Liver fibrosis stage based on the four factors (FIB-4) score or Forns index in adults with chronic hepatitis C.

BACKGROUND: The presence and severity of liver fibrosis are important prognostic variables when evaluating people with chronic hepatitis C (CHC). Although liver biopsy remains the reference standard, non-invasive serological markers, such as the four factors (FIB-4) score and the Forns index, can also be used to stage liver fibrosis. OBJECTIVES: To determine the diagnostic accuracy of the FIB-4 score and Forns index in staging liver fibrosis in people with chronic hepatitis C (CHC) virus, using liver biopsy as the reference standard (primary objective). To compare the diagnostic accuracy of these tests for staging liver fibrosis in people with CHC and explore potential sources of heterogeneity (secondary objectives). SEARCH METHODS: We used standard Cochrane search methods for diagnostic accuracy studies (search date: 13 April 2022). SELECTION CRITERIA: We included diagnostic cross-sectional or case-control studies that evaluated the performance of the FIB-4 score, the Forns index, or both, against liver biopsy, in the assessment of liver fibrosis in participants with CHC. We imposed no language restrictions. We excluded studies in which: participants had causes of liver disease besides CHC; participants had successfully been treated for CHC; or the interval between the index test and liver biopsy exceeded six months. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We performed meta-analyses using the bivariate model and calculated summary estimates. We evaluated the performance of both tests for three target conditions: significant fibrosis or worse (METAVIR stage ≥ F2); severe fibrosis or worse (METAVIR stage ≥ F3); and cirrhosis (METAVIR stage F4). We restricted the meta-analysis to studies reporting cut-offs in a specified range (+/-0.15 for FIB-4; +/-0.3 for Forns index) around the original validated cut-offs (1.45 and 3.25 for FIB-4; 4.2 and 6.9 for Forns index). We calculated the percentage of people who would receive an indeterminate result (i.e. above the rule-out threshold but below the rule-in threshold) for each index test/cut-off/target condition combination. MAIN RESULTS: We included 84 studies (with a total of 107,583 participants) from 28 countries, published between 2002 and 2021, in the qualitative synthesis. Of the 84 studies, 82 (98%) were cross-sectional diagnostic accuracy studies with cohort-based sampling, and the remaining two (2%) were case-control studies. All studies were conducted in referral centres. Our main meta-analysis included 62 studies (100,605 participants). Overall, two studies (2%) had low risk of bias, 23 studies (27%) had unclear risk of bias, and 59 studies (73%) had high risk of bias. We judged 13 studies (15%) to have applicability concerns regarding participant selection. FIB-4 score The FIB-4 score's low cut-off (1.45) is designed to rule out people with at least severe fibrosis (≥ F3). Thirty-nine study cohorts (86,907 participants) yielded a summary sensitivity of 81.1% (95% confidence interval (CI) 75.6% to 85.6%), specificity of 62.3% (95% CI 57.4% to 66.9%), and negative likelihood ratio (LR-) of 0.30 (95% CI 0.24 to 0.38). The FIB-4 score's high cut-off (3.25) is designed to rule in people with at least severe fibrosis (≥ F3). Twenty-four study cohorts (81,350 participants) yielded a summary sensitivity of 41.4% (95% CI 33.0% to 50.4%), specificity of 92.6% (95% CI 89.5% to 94.9%), and positive likelihood ratio (LR+) of 5.6 (95% CI 4.4 to 7.1). Using the FIB-4 score to assess severe fibrosis and applying both cut-offs together, 30.9% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the FIB-4 score when used for assessing significant fibrosis (≥ F2) and cirrhosis (F4) in the main review text. Forns index The Forns index's low cut-off (4.2) is designed to rule out people with at least significant fibrosis (≥ F2). Seventeen study cohorts (4354 participants) yielded a summary sensitivity of 84.7% (95% CI 77.9% to 89.7%), specificity of 47.9% (95% CI 38.6% to 57.3%), and LR- of 0.32 (95% CI 0.25 to 0.41). The Forns index's high cut-off (6.9) is designed to rule in people with at least significant fibrosis (≥ F2). Twelve study cohorts (3245 participants) yielded a summary sensitivity of 34.1% (95% CI 26.4% to 42.8%), specificity of 97.3% (95% CI 92.9% to 99.0%), and LR+ of 12.5 (95% CI 5.7 to 27.2). Using the Forns index to assess significant fibrosis and applying both cut-offs together, 44.8% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the Forns index when used for assessing severe fibrosis (≥ F3) and cirrhosis (F4) in the main text. Comparing FIB-4 to Forns index There were insufficient studies to meta-analyse the performance of the Forns index for diagnosing severe fibrosis and cirrhosis. Therefore, comparisons of the two tests' performance were not possible for these target conditions. For diagnosing significant fibrosis and worse, there were no significant differences in their performance when using the high cut-off. The Forns index performed slightly better than FIB-4 when using the low/rule-out cut-off (relative sensitivity 1.12, 95% CI 1.00 to 1.25; P = 0.0573; relative specificity 0.69, 95% CI 0.57 to 0.84; P = 0.002). AUTHORS' CONCLUSIONS: Both the FIB-4 score and the Forns index may be considered for the initial assessment of people with CHC. The FIB-4 score's low cut-off (1.45) can be used to rule out people with at least severe fibrosis (≥ F3) and cirrhosis (F4). The Forns index's high cut-off (6.9) can be used to diagnose people with at least significant fibrosis (≥ F2). We judged most of the included studies to be at unclear or high risk of bias. The overall quality of the body of evidence was low or very low, and more high-quality studies are needed. Our review only captured data from referral centres. Therefore, when generalising our results to a primary care population, the probability of false positives will likely be higher and false negatives will likely be lower. More research is needed in sub-Saharan Africa, since these tests may be of value in such resource-poor settings.

