FibroScan-AST score for diagnosing fibrotic MASH: A systematic review and meta-analysis of diagnostic test accuracy studies.

BACKGROUND AND AIM: Following the approval of the first agent for the management of metabolic dysfunction-associated steatohepatitis (MASH), identification of patients with fibrotic MASH (MASH with NAS ≥ 4 and fibrosis stage ≥ 2) is crucial. We assessed the performance of FibroScan-aspartate aminotransferase (AST) score (FAST) for ruling in/out fibrotic MASH. METHODS: We searched Medline, Cochrane Library, Web of Science, Scopus, and gray literature sources up to January 11, 2024. Studies were eligible if they assessed the accuracy of FAST score for the detection of fibrotic MASH using biopsy as the reference standard at previously reported thresholds (FAST ≥ 0.67 for ruling-in and ≤ 0.35 for ruling-out fibrotic MASH). We calculated pooled sensitivity and specificity estimates for FAST thresholds alongside 95% confidence intervals following bivariate random- effects models. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: We included 16 studies with 8838 participants. A FAST score ≥ 0.67 yielded a pooled specificity of 0.87 (0.82-0.90) while a FAST score ≤ 0.35 yielded a summary sensitivity of 0.88 (0.83-0.91). At a prevalence of 30%, the positive predictive value for ruling-in fibrotic MASH was 60% while the negative predictive value for ruling-out the target condition was 91%. AST levels, cirrhosis prevalence, and number of pathologists reviewing biopsies were sources of heterogeneity among studies. The certainty of evidence was low to very low. CONCLUSIONS: FAST score can be used as a triage test for ruling out fibrotic MASH. Nevertheless, its low positive predictive value necessitates sequential testing for ruling-in fibrotic MASH.

Accuracy of controlled attenuation parameter for liver steatosis in patients at risk for metabolic dysfunction-associated steatotic liver disease using magnetic resonance imaging: a systematic review and meta-analysis.

Background: The controlled attenuation parameter (CAP) enables the noninvasive assessment of liver steatosis. We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of CAP for identifying liver steatosis in patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the reference standard. Methods: We searched Medline, Embase, Cochrane Library and gray literature sources up to March 2024. We defined MASLD as MRI-PDFF ≥5%. We also assessed the accuracy of CAP for identifying patients with MRI-PDFF ≥10%. We calculated pooled sensitivity and specificity estimates using hierarchical random-effects models. We assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool, and the certainty in meta-analysis estimates using the Grading of Recommendations Assessment, Development and Evaluation framework. Results: We included 8 studies with 1116 participants. The prevalence of MASLD ranged from 65.2-93.9%. Pooled sensitivity and specificity of CAP for MRI-PDFF ≥5% were 0.84 (95% confidence interval [CI] 0.79-0.88) and 0.77 (95%CI 0.68-0.84), respectively, with an area under the receiver operating characteristic curve (AUROC) of 0.88. The pooled sensitivity and specificity for MRI-PDFF ≥10% were 0.83 (95%CI 0.80-0.87) and 0.72 (95%CI 0.59-0.82), with an AUROC of 0.85. The certainty in our estimates was low to very low because of the high risk of bias, inconsistency and imprecision. Conclusions: CAP has acceptable diagnostic accuracy for both MRI-PDFF ≥5% and MRI-PDFF ≥10%. Adequately powered and rigorously conducted diagnostic accuracy studies are warranted to establish the optimal CAP thresholds.

Liver disease in patients with transfusion-dependent ß-thalassemia: The emerging role of metabolism dysfunction-associated steatotic liver disease.

