Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE: The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN: We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥ 0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥ 20 g/day for ≥ 5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS: Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

Definition of an HBsAg to DNA international unit conversion factor by enrichment of circulating hepatitis B virus forms.

Hepatitis B (HBV) virus infection is characterized by the overproduction of subviral particles (SVP) over infectious Dane particles (VP). Precise regulation of the ratio between these forms is unknown, but its fluctuation may have a clinical impact. An enrichment method was applied to assess the SVP/VP ratio in chronically infected patients (CHB) and to compare the sensitivity of HBs antigen (HBsAg) and DNA detection methods. Plasmas from 9 genotype A-D CHB patients were fractionated on Nycodenz(®) gradients, and both HBV DNA and HBsAg were quantified in each collected fraction using standardized techniques expressed in IU/mL. Infection of primary human hepatocytes (PHHs) was performed with crude or fractionated plasma. Independently of the genotype, all plasmas showed a similar rate-zonal separation profile characterized by a bottom DNA-enriched peak surmounted by HBsAg-enriched fractions. Inoculation of PHH with plasma-derived VP-enriched fractions led to long-lasting production of virus in cell supernatants with a SVP/VP ratio similar to that observed in patient plasmas. In the VP fraction, one IU of HBsAg corresponded to approximately 5 million IU of HBV DNA. Rate-zonal gradient separation directly applied on patient plasma allows a better insight into the distribution of VP in HBeAg-positive CHB carriers. This study highlights the sensitivity difference of the techniques classically used to monitor HBV infection and indicates that VP-associated HBsAg contributes modestly to the overall amount of total circulating HBsAg in CHB. Such a fractionation approach should help to understand the fine regulation of HBsAg production over replication at different stages of CHB.

The CUPIC algorithm: an accurate model for the prediction of sustained viral response under telaprevir or boceprevir triple therapy in cirrhotic patients.

Triple therapy using boceprevir or telaprevir remains the reference treatment for genotype 1 chronic hepatitis C in countries where new interferon-free regimens have not yet become available. Antiviral treatment is highly required in cirrhotic patients, but they represent a difficult-to-treat population. We aimed to develop a simple algorithm for the prediction of sustained viral response (SVR) in cirrhotic patients treated with triple therapy. A total of 484 cirrhotic patients from the ANRS CO20 CUPIC cohort treated with triple therapy were randomly distributed into derivation and validation sets. A total of 52.1% of patients achieved SVR. In the derivation set, a D0 score for the prediction of SVR before treatment initiation included the following independent predictors collected at day 0: prior treatment response, gamma-GT, platelets, telaprevir treatment, viral load. To refine the prediction at the early phase of the treatment, a W4 score included as additional parameter the viral load collected at week 4. The D0 and W4 scores were combined in the CUPIC algorithm defining three subgroups: 'no treatment initiation or early stop at week 4', 'undetermined' and 'SVR highly probable'. In the validation set, the rates of SVR in these three subgroups were, respectively, 11.1%, 50.0% and 82.2% (P < 0.001). By replacing the variable 'prior treatment response' with 'IL28B genotype', another algorithm was derived for treatment-naïve patients with similar results. The CUPIC algorithm is an easy-to-use tool that helps physicians weigh their decision between immediately treating cirrhotic patients using boceprevir/telaprevir triple therapy or waiting for new drugs to become available in their country.

Point Shear Wave Elastography by Acoustic Radiation Force Impulse Quantification in Comparison to Transient Elastography for the Noninvasive Assessment of Liver Fibrosis in Chronic Hepatitis C: A Prospective International Multicenter Study.