Predictive Risk Factors and Scoring Systems Associated with the Development of Hepatocellular Carcinoma in Chronic Hepatitis B.

Chronic hepatitis B (CHB) infection constitutes a leading cause of hepatocellular carcinoma (HCC) development. The identification of HCC risk factors and the development of prognostic risk scores are essential for early diagnosis and prognosis. The aim of this observational, retrospective study was to evaluate baseline risk factors associated with HCC in CHB. Six hundred thirty-two consecutive adults with CHB (n = 632) [median age: 46 (IQR: 24)], attending the outpatients' Hepatology clinics between 01/1993-09/2020 were evaluated. Core promoter mutations and cirrhosis-HCC (GAG-HCC), Chinese University-HCC (CU-HCC), risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B), Fibrosis-4 (FIB-4), and Platelet Age Gender-HBV (PAGE-B) prognostic scores were calculated, and receiver operating curves were used to assess their prognostic performance. HCC was developed in 34 (5.38%) patients. In the multivariable Cox regression analysis, advanced age (HR: 1.086, 95% CI: 1.037-1.137), male sex (HR: 7.696, 95% CI: 1.971-30.046), alcohol abuse (HR: 2.903, 95% CI: 1.222-6.987) and cirrhosis (HR: 21.239, 95% CI: 6.001-75.167) at baseline were independently associated with the development of HCC. GAG-HCC and PAGE-B showed the highest performance with c-statistics of 0.895 (95% CI: 0.829-0.961) and 0.857 (95% CI: 0.791-0.924), respectively. In the subgroup of patients with cirrhosis, the performance of all scores declined. When treated and untreated patients were studied separately, the discriminatory ability of the scores differed. In conclusion, HCC development was independently associated with advanced age, male sex, alcohol abuse, and baseline cirrhosis among a diverse population with CHB. GAG-HCC and PAGE-B showed high discriminatory performance to assess the risk of HCC development in these patients, but these performances declined in the subgroup of patients with cirrhosis. Further research to develop scores more specific to certain CHB subgroups is needed.

Evaluation of PAGE-B Score for Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients: Reliability, Validity, and Responsiveness.

