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Nonalcoholic fatty liver disease (NAFLD) is closely associated with an increased risk of cardiovascular disease. We aimed to determine whether the fibrosis-4 index (FIB-4) can identify patients with NAFLD at highest risk of cardiovascular events.We analyzed data from 81,108 patients with (i) a diagnosis of NAFLD, (ii) nonalcoholic steatohepatitis (NASH), or (iii) at risk (RISK) of NASH. The outcome of interest was major adverse cardiovascular events (MACE) defined by myocardial infarction, hospitalization for unstable angina or heart failure, and coronary revascularization.The mean age was 62 years, and 49.6% were men. Among 67,273 patients without previous cardiovascular disease, 9,112 (13.5%) experienced MACE over median follow-up of 3 years. In univariate analysis, a FIB-4 ≥2.67 was a significant predictor of MACE overall (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.63-2.04, P0.001) and across all baseline groups. After adjusting for established cardiovascular risk factors, FIB-4 ≥2.67 remained the strongest predictor of MACE overall (adjusted HR [aHR] 1.80, 95% CI 1.61-2.02, P0.001) and was consistently associated with myocardial infarction (aHR 1.46, 95% CI 1.25-1.70, P0.001), hospitalization for unstable angina (aHR 1.24, 95% CI 1.03-1.49, P = 0.025), hospitalization for heart failure (aHR 2.09, 95% CI 1.86-2.35, P0.001), coronary artery bypass graft (aHR 1.65, 95% CI 1.26-2.17, P0.001), and percutaneous coronary intervention (aHR 1.72, 95% CI 1.21-2.45, P = 0.003).In a large, real-world cohort of patients with NAFLD, NASH, or at RISK of NASH, the FIB-4 score was the strongest independent predictor of MACE, beyond established cardiovascular risk factors and baseline liver diagnosis.

Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Liver fibrosis is part of the structural and functional alterations in most chronic liver diseases. It is one of the main prognostic factors as the amount of fibrosis is correlated with the risk of developing cirrhosis and liver-related complications in viral and nonviral chronic liver diseases [1,2]. Liver biopsy has traditionally been considered the reference method for evaluation of tissue damage such as hepatic fibrosis in patients with chronic liver disease. Pathologists have proposed robust scoring system for staging liver fibrosis such as the semi-quantitative METAVIR score [3,4]. In addition computer-aided morphometric measurement of collagen proportional area, a partly automated technique, provides an accurate and linear evaluation of the amount of fibrosis [5]. Liver biopsy gives a snapshot and not an insight into the dynamic changes during the process of fibrogenesis (progression, static or regression). However, immunohistochemical evaluation of cellular markers such as smooth muscle actin expression for hepatic stellate cell activation, cytokeratin 7 for labeling ductular proliferation or CD34 for visualization of sinusoidal endothelial capillarization or the use of two-photon and second harmonic generation fluorescence microscopy techniques for spatial assessment of fibrillar collagen, can provide additional ‘‘functional’’ information [6,7]. All these approaches are valid provided that the biopsy is of sufficient size to represent the whole liver [4,8]. Indeed, liver biopsy provides only a very small part of the whole organ and there is a risk that this part might not be representative for the amount of hepatic fibrosis in the whole liver due to heterogeneity in its distribution [9]. Extensive literature has shown that increasing the length of liver biopsy decreases the risk of sampling error. Except for cirrhosis, for which micro-fragments may be sufficient, a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, though 15 mm is considered sufficient in most studies [10]. Not only the length but also the caliber of the biopsy needle is important in order to obtain a piece of liver of adequate size for histological evaluation, with a 16 gauge needle being considered as the most appropriate [11] to use for percutaneous liver biopsy. Interobserver variation

Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need.We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea.Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