PURPOSE: The aim of the present prospective European multicenter study was to demonstrate the non-inferiority of point shear wave elastography (pSWE) compared to transient elastography (TE) for the assessment of liver fibrosis in patients with chronic hepatitis C. MATERIALS AND METHODS: 241 patients with chronic hepatitis C were prospectively enrolled at 7 European study sites and received pSWE, TE and blood tests. Liver biopsy was performed with histological staging by a central pathologist. In addition, for inclusion of cirrhotic patients, a maximum of 10 % of patients with overt liver cirrhosis confirmed by imaging methods were allowed by protocol (n = 24). RESULTS: Owing to slower than expected recruitment due to a reduction of liver biopsies, the study was closed after 4 years before the target enrollment of 433 patients with 235 patients in the 'intention to diagnose' analysis and 182 patients in the 'per protocol' analysis. Therefore, the non-inferiority margin was enhanced to 0.075 but non-inferiority of pSWE could not be proven. However, Paired comparison of the diagnostic accuracy of pSWE and TE revealed no significant difference between the two methods in the 'intention to diagnose' and 'per protocol' analysis (0.81 vs. 0.85 for F ≥ 2, p = 0.15; 0.88 vs. 0.92 for F ≥ 3, p = 0.11; 0.89 vs. 0.94 for F = 4, p = 0.19). Measurement failure was significantly higher for TE than for pSWE (p = 0.030). CONCLUSION: Non-inferiority of pSWE compared to TE could not be shown. However, the diagnostic accuracy of pSWE and TE was comparable for the noninvasive staging of liver fibrosis in patients with chronic hepatitis C.

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels.

Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin.

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) α-2b or IFN α-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α-2b and/or PEG-IFN α-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN α-2b and 366 with SVR following treatment with PEG-IFN α-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α-2b and three patients treated with PEG-IFN α-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN α-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN α-2b. Successful treatment of hepatitis C with PEG-IFN α-2b or IFN α-2b leads to clinical cure of hepatitis C in the vast majority of cases.

Liver Assessment in Patients with Ataxia-Telangiectasia: Transient Elastography Detects Early Stages of Steatosis and Fibrosis.

Background: Ataxia-telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition, and altered body composition. Liver diseases with steatosis, fibrosis, and hepatocellular carcinoma are frequent findings in older patients but sensitive noninvasive diagnostic tools are lacking. Objectives: To determine the sensitivity of transient elastography (TE) as a screening tool for early hepatic tissue changes and serum biomarkers for liver disease. Methods: Thirty-one A-T patients aged 2 to 25 years were examined prospectively from 2016-2018 by TE. In addition, we evaluated the diagnostic performance of liver biomarkers for steatosis and necroinflammatory activity (SteatoTest and ActiTest, Biopredictive, Paris) compared to TE. For calculation and comparison, patients were divided into two groups (<12, >12 years of age). Results: TE revealed steatosis in 2/21 (10%) younger patients compared to 9/10 (90%) older patients. Fibrosis was present in 3/10 (30%) older patients as assessed by TE. We found a significant correlation of steatosis with SteatoTest, alpha-fetoprotein (AFP), HbA1c, and triglycerides. Liver stiffness correlated significantly with SteatoTest, ActiTest, HbA1c, and triglycerides. Conclusion: Liver disease is a common finding in older A-T patients. TE is an objective measure to detect early stages of steatosis and fibrosis. SteatoTest and ActiTest are a good diagnostic assessment for steatosis and necroinflammatory activity in patients with A-T and confirmed the TE results.

Evolution of biomarkers of liver fibrosis and liver insufficiency in hepatitis C virus-infected patients treated with pegylated interferon plus ribavirin and rituximab.

Therapeutic options in hepatitis C virus (HCV)-related vasculitis may target the viral trigger using antiviral therapy [pegylated interferon plus ribavirin (PEG-IFN/RBV)], and/or the downstream B-cell arm of autoimmunity with rituximab (RTX). To date, no study has compared the efficacy of RTX combined with PEG-IFN/RBV on biomarkers of liver insufficiency in patients with severe liver fibrosis. Twenty-eight untreated HCV-related vasculitis patients with severe liver fibrosis (Metavir F3-F4) were included: 14 patients received RTX plus PEG-IFN/RBV and 14 patients PEG-IFN/RBV. The main clinical and biological data were recorded and compared at baseline, month 3 (M3), M12 and M24 of follow-up. Baseline epidemiological, clinical, virological and immunological features were similar between the groups. The virological response did not differ between cases and controls. The alanine aminotransferase (ALT) level and HCV viral load did not increase in patients treated with RTX. Serum albumin levels increased in patients treated with RTX at M3 and M6 (108% and 111% of baseline value; P = 0.06 and P = 0.13), whereas it was stable in patients treated without RTX. FibroTest values decreased from 0.70 at baseline to 0.59 at M3 (P = 0.5) and returned to 0.69 at M24 in the RTX-PEG-IFN/RBV group, whereas they were stable in the PEG-IFN/RBV group. RTX is safe in patients with severe HCV liver fibrosis and vasculitis. No beneficial effects of RTX were evidenced on liver fibrosis progression, but we found interesting correlations with the serum albumin level, FibroTest values and B-cell count.