Chronic hepatitis B (CHB) constitutes a major global public health issue, affecting millions of individuals. Despite the implementation of robust vaccination programs, the hepatitis B virus (HBV) significantly influences morbidity and mortality rates. CHB emerges as one of the leading causes of hepatocellular carcinoma (HCC), introducing a major challenge in the effective management of CHB patients. Therefore, it is of utmost clinical importance to diligently monitor individuals with CHB who are at high risk of HCC development. While various prognostic scores have been developed for surveillance and screening purposes, their accuracy in predicting HCC risk may be limited, particularly in patients under treatment with nucleos(t)ide analogues. The PAGE-B model, incorporating age, gender, and platelet count, has exhibited remarkable accuracy, validity, and reliability in predicting HCC occurrence among CHB patients receiving HBV treatment. Its predictive performance stands out, whether considered independently or in comparison to alternative HCC risk scoring systems. Furthermore, the introduction of targeted adjustments to the calculation of the PAGE-B score might have the potential to further improve its predictive accuracy. This review aims to evaluate the efficacy of the PAGE-B score as a dependable tool for accurate prediction of the development of HCC in CHB patients. The evidence discussed aims to provide valuable insights for guiding recommendations on HCC surveillance within this specific population.

Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?

Hepatocellular carcinoma (HCC) remains a global health challenge that urgently calls for innovative therapeutic strategies. Chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising avenue for HCC treatment. However, the therapeutic efficacy of CAR T immunotherapy in HCC patients is significantly compromised by some major issues including the immunosuppressive environment within the tumor, antigen heterogeneity, CAR T cell exhaustion, and the advanced risk for on-target/off-tumor toxicity. To overcome these challenges, many ongoing preclinical and clinical trials are underway focusing on the identification of optimal target antigens and the decryption of the immunosuppressive milieu of HCC. Moreover, limited tumor infiltration constitutes a significant obstacle of CAR T cell therapy that should be addressed. The continuous effort to design molecular targets for CAR cells highlights the importance for a more practical approach for CAR-modified cell manufacturing. This review critically examines the current landscape of CAR T cell therapy for HCC, shedding light on the changes in innate and adaptive immune responses in the context of HCC, identifying potential CAR T cell targets, and exploring approaches to overcome inherent challenges. Ongoing advancements in scientific research and convergence of diverse treatment modalities offer the potential to greatly enhance HCC patients' care in the future.

Adrenal insufficiency in liver diseases - pathophysiology and underlying mechanisms.

Relative adrenal insufficiency (RAI) is common in critically ill patients with cirrhosis, but it has been also documented in non-critically ill patients. Its pathophysiology is complex and not well understood yet. In this review, we aimed to present potential mechanisms and causal pathways implicated in the pathogenesis of RAI in cirrhosis. There is accumulating evidence supporting a suboptimal baseline adrenal function in cirrhosis mainly due to decreased cortisol synthesis and metabolism rates from the adrenal gland. Apart from this peripheral impairment, more recent studies suggest that there is a greater defect in the central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis (hypothalamus/pituitary gland). Pro-inflammatory mediators, which are elevated in cirrhosis, have been also implicated through suppression of the HPA axis, decrease in cortisol synthesis and tissue glucocorticoid resistance. All abovementioned support the hepatoadrenal syndrome hypothesis that during episodes of acute decompensation there is suboptimal adrenocortical response that leads to worse outcomes. In conclusion, the complex pathophysiology of adrenal dysfunction in cirrhosis has not been fully elucidated yet and further research is needed in order to better understand this rather common entity in cirrhosis.

Exploring the role of IL-1ß in inflammatory bowel disease pathogenesis.

