed by real-time polymerase chain reaction, the Architect HBsAg assay and Cobas TaqMan HBV test respectively. RESULTS: All patients were infected with HDV-genotype 1. Thirty-five patients (48%) had significant fibrosis (Ishak 3-4) and 15 (20.5%) had cirrhosis. HDV viraemia ranged from 1.1 x 10(3) to 8.4 x 10(7) copies/ml with 60% of patients showing HDV-RNA levels above 10(5) copies/ml accompanied by low HBV viraemia (<10(5) copies/ml). However, HDV-RNA and HBV-DNA levels showed no direct inverse correlation. HDV-RNA correlated positively with HBsAg and negatively with age. HBsAg correlated negatively with age and positively with histological grading. Only gamma-glutamyltranspeptidase was independently associated with cirrhosis (P=0.032), while no biochemical parameter was associated with grading. CONCLUSIONS: (i) HBsAg levels correlated with HDV viraemia in chronic HDV. (ii) Biochemical parameters did not accurately indicate the stage and grade of liver disease in chronic HDV and thus liver biopsy seems to remain the major tool for the evaluation of delta hepatitis patients.

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.

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.

Adjuvant therapeutic plasma exchange in liver failure: assessments of clinical and laboratory parameters.

BACKGROUND: Therapeutic plasma exchange (TPE) seems to be an effective approach for clearing toxins, immune-mediated antigens, and other particles from the circulation. The aim of this study was to analyze the positive effects of TPE on clinical and biochemical parameters of liver failure. PATIENTS AND METHODS: Between January 2001 and March 31, 2005 individuals (men/women, 17/14; median age, 42.7+/-15.8 y) with acute and chronic liver failure who underwent a total of 113 TPEs (median session 3.7) were retrospectively reviewed. TPE was performed using the Fresenius AS-TEC 204 cell separator (Fresenius AG, Germany). The indication for TPE was severe coagulopathy (prothrombin time >20 s), severe hepatic encephalopathy, hyperbilirubinemia, and candidacy for liver transplantation. All patients were examined before and immediately after the last TPE session. RESULTS: When compared with baseline, there was significant improvement in hepatic encephalopathy stage (from median score 3.0 to 1.0, P=0.001), serum prothrombin time (from median 26.0 to 20.0 s, P=0.003), aminotransferases (P<0.001), and total bilirubin levels (from median 35.0 to 23.3 mg/dL, P<0.001) after TPE. Thirteen of the thirty-one individuals (41.9%) died in the hospital. The mean follow-up period of 18 survival patients was 35.9+/-5.6 months and 10 of those survived (55.6%, 10/18). No serious adverse effect of TPE was observed in any of the patients during or after completion of TPE. Only 6 patients experienced minor transfusion reactions. CONCLUSIONS: TPE seems to be effective in improving hepatic encephalopathy stage and liver tests in individuals with acute and chronic liver failure. The data suggest that TPE is safe and tolerable in such individuals, however, overall survival remains poor despite TPE.

PPAR-alpha L162V polymorphism in human hepatocellular carcinoma.