Perioperative management of combined heart-liver transplantation in patients with cirrhosis, renal insufficiency, or pulmonary hypertension.

UNLABELLED: STATING THE MAIN PROBLEM: Only few reports have detailed perioperative management and outcome of combined heart and liver transplantation (CHLT), and none describe the long-term renal function. METHODS: Three patients presented clinical signs of cardiomyopathy with reduced ejection fraction and proven cirrhosis with evidence of portal hypertension. Two of them presented renal failure, and the other pulmonary hypertension. After cardiac transplantation and closure of the sternum, liver transplantation was performed using systematically venovenous double-limb (portal and caval) bypass. RESULTS: Mean cold ischemic time for heart and liver was 2 h 46 min and 12 h 47 min, respectively. Intraoperative hemodynamics remained grossly stable during surgery. Mean transfusions were 12 red blood cell packs. All three patients received anti-R-Il2 antibodies at post-operative day 1 and 4. Mean plasma creatinine concentration was 90 ± 8 µmol/L one yr post-CHLT, vs 160 ± 62 µmol/L pre-CHLT. All three patients are alive with functional grafts after a mean follow-up of 26 months (12-38). CONCLUSION: CHLT could be performed safely through two consecutive and independent usual procedures. Perioperative hemodynamic stability, minimal blood loss, and routine splanchnic decompression are probably major determinants of a favorable outcome and good long-term renal function.

Evaluation of FibroTest-ActiTest in children with chronic hepatitis C virus infection.

FibroTest-ActiTest (FT-AT) has been validated in adults with chronic hepatitis C virus (HCV) infection as a noninvasive alternative to liver biopsy (LB), but there are few data of its use in children. The objective of the present study was to evaluate FT-AT in children with HCV infection and to compare FT-AT analysis with liver histology. A total of 43 serum samples from 38 children with chronic HCV infection were analyzed retrospectively. Histological evaluation was performed according to the METAVIR scoring system. In 16 of the children, 21 serum samples were tested with FT-AT and compared to 21 LB (serum/LB pairs) in nontransplanted and liver-transplanted children. FT-AT was also measured in 22 infected children without LB and in 50 healthy controls. FT-AT values in controls were comparable to those of healthy adults, validating the adult FT-AT parameters in children. In most infected children (74%), the FT-AT score was

ActiTest accuracy for the assessment of histological activity grades in patients with chronic hepatitis C, an overview using Obuchowski measure.

BACKGROUND: ActiTest (AT) is a biomarker of liver necro-inflammatory histological activity validated in patients with chronic hepatitis C (HCV). AIM: The aim was to assess the accuracy of AT in comparison with alanine aminotransferase (ALT) the standard of care. METHODS: Methods used an integrated database of individual data and the new recommended Obuchowski measures. An updated "classical" meta-analysis of AT validation studies was also performed. The main end points were the area under the ROC curves (AUROCs) for the diagnosis of each histological activity grade defined using METAVIR scoring system. To avoid repeated tests and the spectrum effect of activity grades prevalence, the comparison of AT and ALT accuracies used the Obuchowski method. RESULTS: For the individual analysis, a total of 1250 patients were included and for the meta-analysis six studies (2017 patients) were included. The overall accuracy of AT for the diagnosis of any activity grade (Obuchowski measure=0.850) was significantly higher than the accuracy of ALT (Obuchowski measure=0.837; P=0.009). The updated standard meta-analysis confirmed the accuracy of AT (p<0.0001) both in independent AUROC=0.79 (95% CI, 0.73-0.85) and in non independent studies AUROC=0.74 (95% CI, 0.67-0.81). CONCLUSIONS: The accuracy of AT for grading the necro-inflammatory activity of patients with HCV was significantly higher than ALT serum activity alone, the standard biomarker.