Interleukin 1ß (IL-1ß) is a significant mediator of inflammation and tissue damage in IBD. The balance between IL-1ß and its endogenous inhibitor-IL-1Ra-, plays a critical role in both initiation and regulation of inflammation. However, the precise role of IL-1ß as a causative factor in IBD or simply a consequence of inflammation remains unclear. This review summarizes current knowledge on the molecular and cellular characteristics of IL-1ß, describes the existing evidence on the role of this cytokine as a modulator of intestinal homeostasis and an activator of inflammatory responses, and also discusses the role of microRNAs in the regulation of IL-1ß-related inflammatory responses in IBD. Current evidence indicates that IL-1ß is involved in several aspects during IBD as it greatly contributes to the induction of pro-inflammatory responses through the recruitment and activation of immune cells to the gut mucosa. In parallel, IL-1ß is involved in the intestinal barrier disruption and modulates the differentiation and function of T helper (Th) cells by activating the Th17 cell differentiation, known to be involved in the pathogenesis of IBD. Dysbiosis in the gut can also stimulate immune cells to release IL-1ß, which, in turn, promotes inflammation. Lastly, increasing evidence pinpoints the central role of miRNAs involvement in IL-1ß-related signaling during IBD, particularly in the maintenance of homeostasis within the intestinal epithelium. In conclusion, given the crucial role of IL-1ß in the promotion of inflammation and immune responses in IBD, the targeting of this cytokine or its receptors represents a promising therapeutic approach. Further research into the IL-1ß-associated post-transcriptional modifications may elucidate the intricate role of this cytokine in immunomodulation.

Low Urinary Free Cortisol as a Risk Factor for Patients with Variceal Bleeding.

Background and Objectives: Specificity and reliability issues of the current cortisol assessment methods lead to limitations on the accurate assessment of relative adrenal insufficiency. Although free cortisol provides a more accurate evaluation of adrenal cortisol production, the expense and time-consuming nature of these assays make them impractical for routine use. Research has, thus, focused on alternative methods, such as indirectly measuring free cortisol using Coolens' equation or directly assessing salivary cortisol concentration, which is considered a more favorable approach despite associated challenges like sampling issues and infection risks. The aim of this study was to explore correlations between 24 h urinary free cortisol (UFC), free plasma cortisol, serum total cortisol, and salivary cortisol as potential reliable indices of free cortisol in the setting of variceal bleeding. Additionally, we assessed the predictive value of UFC for 6-week mortality and 5-day treatment failure in patients with liver cirrhosis and variceal bleeding. Materials and Methods: A total of 40 outpatients with liver cirrhosis and variceal bleeding were enrolled. Free cortisol levels in serum, saliva, and urine were assessed using the electrochemiluminescence immunoassay method. For the measurement of plasma-free cortisol, a single quadrupole mass spectrometer was employed. The quantification of free cortisol was fulfilled by analyzing the signal response in the negative ESI-MS mode. Results: UFC was significantly correlated to free plasma cortisol. Negative correlations were demonstrated between UFC, the Child-Pugh (CP) score, and C reactive protein (CRP) levels. In the multivariate analysis, CP stage C was associated with 6-week mortality risk and portal vein thrombosis with 5-day treatment failure using Cox regression and binary logistic regression analyses, respectively. Patients who experienced rebleeding, infection, or death (or any combination of these events) presented with lower levels of UFC. Conclusions: This study suggests that low levels of UFC may impose a risk factor for patients with liver cirrhosis and variceal bleeding. The use of UFC as an index of adrenal cortisol production in variceal bleeding warrants further investigation.

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder.

Endotoxin Translocation and Gut Barrier Dysfunction Are Related to Variceal Bleeding in Patients With Liver Cirrhosis.

