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In a trial involving patients with primary biliary cholangitis, treatment with elafibranor, a dual PPAR-α and PPAR-δ agonist, led to greater improvements in biochemical indicators of cholestasis than placebo.

Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25–30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per μL, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 μg of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659. Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1·84, 95% CI 0·86–3·91, p=0·12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D. The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.

Background Both C reactive protein (CRP) and procalcitonin (PCT) are well known acute phase reactant proteins. CRP was reported to increase in metabolic syndrome and type-2 diabetes. Similarly altered level of serum PCT was found in chronic liver diseases and cirrhosis. The liver is considered the main source of CRP and a source of PCT, however, the serum PCT and CRP levels in non-alcoholic fatty liver disease (NAFLD) were not compared previously. Therefore we aimed to study the diagnostic and discriminative role of serum PCT and CRP in NAFLD. Methods Fifty NAFLD cases and 50 healthy controls were included to the study. Liver function tests were measured, body mass index was calculated, and insulin resistance was determined by using a homeostasis model assessment (HOMA-IR). Ultrasound evaluation was performed for each subject. Serum CRP was measured with nephalometric method. Serum PCT was measured with Kryptor based system. Results Serum PCT levels were similar in steatohepatitis (n 20) and simple steatosis (n 27) patients, and were not different than the control group (0.06 ± 0.01, 0.04 ± 0.01 versus 0.06 ± 0.01 ng/ml respectively). Serum CRP levels were significantly higher in simple steatosis, and steatohepatitis groups compared to healthy controls (7.5 ± 1.6 and 5.2 ± 2.5 versus 2.9 ± 0.5 mg/dl respectively p < 0.01). CRP could not differentiate steatohepatitis from simple steatosis. Beside, three patients with focal fatty liver disease had normal serum CRP levels. Conclusion Serum PCT was within normal ranges in patients with simple steatosis or steatohepatitis and has no diagnostic value. Serum CRP level was increased in NAFLD compared to controls. CRP can be used as an additional marker for diagnosis of NAFLD but it has no value in discrimination of steatohepatitis from simple steatosis.

Thrombocytopenia is a common complication of chronic liver diseases, but its pathogenesis is not clear. Although generally attributed to hypersplenism, other factors should also be considered. We investigated the relationship between the peripheral platelet count and the degree of fibrosis in patients with chronic viral hepatitis. In an effort to avoid the effects of hypersplenism, we excluded patients with splenomegaly and/or bi- or pan-cytopenia. Seven hundred eighty-four patients (265 chronic viral hepatitis C and 519 chronic viral hepatitis B) were included in the study. Univariate analysis showed that the peripheral platelet count had a negative correlation with fibrosis score, necroinflammatory activity, and age in both groups. In multivariate analysis, the peripheral platelet count had a similar correlation with the fibrosis score and age, but not with necroinflammatory activity, in both groups. The peripheral platelet count decreased more significantly in females with chronic hepatitis C but not in the chronic hepatitis B group. In conclusion, a decrease in peripheral platelet count may be a sign of an increase in the degree of fibrosis during the course of chronic viral hepatitis B and C and factors other than hypersplenism may play a role in this decrease in the peripheral platelet count.

Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response. 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 μg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 μg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32–52 the pegylated interferon dose was 50 μg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment. 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0·91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0·01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0·01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%). Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.

Chronic delta hepatitis represents a major health burden. Until recently, pegylated interferon-alfa-2a (PEG-IFNα) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). The aim of this study was to evaluate 10-year long-term clinical and virological outcomes after 96 weeks of treatment with PEG-IFNα with or without tenofovir disoproxil fumarate (TDF). We conducted a retrospective follow-up study of the Hep-Net-International-Delta-Hepatitis-Intervention-Study 2 (HIDIT-II trial). Patients had received 96 weeks of treatment with either PEG-IFNα-2a plus TDF or PEG-IFNα-2a alone. Patients were included if they had completed the 96-week treatment period and had at least one follow-up visit (PEG-IFNα-2a + TDF; n = 51, PEG-IFNα-2a alone; n = 56). Patients who received PEG-IFNα-2a + TDF were younger (37 vs. 42 years) and no significant differences were observed in other baseline characteristics between the two treatment arms. A total of 26 patients (24%) developed one or more liver-related endpoints after a mean time of 8.4 years. The incidence of endpoints was significantly lower in the combination group (14% vs. 34%, p = 0.02). The development of liver-related endpoints was also associated with non-response to therapy (HDV RNA and HBsAg), elevated HBV DNA at week 72, and baseline age, cirrhosis, platelets, INR, AST, GGT, bilirubin and albumin according to the Cox regression model. The long-term follow-up of this large randomised clinical trial demonstrates that combination therapy with TDF and virological response to PEG-IFNα-2a (undetectable HDV RNA and HBsAg loss) were associated with better clinical outcomes. NCT00932971, EudraCT 2008-005560-13.