Impact of adefovir dipivoxil on liver fibrosis and activity assessed with biochemical markers (FibroTest-ActiTest) in patients infected by hepatitis B virus.

SUMMARY: The aim was to assess the utility of FibroTest-ActiTest (FT-AT) as noninvasive markers of histological changes in patients with chronic hepatitis. Patients with chronic hepatitis B (HBeAg+ and HBeAg-) randomized in two trials of adefovir (ADV) vs placebo, with available paired liver biopsies and FT-AT at baseline and after 48 weeks of treatment were included. The predictive value of FT-AT was assessed using the area under the receiver operating characteristics curves (AUROCs) for the diagnosis of bridging fibrosis, cirrhosis and moderate-severe necroinflammatory activity. The impact of treatment with ADV vs placebo was assessed on liver injury according to baseline stage and virological response at 48 weeks. The analysis of 924 estimates for the diagnosis of bridging fibrosis, cirrhosis and moderate or severe necroinflammatory activity yielded FT-AT AUROCs: 0.76 +/- 0.02 (standardized 0.81 +/- 0.02), 0.81 +/- 0.02 and 0.80 +/- 0.01, respectively. Similar impacts of ADV on liver fibrosis and activity were observed both with paired biopsy (fibrosis stage from 1.6 to 1.4, activity grade from 2.5 to 1.3) and paired biomarkers (FT from 0.44 to 0.40, AT from 0.62 to 0.25) (P < 0.0001). FibroTest-ActiTest provides a quantitative estimate of liver fibrosis and necroinflammatory activity in patients with chronic hepatitis B and may be an alternative to reduce the need for liver biopsy.

[Nonalcoholic fatty liver disease: 30 years research changed NASH]. / Stéatohépatite métabolique: 30 ans de recherches qui ont changé la NASH.

Since the first description of nonalcoholic steatohepatitis (NASH) in 1980, much progress has been made towards its individualisation as a liver disease with potentially serious consequences. The identification of insulin resistance as a major determinant of steatogenesis and possibly of liver disease progression helped to identify a cause of this condition, which was amenable to therapeutic intervention and prompted screening for liver injury in patients with metabolic risk factors. The demonstration that steatohepatitis can coexist with other liver diseases with a detrimental effect on liver fibrosis helped this condition to be recognized as an independent hepatic disease no longer depending on exclusion of other chronic liver conditions. The robust increase in liver-related mortality, the fact that cirrhosis is a frequent and independent cause of death, as well as the significant decrease in overall mortality clearly showed the potential for severity of steatohepatitis. The data showing that steatohepatitis worsens insulin resistance and increases the risk for cardiovascular events and mortality forged the concept of extrahepatic complications of fat. Future research should focus on devising non-invasive strategies for screening of patients at risk, on understanding the natural history and risk factors of cirrhosis and hepatic carcinogenesis, and on optimizing therapeutic strategies integrating diet and lifestyle changes with targeted pharmacological agents.

Impact of interferon-alpha treatment on liver fibrosis in patients with chronic hepatitis B: an overview of published trials.

BACKGROUND: The impact of interferon treatment in patients with hepatitis B virus (HBV) infection on fibrosis progression in comparison with its natural history has yet to be assessed in any large-scale randomized studies. The present report is a review of the evidence-based data published so far. METHODS: Studies were included if they had at least two repeated estimates of liver fibrosis per patient treated with interferon-alpha (whether pegylated or not). Meta-analysis was performed using a random-effects model. RESULTS: Altogether, 13 studies were included in the review, involving a total of 707 HBV patients treated with interferon-alpha-2a or -2b for 12-83 months. Only one study included pegylated interferon as monotherapy. A total of 787 untreated patients were also followed. Only one study used a non-invasive biomarker. There was a significant reduction in the fibrosis progression rate, with a risk reduction of 0.49 (95% CI: -0.64--0.34; chi(2)=119; degrees of freedom [DF]=6; P<0.0001), and significant heterogeneity (Cochran Q=81; P<0.0001). This significant impact was similar for both randomized (reduction of risk: -0.45; 95% CI: -0.64--0.26; P<0.0001) and not-randomized (controlled) studies (reduction of risk: -0.53; 95% CI: -0.79--0.28; P<0.0001). CONCLUSION: According to these findings, the benefit of interferon treatment on fibrosis progression is clinically significant in patients with advanced fibrosis by the reduction of fibrosis progression to cirrhosis. Pegylated interferon now needs to be compared, in terms of benefit-risk factors, with the new generation of HBV treatments (such as entecavir and tenofovir), using non-invasive biomarkers.