Background: Bacterial infections are associated with the risk of variceal bleeding through complex pathophysiologic pathways. Objectives: The primary objective of the present case-control study was to investigate the role of bacterial translocation and intestinal barrier dysfunction in the pathogenesis of variceal bleeding. A secondary objective was to determine independent predictors of key outcomes in variceal bleeding, including bleeding-related mortality. Methods: Eighty-four (n = 84) consecutive patients participated in the study, 41 patients with acute variceal bleeding and 43 patients with stable cirrhosis, and were followed up for 6 weeks. Peripheral blood samples were collected at patient admission and before any therapeutic intervention. Results: Child-Pugh (CP) score (OR: 1.868; p = 0.044), IgM anti-endotoxin antibody levels (OR: 0.954; p = 0.016) and TGF-ß levels (OR: 0.377; p = 0.026) were found to be significant predictors of variceal bleeding. Regression analysis revealed that albumin (OR: 0.0311; p = 0.023), CRP (OR: 3.234; p = 0.034) and FABP2 levels (OR:1.000, p = 0.040), CP score (OR: 2.504; p = 0.016), CP creatinine score (OR: 2.366; p = 0.008), end-stage liver disease model (MELD), Na (OR: 1.283; p = 0.033), portal vein thrombosis (OR: 0.075; p = 0.008), hepatocellular carcinoma (OR: 0.060; p = 0.003) and encephalopathy (OR: 0.179; p = 0.045) were significantly associated with 6-week mortality. Conclusions: Bacterial translocation and gut barrier impairment are directly related to the risk of variceal bleeding. Microbiota-modulating interventions and anti-endotoxin agents may be promising strategies to prevent variceal bleeding.

Natural history of grade 1 ascites in patients with liver cirrhosis.

BACKGROUND: No evidence is available on the natural history of grade 1 ascites and its progression to grade 2/3 in patients with liver cirrhosis. The aim of the current study was to address this issue, to assess the development of main comorbid disorders closely related to ascites progression, and to identify the predictive factors for survival in this setting. METHODS: Consecutive Caucasian cirrhotic patients with grade 1 ascites were retrospectively analyzed. None of patients was under treatment with diuretics at diagnosis. Control groups consisted of 145 cirrhotics with grade 2/3 ascites and 175 cirrhotics without ascites. RESULTS: Diuretics were initiated in 58 patients with grade 1 ascites at baseline by the attending physician. At the last follow up, 29 patients had no ascites, 33 patients had grade 1 and 38 patients had grade 2/3 ascites. No variable was found to be an independent predictor of grade 2/3 ascites. Seven patients developed spontaneous bacterial peritonitis while under treatment with diuretics; at that time only 1 patient had grade 1 ascites. The mortality rate was similar among all examined groups. CONCLUSIONS: This study suggests that the presence of grade 1 ascites does not constitute a precursor of grade 2/3 ascites in patients with cirrhosis. Thus, patients with grade 1 ascites do not require specific treatment with diuretics.

Vitamin D-related immunomodulation in patients with liver cirrhosis.

OBJECTIVE(S): Increasing evidence indicates that vitamin D status is linked to severity of liver cirrhosis and patients' survival. However, the potential role of vitamin D-related immunomodulation in hepatic decompensation and patients' mortality in relation to vitamin D deficiency remains unknown. The aim of the current study is to evaluate the association between vitamin D status and vitamin D binding protein (VDBP) levels with serum cytokine and lipopolysaccharide binding protein (LBP) and to examine their role on disease severity and cirrhotics' mortality. METHODS: One hundred consecutive Caucasian patients with liver cirrhosis were enrolled in the study. 25(OH)D, VDBP, and LBP concentrations were assessed by ELISA. Cytokine tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), IL-1ß, IL-8, IL-10, and IL-12 levels were determined by Cytometric Bead Array. RESULTS: 25(OH)D levels were inversely correlated with CP score, MELD, IL-6, and CP stage and VDBP levels with CP score, MELD, IL-6, IL-8, LBP, and CP stage. Cirrhotics with 25(OH)D deficiency and severe deficiency had significantly higher CP score, increased IL-6 levels and lower VDBP levels. In the multivariate analysis, the independent prognostic factors associated with patients' survival were CP stage B [hazard ratio = 6.75; 95% confidence interval (CI) 1.32, 34.43; P = 0.022], CP stage C (hazard ratio = 7.39; 95% CI 1.41, 38.81; P = 0.018), the presence of hepatocellular carcinoma (hazard ratio = 4.50; 95% CI 1.54, 13.13; P = 0.006) and 25(OH)D levels (hazard ratio = 0.87; 95% CI 0.80, 0.95; P = 0.002). CONCLUSION: The results show that vitamin D status and VDBP levels are associated with liver cirrhosis severity and patients' mortality, possibly through a proinflammatory immune response.