Background Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders. Silymarin, extracted from the milk thistle plant, Silybum marianum (L) Gaertn. (Asteraceae), has been most widely used for various liver disorders, including chronic hepatitis C, B, and alcoholic liver disease. However, the safety and efficacy of silymarin have not been studied systematically in chronic hepatitis C. Purpose We describe our strategy for a phased approach for studying the impact of silymarin in hepatitis C, in the context of the unique challenges of botanical product clinical trials and the development of specific and curative antiviral therapy. Methods This multicenter, randomized, double-masked, placebo-controlled trial was conducted with four clinical centers and a data-coordinating center in the United States, to assess the impact of silymarin therapy in patients with chronic hepatitis C who failed conventional antiviral therapy. Results Key aspects relevant to performing clinical trials of botanical products include early identification of an appropriate product with standard product chemistry, acquisition of pharmacokinetic and dosing information, selection of the appropriate study group, and choosing rigorous outcome variables. Potential limitations Trial participants were chronic hepatitis C patients who were nonsustained virologic responders to IFN-based therapy; therefore, the findings are not generalizable to all hepatitis C populations. Further, alanine aminotransferase, a biochemical liver test, rather than hepatitis viral RNA or liver histology was the primary end point. Conclusions The challenges identified and addressed during development of this United States multicenter Phase II trial to evaluate silymarin for treatment of patients with chronic hepatitis C infection who had failed to respond successfully to previous IFN-based therapy are common and must be addressed to conduct rigorous trials of botanical products.

Background Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. Methods We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the leadin period). Subsequently, group 1 (the control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon– ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon–ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. Results A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P

Non-invasive diagnosis of compensated cirrhosis is important. We therefore compared liver stiffness by transient elastography, APRI score, AST/ALT ratio, hyaluronic acid and clinical signs to determine which modality performed best at identifying compensated cirrhosis.Patients undergoing evaluation at a single center were recruited and had clinical, serological, endoscopy, radiological imaging, liver stiffness measurement and liver biopsy. Patients were stratified into cirrhotic and non-cirrhotic.In 404 patients (124 cirrhosis), transient elastography was diagnostically superior to the other modalities yielding an AUC 0.9 +/- 0.04 compared with hyaluronic acid (AUC 0.81 +/- 0.04: P0.05), clinical signs (AUC 0.74 +/- 0.04: P0.05), APRI score (AUC 0.71 +/- 0.03: P0.05) and AST/ALT ratio (AUC 0.66 +/- 0.03: P0.05). The optimum cut-off for transient elastography was 12 kPa giving a sensitivity of 89% and specificity of 87% for cirrhosis. In 238 hepatitis C patients (87 cirrhosis), transient elastography yielded an AUC 0.899 +/- 0.02 for cirrhosis and in 166 non-HCV patients (37 cirrhosis) the results were similar with an AUC 0.928 +/- 0.03; with transient elastography being superior to HA, APRI, AST/ALT and clinical signs for all etiologies of cirrhosis (P0.05 for all). Importantly, transient elastography was statistically superior at identifying cirrhosis in 38 biopsy proven Childs Pugh A cirrhotics with no clinical, biochemical or radiological features of cirrhosis or portal hypertension (AUC 0.87 +/- 0.04).Transient elastography accurately identified compensated cirrhosis; a liver stiffness of12 kPa represents an important clinical measurement for the diagnosis of cirrhosis.

Post marketing studies of Interferon-beta (IFN beta) therapy in multiple sclerosis (MS) have demonstrated surprisingly high rates of hepatotoxicity. Grade 3 hepatotoxicity (AST and ALT5 to 20 upper limit normal) or higher has been observed in as many as 1.4% of MS patients on IFN beta. We report three cases of IFN beta induced hepatitis in MS and discuss the pathology findings and possible mechanisms of drug-induced liver injury.