BACKGROUND/AIMS: Several lines of evidence suggest that peroxisome proliferator-activated receptor alpha may be involved in hepatocarcinogenesis. L162V polymorphism of the peroxisome proliferator-activated receptor alpha gene enhances the transactivation activity of this transcription factor. The aim of this study was to determine the frequency and clinical correlates of peroxisome proliferator-activated receptor alpha L162V polymorphism in hepatitis virus-induced hepatocellular carcinoma. METHODS: 90 hepatocellular carcinoma patients diagnosed at Ankara University Gastroenterology Clinic between January 2002 and July 2003 and 80 healthy controls with normal body mass index, blood chemistry and with negative viral serology were included. peroxisome proliferator-activated receptor alpha L162V polymorphism was determined by PCR-RFLP. RESULTS: hepatocellular carcinoma etiologies were as follows: 56 HBV, 12 HBV+HDV, 22 HCV. Eighty-seven patients (97%) were cirrhotic, and 60 patients (67.5%) had advanced tumors. In 83 (92%) of 90 hepatocellular carcinoma patients, gene segment including polymorphic region could be amplified by PCR (50 HBV, 12 HBV+HDV, 21 HCV) and 6 of them (7.2%, all infected with HBV) had L162V polymorphism, while 2 (2.5%) of 80 controls had this polymorphism (p=0.162). This trend became more remarkable when only HBV (HBV+HDV)-infected patients were compared with controls (6/62, 9.7% vs. 2/80, 2.5%, respectively, p=0.071). Five of 6 patients with L162V had advanced disease. CONCLUSIONS: Peroxisome proliferator-activated receptor alpha L162V polymorphism tends to occur in HBV-induced hepatocellular carcinoma and is absent in HCV-related hepatocellular carcinoma. These findings may show clues for the existence of different carcinogenesis mechanisms in these two common etiologies. Frequent occurrence of advanced disease in patients with L162V polymorphism suggests a role for this polymorphism in tumor progression.

Pegylated interferon-alpha plus taurine in treatment of rat liver fibrosis.

AIM: To investigate the antifibrotic effects of peginterferon-alpha 2b and taurine on oxidative stress markers and hepatocellular apoptosis. METHODS: Sixty rats with CCl4-induced liver fibrosis were divided into 4 groups (n=15). Group 1 was left for spontaneous recovery (SR). Groups 2-4 received peginterferon-alpha 2b, taurine, and their combination, respectively, for four weeks. Histological fibrosis scores, histomorphometric analysis, tissue hydroxyproline, tissue MDA, GPx and SOD activities were determined. Activated stellate cells and hepatocellular apoptosis were also evaluated. RESULTS: The degree of fibrosis decreased in all treatment groups compared to spontaneous recovery group. Taurine alone and in combination with peginterferon-alpha 2b reduced oxidative stress markers, but peginterferon-alpha 2b alone did not. Apoptotic hepatocytes and activated stellate cells were higher in groups 2-4 than in group 1. Combined taurine and peginterferon-alpha 2b further reduced fibrosis and increased activated stellate cell apoptosis, but could not improve oxidative stress more than taurine alone. CONCLUSION: Peginterferon-alpha 2b exerts anti-fibrotic effects on rat liver fibrosis. It seems ineffective against oxidative stress in vivo. Peginterferon-alpha 2b in combination with taurine seems to be an antifibrotic strategy.

Antituberculous therapy-induced fulminant hepatic failure: successful treatment with liver transplantation and nonstandard antituberculous therapy.

Standard antituberculous therapy including isoniazid, rifampin, ethambutol, and pyrazinamide is widely used for the treatment of active tuberculosis. Its most important side effect is hepatotoxicity, ranging from asymptomatic transaminitis to fulminant hepatic failure. A 19-year-old woman was admitted to our unit due to jaundice and unconsciousness. According to her past medical history, she was diagnosed as having extrapulmonary tuberculosis and had been prescribed standard antituberculous therapy. The patient became icteric and unconscious on the fourth day after therapy initiation. She was diagnosed with drug-induced acute fulminant hepatic failure and underwent living-related liver transplantation. Nonhepatotoxic antituberculous therapy (cycloserine, ciprofloxacin, streptomycin, and ethambutol) and low-dose immunosuppressive therapy were started after transplantation. Currently the patient is very well with normal graft function 42 months after transplantation. Here we report a case of a patient with acute fulminant hepatic failure caused by isoniazid, rifampicin, or both, who was successfully treated with living-related liver transplantation and a relatively less hepatotoxic antituberculous therapy. In conclusion, liver transplantation is a feasible therapy for individuals with standard antituberculous therapy-induced hepatic failure. Nonhepatotoxic antituberculous therapy may achieve control of active tuberculosis in such individuals after transplantation.