Cardiovascular morbidity and mortality is increased post-liver transplantation even in recipients with no pre-existing risk factors.

BACKGROUND/AIMS: Post-liver transplant (LT) metabolic syndrome (PTMS) and cardiovascular (CVS) mortality are becoming increasingly prevalent following sustained improvements in post-LT survival. We investigated the prevalence and predictors of PTMS and CVS complications in a cohort of consecutive LT recipients. METHODS: We reviewed prospectively collected data of patients (n = 928) who underwent LT (1995-2013) and survived at least 1-year post-LT or died before that due to a major CVS complication. RESULTS: Median follow-up was 85 months (IQR = 106). The prevalence of PTMS was 22.4% and it developed de novo in 183 recipients (19.7%). A total of 187 (20.2%) patients developed at least one CVS event post-LT within a median of 49 months (IQR = 85). Overall mortality rate was 22.6% (n = 210). Causes of death were CVS events (n = 45, 21.4%), malignancies (21%), liver-related deaths (20%) and infections (6.7%). Independent predictors of major CVS events were: documented CVS disease pre-LT (Hazard Ratio (HR) = 3.330; 95% CI = 1.620-6.840), DM (HR = 1.120; 95% CI 1.030-1.220), hypertension (HR = 1.140; 95% CI 1.030-1.270), dyslipidaemia (HR = 1.140; 95% CI 1.050-1.240) and creatinine levels at 1 year (HR = 1.010; 95% CI = 1.005-1.013). Among LT recipients without pre-LT CVS disease or MS components (n = 432), 85 recipients developed ≥1 CVS events (19.7%) with independent predictors being DM (HR = 1.150; 95% CI = 1.010-1.320), creatinine levels at 1 year (HR = 1.020; 95% CI = 1.010-1.030) and hypertension (HR = 1.190; 95% CI = 1.040-1.360). CONCLUSIONS: Post-LT patients are at increased risk of CVS morbidity even in the absence of pre-existing metabolic risk factors. Renal sparing immunosuppressive protocols might reduce CVS events post-LT.

Pharmacological interventions for acute hepatitis C infection.

BACKGROUND: Hepatitis C virus (HCV) is a single-stranded RNA (ribonucleic acid) virus that has the potential to cause inflammation of the liver. The traditional definition of acute HCV infection is the first six months following infection with the virus. Another commonly used definition of acute HCV infection is the absence of HCV antibody and subsequent seroconversion (presence of HCV antibody in a person who was previously negative for HCV antibody). Approximately 40% to 95% of people with acute HCV infection develop chronic HCV infection, that is, have persistent HCV RNA in their blood. In 2010, an estimated 160 million people worldwide (2% to 3% of the world's population) had chronic HCV infection. The optimal pharmacological treatment of acute HCV remains controversial. Chronic HCV infection can damage the liver. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of acute HCV infection through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead we assessed the comparative benefits and harms of different interventions versus each other or versus no intervention using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to April 2016 to identify randomised clinical trials on pharmacological interventions for acute HCV infection. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with acute HCV infection. We excluded trials which included previously liver transplanted participants and those with other coexisting viral diseases. We considered any of the various pharmacological interventions compared with placebo or each other. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on the available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months.There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons.Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.

Prognostic significance of vitamin D receptor (VDR) gene polymorphisms in liver cirrhosis.

Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1ß and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1ß levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.

Muscle fat infiltration assessed by total psoas density on computed tomography predicts mortality in cirrhosis.