The purpose of this clinical study was to determine if the expression of the TLR2 and/or TLR4 genes is involved in triggering the auto-inflammatory attacks in patients with familial Mediterranean fever (FMF). Thirty patients with FMF and 20 healthy control subjects were recruited. Comparisons were made in TLR2 and TLR4 gene expression levels during FMF attack episodes and attack-free periods, as well as with baseline levels in healthy control subjects. There was no significant difference in TLR2 and TLR4 gene expression between the attacks and attack-free periods in the entire group of FMF patients. However, among female patients, expression level of TLR4 gene was significantly higher during the attack than in the attack-free period ( TLR2 Log 2.04 ± 0.14 vs. 2.52 ± 0.10, respectively, P  = 0.02). There was not a significant difference between FMF patients and healthy subjects. The patients who had higher levels of TLR2 expression during the acute attack experienced their first attacks at an earlier age ( r  = −0.571; P  = 0.001). The frequency of attacks, acute-phase response, MEFV mutations, and colchicine response were not associated with TLR2 and TLR4 levels. We conclude that changes in the expression of TLR2 and TLR4 genes do not appear to be involved in triggering FMF attacks. A higher level of TLR2 expression during acute attack may be related to the early onset of the disease. Further studies using specific cell populations such as neutrophils, monocytes, and dendritic cells may be useful to explore any changes in the sensitivity of toll-like receptors to their agonists, such as lipopolysaccharides, in the onset of attacks.

The samples of hepatocellular carcinoma from Turkey, a country with a high prevalence of hepatitis B virus and hepatitis C virus, but low dietary exposure to aflatoxin B1, were examined in order to detect the frequency of mutant p53 and its association with clinical and pathological data. Fifty-two samples of hepatocellular cancer from the patients who were diagnosed in our clinic were included in this study. The mutant p53 protein was searched for by specific enzyme-linked immunosorbent assay. Of 52 patients with hepatocellular carcinoma, 26 (50%) had the mutant p53. The incidence of p53 mutation in hepatocellular cancer patients with chronic liver disease due to hepatitis B virus infection was significantly higher than in those with chronic liver disease due to alcohol, indicating that not alcohol but hepatitis B virus, in fact induces the mutations in p53 gene. In addition, it has been shown that the p53 mutation was significantly associated with the diameter of tumor nodule and the degree of cellular differentiation in hepatocellular cancer. The p53 mutation rate found in our study is concordant for a geography where hepatitis B virus and hepatitis C virus are common. Hepatitis B virus and possibly hepatitis C virus, but not alcohol, should be responsible, to a degree, for the mutational change in p53 protein in hepatocellular cancer patients with chronic liver disease. The p53 mutation is a late event in hepatocarcinogenesis because it is related with cellular differentiation and tumor diameter. The specific ELISA can be a useful screening test in future studies to select the patients for gene therapy using wild-type p53.

This multicenter retrospective study analyzed 336 patients (236 adults, 100 children) who underwent liver transplantation (LT) for acute liver failure (ALF) between 2002 and 2019 across 14 centers in Türkiye. The aim was to evaluate pretransplant factors influencing short-term posttransplant survival. Median MELD and PELD scores were 31 and 30, respectively. The most common ALF etiologies were viral, indeterminate, and drug-induced causes. Living donor liver transplantation (LDLT) was more common in children (86.0%) than adults (57.2%). Mean posttransplant survival was 166±9 months in children and 117±6 months in adults. In adults, LDLT significantly improved survival compared to deceased donor LT (DDLT), with survival of 135 vs. 89 months ( p =0.0012). Although pediatric LDLT recipients had longer mean survival than DDLT recipients (167 vs. 132 months), this difference was not statistically significant ( p =0.5959). Three-month mortality was associated with low albumin and grade 4 hepatic encephalopathy (HE) in children. In adults, independent predictors of early mortality included DDLT, serum sodium >140 mEq/L, MELD >35, pH <7.3, and grade 4 HE. Our data suggest that LDLT may offer a survival advantage, particularly in adults with ALF. Identifying pretransplant risk factors is essential for improving early outcomes and guiding clinical decision-making.