[Non-invasive evaluation of liver fibrosis in hepatitis C]. / Evaluation non-invasive de la fibrose hépatique au cours de l'hépatite C.

In 2007, the << Haute Autorité de Santé >> recommended FibroScan, FibroTest or liver biopsy for the initial diagnosis of fibrosis in patients with hepatitis C without co morbidities. These methods have to be interpreted according to the clinical situation, keeping in mind negative and positive false results. For FibroTest, hemolysis, Gilbert syndrome or acute inflammation can modify the result. Pre-analytical and analytical conditions of FibroTest have to be respected according to manufactory recommendations. For FibroScan, the numbers of measurements, the rate of successful measurements, and the interquartile range have to be correct. In case of suspicious results, FibroTest or FibroScan have to be done again. The liver biopsy, FibroTest, and FibroScan are less relevant for the distinction of two adjacent stages of fibrosis. However, their performances are excellent for the diagnosis of severe fibrosis or cirrhosis compared to moderate fibrosis.

[Adherence to pegylated combination therapy in patients with chronic hepatitis C. Importance of the hepatologist, general practitioner, and nurse]. / Adhésion à la bithérapie pégylée au cours de l'hépatite chronique C. Importance du trio hépatologue, médecin généraliste, infirmière.

Adhesion to pegylated combination therapy is a key factor for therapeutic success in patients HCV infected. To optimize it, goals to reach are to limit dose reduction and premature discontinuation of treatment due to adverse events ; to improve the patient compliance to treatment, particularly during the first three months, particularly to ribavirin. Therapeutic education, management of psychiatric adverse events, epoetin alfa, have demonstrated their benefit in terms of sustained virologic response or quality of life. Preparing the treatment with the patient and a multi-disciplinary team, setting successive therapeutic goals with the predictive value of the early virologic response will promote adhesion to treatment. A hepatitis C training program for general practitioners (GP) allows an efficient follow-up of treated patients by a trio hepatologist - GP - nurse and a concrete implication of GP in the field of hepatitis C. Further developments are needed for : taking in account the patient quality of life during treatment to anticipate premature discontinuation, promotion of therapeutic education by specialized nurses, standardization of the diagnosis of depression during treatment, and regular updating of general practitioners on antiviral C treatment.

Methodological aspects of the interpretation of non-invasive biomarkers of liver fibrosis: a 2008 update.

This review summarizes the methodological aspects of the interpretation of non-invasive biomarkers in liver fibrosis. A scoring system has been updated to better compare the quality of fibrosis biomarkers. Several methodological issues are related to the classical methodology using biopsy, as this is considered the gold standard. However, from evidence-based data, it appears that the methodology needs to change to prevent flawed conclusions among key opinion leaders as well as in obsolete guidelines. As waiting for the perfect biomarker for the diagnosis of advanced fibrosis to come along is probably a waste of time, in the meantime, methods can be improved. The main proposals for improving the methodology are, to take into account the spectrum bias, to assess accuracy between adjacent stages, to compare biomarkers in the same patient, to assess the cause of failure among discordant cases and to use specific statistical methods adapted for imperfect gold standards.

Continuous infusion of high-dose omeprazole is more effective than standard-dose omeprazole in patients with high-risk peptic ulcer bleeding: a retrospective study.