BACKGROUND: Ongoing evidence suggests that sarcopenia adversely affects outcomes in cirrhosis. The aim of this study was to evaluate muscle fat infiltration as a component of sarcopenia and its prognostic value in this setting. METHODS: In 98 consecutive patients with cirrhosis, muscle density was measured during a computed tomography scan at the level of the fourth to fifth lumbar (L4) vertebrae. Univariate and multivariate Cox regression analysis was used to determine predictors of survival. RESULTS: Body mass index: median 26 (range 17-45.2); model for end-stage liver disease (MELD) score: median 11 (6-29); Child-Pugh (CP) score: median 7 (5-13), CP class: A=49 (50.5%), B=39 (40%), C=10 (9.5%); hepatocellular carcinoma: 14 (14.3%); follow up: median 45 (1-140) months. Median L4 total psoas area (TPA): 2022 (777-3806) mm2; L4 average total psoas density (ATPD): 42.52 (21.26-59.8) HU. ATPD was significantly correlated with age (r=-0.222, P=0.034), creatinine (r=-0.41, P<0.001), albumin (r=0.224, P=0.035), MELD score (r=-0.218, P=0.034), and TPA (r=0.415, P<0.001). Fifty-four patients (55.1%) died during follow up. In the multivariate analysis, higher CP score (hazard ratio [HR] 1.2, 95% confidence interval [CI] 1.04-1.41), advanced age (HR 1.038, 95%CI 1.006-1.07) and lower ATPD (HR 0.967, 95%CI 0.937-0.997) were predictors of mortality. CONCLUSION: Muscle fat infiltration, as a result of sarcopenia, is a negative predictive factor of survival in cirrhosis, emphasizing the need for early identification of this subgroup of patients.

A meta-analysis on the prognostic significance of inferolateral early repolarization pattern in Brugada syndrome.

Aims: The early repolarization (ER) pattern has been linked to an increased risk for arrhythmic death in various clinical settings. There are limited and conflicting data regarding the prognostic significance of ER pattern in Brugada syndrome (BS). The aim of this meta-analysis was to provide a detailed analysis of the currently available studies regarding the arrhythmic risk in patients with BS and ER pattern. Methods and results: Current databases were searched until May 2015. A random-effect meta-analysis of the effect of ER pattern on the incidence of arrhythmic events in patients with BS was performed. Five studies were included comprising a total of 1375 patients with BS. An ER pattern was reported in 177 patients (12.8%). During follow-up (44.9-93 months), 143 patients (10.4%) suffered an arrhythmic event. Overall, BS patients with ER pattern displayed an increased risk of arrhythmic events compared to patients without ER (OR 3.29, 95% CI: 2.06 to 5.26, P < 0.00001; Heterogeneity: P = 0.11, I2 = 48%). Three studies provided data regarding ER pattern location. Inferior, lateral, or inferolateral ER pattern location was observed in 20.3%, 32.2%, and 48%, respectively. An inferolateral ER location conferred the higher arrhythmic risk (OR 4.87, 95% CI: 2.64 to 9.01, P< 0.00001; Heterogeneity: P = 0.85, I2 = 0%). Conclusion: This meta-analysis suggests that the ER pattern is associated with a high risk of arrhythmic events in patients with BS. In particular, BS patients with inferolateral ER (global ER pattern) displayed the highest arrhythmic risk.

Low-voltage areas detected by high-density electroanatomical mapping predict recurrence after ablation for paroxysmal atrial fibrillation.