As with many types of cancer, cell motility is an important factor in the progression and metastasis of hepatocellular carcinomas (HCC). HCC is associated with significant fibrosis in the liver. The fibrotic microenvironment in the liver is characterized by an altered composition of the extracellular matrix (ECM) and an abundance of growth factors that are likely conducive to migration of HCC cells. The purpose of this study was to delineate promigratory stimuli within the fibrotic microenvironment and to identify specific targets for prevention of HCC cell migration. We used a modified Boyden chamber system that allowed distinction between chemotactic (indirect stimulation) and haptotactic (direct stimulation) migration of two distinct HCC cell lines across the ECM-coated membrane. Fibrotic microenvironment-associated growth factors, such as transforming growth factor beta1 (TGF-beta1), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF), induced chemotactic and haptotactic migration of HepG2 and Chang cells. Neutralizing antibodies to individual growth factors significantly decreased chemotactic and haptotactic migration. Haptotactic stimulation, but not chemotactic stimulation of HCC cell lines with TGF-beta1, bFGF, and EGF, induced production of matrix metalloproteinase (MMP) 2, a potential mediator of migration. Inhibition of MMPs significantly decreased haptotactic migration induced by individual growth factors but had an insignificant effect on chemotactic migration, suggesting an MMP-independent migration in this setting. Inhibition of cell-ECM interactions with blocking antibodies to alpha1 and alpha2 integrins were sufficient to inhibit both haptotactic and chemotactic migration induced by individual growth factors, strongly suggesting that targeting these integrins to abrogate pathogenic cell-ECM interactions might be a promising tool for inhibiting growth factor-induced invasion and metastasis of HCC.

Context The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. Objective To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. Intervention Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. Main Outcome Measures The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. Results After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, −4.3 [95% CI, −17.3 to 8.7] U/L for placebo, −14.4 [95% CI, −41.6 to 12.7] U/L for 420-mg silymarin, −11.3 [95% CI, −27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, −0.05 to 0.18] log 10 IU/mL for placebo, −0.03 [95% CI, −0.18 to 0.12] log 10 IU/mL for 420-mg silymarin, 0.04 [95% CI, −0.08 to 0.16] log 10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. Conclusion Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. Trial Registration clinicaltrials.gov Identifier: NCT00680342

Sigmoidoscopy is an effective screening test for colorectal cancer but has yet to have a major impact on mortality because, in part, of inadequate utilization by physicians. To address concerns of inefficient use of time and resources, we examined the feasibility of high volume, single-day flexible sigmoidoscopy (FS) screening sessions using an innovative fiberoptic sigmoidoscope with a disposable sheath system.All City of Boston employees over the age of 50 yr (n = 6137) were invited by mail to undergo a screening FS at Boston City Hospital (BCH). Respondents (n = 564) were contacted by phone by the program coordinator on receipt of a prepaid postcard and were scheduled (n = 227) consecutively into 15-min slots on 1 of 6 1/2-day (3-h) weekend sessions. Preregistration was completed at BCH during the week before each session and included enrollment, completion of a brief risk questionnaire, documentation of informed consent, and bowel prep instructions. Procedures were performed by three physician endoscopists rotating among four endoscopy rooms per session. Each room was staffed with a nurse to aid in patient care and a technician to set up equipment.A total of 198 of the 227 (87%) scheduled patients underwent screening FS during the three sessions. Physicians performed a mean of 3.5 procedures per room per hour, or 4.7 procedures per hour overall, with a mean depth of scope insertion of 51 +/- 10 cm and a mean procedure time of 4.7 +/- 3.3 min. Equipment set-up time and patient turnaround time averaged 4.6 +/- 1.7 min and 11.0 +/- 6.0 min, respectively. Polyps were detected in 29 (14.6%) patients, and a Dukes' A cancer was detected in one (0.5%). The only complication was a cardiac arrhythmia. A crude estimate of direct costs approximated $ 75 per examination.High volume, single-day FS using the fiberoptic sigmoidoscope with a disposable sheath system offers an effective strategy for enhancing physicians compliance, and possibly patient compliance, with screening sigmoidoscopy through more efficient use of time and resources.