UNLABELLED: High-dose omeprazole reduces the rate of recurrent bleeding after endoscopic treatment of peptic ulcer bleeding. However, the effectiveness of high-dose vs. standard-dose omeprazole in peptic ulcer bleeding has never been shown. AIM: To compare the benefits of high-dose vs. standard-dose omeprazole in peptic ulcer bleeding. METHODS: We reviewed the medical files of patients admitted between 1997 and 2004 for high-risk peptic ulcer bleeding who had undergone successful endoscopic treatment. We distinguished 2 periods: before 2001, standard-dose omeprazole (40 mg/day intravenously until alimentation was possible, then 40 mg/day orally for 1 week); after 2001, high-dose omeprazole (80 mg bolus injection, then 8 mg/h continuous infusion for 72 h, then 40 mg/day orally for 1 week). During both periods, patients subsequently received omeprazole, 20 mg/day, orally for 3 weeks. RESULTS: We enrolled 114 patients (period 1, n = 45, period 2, n = 69). Therapy with high-dose omeprazole significantly decreased the occurrence of poor outcome (27 vs. 12%, P = 0.04), rebleeding (24 vs. 7%, P = 0.01), mortality due to haemorrhagic shock (11 vs. 0%, P < 0.001) and need for surgery (9 vs. 1%, P = 0.05). CONCLUSIONS: In this retrospective study, high-dose omeprazole reduced the occurrence of rebleeding, need for surgery and mortality due to hemorrhagic shock in patients with high-risk peptic ulcer bleeding, as compared with standard-dose omeprazole.

Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability.

BACKGROUND: In non-alcoholic fatty liver disease, histological lesions display a significant sampling variability that is ignored when interpreting histological progression during natural history or therapeutic interventions. AIM: To provide a method taking into account sampling variability when interpreting crude histological data, and to investigate how this alters the conclusions of available studies. METHODS: Natural history studies detailing histological progression and therapeutic trials were compared with the results of a previously published sampling variability study. RESULTS: Natural history studies showed an improvement in steatosis, which was significantly higher than expected from sampling variability (47% vs. 8%, P < 0.0001). In contrast, no study showed a change in activity grade or ballooning higher than that of sampling variability. There was only a marginal effect on fibrosis with no convincing demonstration of a worsening of fibrosis, a conclusion contrary to what individual studies have claimed. Some insulin sensitizing drugs and anti-obesity surgery significantly improved steatosis, while most did not significantly impact on fibrosis or activity. CONCLUSIONS: Sampling variability of liver biopsy is an overlooked confounding factor that should be considered systematically when interpreting histological progression in patients with non-alcoholic fatty liver disease.

Variability of the area under the receiver operating characteristic curves in the diagnostic evaluation of liver fibrosis markers: impact of biopsy length and fragmentation.

BACKGROUND: The area under the receiver operating characteristic (ROC) curve is widely used as an estimate of the diagnostic value for fibrosis markers. Biopsy length and fragmentation are known as risk factors of false positive or false negative of biopsy but their quantitative impact on area under the receiver operating characteristic curve variability has not been assessed. AIM: To assess these relationships to better compare the fibrosis markers. METHODS: The area under the ROC curves of FibroTest for the diagnosis of fibrosis was estimated in patients with chronic hepatitis C using an integrated database including 1312 patients with FibroTest and biopsy. To take into account the biopsy length, we used two adjustment factors: one in which an observed area under the ROC curve could be adjusted according to the relative area under the receiver operating characteristic curve of a biopsy of a given length vs. the entire liver and one taking into account the prevalence of each fibrosis stage defining advanced and non-advanced fibrosis. RESULTS: The mean biopsy length was smaller for cirrhosis (F4, 16 mm) vs. F3, (18 mm, P=0.01) and F0 (19 mm, P=0.01). The mean number of fragments was higher for cirrhosis (F4=4.1 fragments) vs. all the other stages (F0=1.9, F1=1.9, F2=1.9, F3=2.3; P<0.001 vs. F4). The FibroTest area under the ROC curves for the diagnosis of advanced fibrosis, adjusted for stages' prevalence, ranged from 0.80 to 0.98 depending on biopsy length and fragmentation, respectively. CONCLUSION: The comparison of the area under the ROC curves of fibrosis markers should take into account the biopsy length and fragmentation.