INTRODUCTION: We aimed to evaluate the extent of atrial fibrosis in paroxysmal atrial fibrillation (AF) and the correlation with ablation outcomes after pulmonary vein antral isolation (PVΑI) using a mapping system with high-resolution and high-spatial sampling. METHODS AND RESULTS: We prospectively enrolled 80 consecutive patients (45 males, median age 60.26 years) with symptomatic paroxysmal AF who were scheduled for PVAI. Prior to PVAI, high-density bipolar voltage mapping (median number of 2,485 points) was carried out during sinus rhythm in all patients. Criteria for an adequate left atrium (LA) shell were > 2,000 points. Each acquired point was classified according to the peak-to-peak bipolar voltage electrogram based on two criteria (criterion A: healthy > 0.8 mV, border zone: 0.4-0.8 mV and scarred: < 0.4 mV, criterion Β: healthy: > 0.5 mV, border zone: 0.25-0.5 mV and scarred: < 0.25 mV). The extent of low-voltage area < 0.4 mV significantly predicted atrial tachyarrhythmia recurrence after the blanking period (P = 0.002). In univariate analysis, the presence of LA voltage areas < 0.4 mV more than 10% of the total surface area was the only significant predictor of arrhythmia recurrence. The analysis based on window B cutoff values failed to demonstrate any predictors of arrhythmia recurrence. CONCLUSION: These data demonstrate that the existence of LA voltage areas < 0.4 mV more than 10% of the total LA surface area predicts arrhythmia recurrence following PVAI for paroxysmal AF.

Lactate serum concentrations during treatment with nucleos(t)ide analogues in hepatitis B with or without cirrhosis.

OBJECTIVE: The aim of this study is to evaluate the clinical implications of lactate concentrations in patients with hepatitis B with or without cirrhosis during treatment with nucleos(t)ide analogues. PATIENTS AND METHODS: One hundred and seven consecutive patients with chronic hepatitis B and median age 57 (24-85) years were prospectively included. Lactate concentrations were measured at baseline and at 12, 24, 36, 48, and 60 months following the baseline measurements. Eight (n=8, 7.5%) patients received lamivudine, 38 (n=38, 35.5%) patients received tenofovir, 34 (n=34, 31.8%) patients received entecavir, and 27 (n=27, 25.2%) patients received combined therapy. RESULTS: None of the patients developed lactic acidosis during follow-up [median: 58 (6-155) months]. Overall, no trends of the lactic acid evolution were observed over time; however, there was a nonsignificant increasing trend in patients with cirrhosis up to 24 months of treatment. This increasing trend was significant in female patients with cirrhosis (P=0.016). The age of the patients, the presence of cirrhosis, and hepatocellular carcinoma were strongly associated with the survival of all patients. In the group of cirrhotic patients, the only independent prognostic factor that was associated with patients' survival was the Child-Pugh class. CONCLUSION: None of the patients developed lactic acidosis. There is an indication of an increasing trend of lactic acid levels up to 24 months of therapy in female cirrhotic patients.

Bacterial load and cytokine profile in patients with cirrhosis following therapy with proton pump inhibitors: a prospective cohort study.

BACKGROUND: The aim of this study was to explore the presence of bacterial products and the cytokine profile in outpatients with cirrhosis before and after short-term (4-8 weeks) administration of proton pump inhibitors (PPIs). METHODS: Seventeen patients with cirrhosis-male/female: 12/5; age: median 59.2 years (49-65); etiology: HBV±HDV 23.5%, HCV 17.7%, alcohol 41.2%, other 17.6%; Child-Pugh score: median 7.5 (5-12); Model for End-stage Liver Disease: 10.5 (7-21); ascites (%): 3 (17.7)-attending the outpatient clinics were included. None had hepatocellular carcinoma. Indications for PPIs were: esophagitis (n=6, 35.3%), peptic ulcer (n=10, 58.6%) and other (n=1, 5.9%). Bacterial DNA in serum and the levels of endotoxin, lipopolysaccharide binding protein, transforming growth factor-ß, interleukin -1ß, -6, -8, -12, -10, tumor necrosis factor-α and nitric oxide were assessed at baseline (time 1) and at the end of treatment (time 2). The Wilcoxon signed rank test was used to evaluate significant differences in the parameters assayed before and after PPI administration. RESULTS: No patients developed infection during the study period. Bacterial DNA was not detected before or after treatment. No significant differences were observed between the concentrations of any indices between times 1 and 2 (P>0.05). Subgroup analysis according to Child-Pugh stage yielded similar results. CONCLUSION: Short-term administration of PPIs had no effect on bacterial DNA, bacterial products or cytokine concentrations in patients with liver cirrhosis.