In this Editorial, we highlight the possible role that metabolism dysfunction-associated steatotic liver disease (MASLD) may play in the future, regarding liver disease in patients with transfusion-dependent ß-thalassemia (TDBT). MASLD is characterized by excessive accumulation of fat in the liver (hepatic steatosis), in the presence of cardiometabolic factors. There is a strong correlation between the occurrence of MASLD and insulin resistance, while its increased prevalence parallels the global epidemic of diabetes mellitus (DM) and obesity. Patients with TDBT need regular transfusions for life to ensure their survival. Through these transfusions, a large amount of iron is accumulated, which causes saturation of transferrin and leads to the circulation of free iron molecules, which cause damage to vital organs (primarily the liver and myocardium). Over the past, the main mechanisms for the development of liver disease in these patients have been the toxic effect of iron on the liver and chronic hepatitis C, for which modern and effective treatments have been found, resulting in successful treatment. Additional advances in the treatment and monitoring of these patients have led to a reduction in deaths, and an increase in their life expectancy. This increased survival makes them vulnerable to the onset of diseases, which until recently were mainly related to the non-thalassemic general population, such as obesity and DM. There is insufficient data in the literature regarding the prevalence of MASLD in this population or on the risk factors for its occurrence. However, it was recently shown by a study of 45 heavily transfused patients with beta-thalassemia (Padeniya et al, BJH), that the presence of steatosis is a factor influencing the value of liver elastography and thus liver fibrosis. These findings suggest that future research in the field of liver disease in patients with TDBT should be focused on the occurrence, the risk factors, and the effect of MASLD on these patients.

Efficacy of pharmacologic interventions on magnetic resonance imaging biomarkers in patients with nonalcoholic fatty liver disease: systematic review and network meta-analysis.

BACKGROUND AND AIM: Several agents are under investigation for nonalcoholic fatty liver disease (NAFLD). We assessed the comparative efficacy of pharmacologic interventions for patients with NAFLD focusing on magnetic resonance imaging (MRI) biomarkers. METHODS: We searched Medline, Embase, and CENTRAL. We included randomized controlled trials of more than 12 weeks of intervention that recruited patients with biopsy-confirmed or MRI-confirmed NAFLD and assessed the efficacy of interventions on liver fat content (LFC) and fibrosis by means of MRI. We performed random-effects frequentist network meta-analyses and assessed confidence in our estimates using the CINeMA (Confidence in Network Meta-Analysis) approach. RESULTS: We included 47 trials (8583 patients). Versus placebo, thiazolidinediones were the most efficacious for the absolute change in LFC, followed by vitamin E, fibroblast growth factor (FGF) analogs, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with mean differences ranging from -7.46% (95% confidence interval [-11.0, -3.9]) to -4.36% (-7.2, -1.5). No differences between drug classes were evident. Patients receiving GLP-1 RAs or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs were more likely to achieve ≥30% relative reduction in LFC. Among agents, efruxifermin produced the largest reduction in LFC compared to placebo [-13.5% (-18.5, -8.5)], followed by pioglitazone, while being superior to most interventions. The effect of interventions on magnetic resonance elastography assessed fibrosis was small and insignificant. The confidence in our estimates was low to very low. CONCLUSIONS: Several drug classes may reduce LFC in patients with NAFLD without a significant effect on fibrosis; nevertheless, trial duration was small, and confidence in the effect estimates was low.

Efficacy of Newer Nucleos(t)ide Analogs After Hepatitis B Immunoglobulin Discontinuation Against Hepatitis B and D Recurrence in Liver Transplant Recipients.

BACKGROUND: The use of nucleos(t)ide analogs (NAs) with a high genetic barrier to resistance, namely entecavir and tenofovir, has improved the efficacy of antiviral prophylaxis against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, the optimal duration and dosage of hepatitis B immunoglobulin (HBIG) administration, particularly in patients transplanted for HBV and hepatitis D virus (HDV) coinfection, remains controversial. METHODS: We evaluated 28 patients transplanted for HBV/HDV cirrhosis. After LT, each patient received a fixed scheme of low-dose HBIG plus NA for 6 mo post-LT and then continued with long-term NA prophylaxis (entecavir: 8, tenofovir: 20 patients). RESULTS: During 72 mo of follow-up, reappearance of hepatitis B surface antigen at low titers was observed in 1 (3.6%) patient at 33 mo after HBIG discontinuation, which became negative after a single dose of HBIG 1000 IU/L, whereas both serum HBV DNA and HDV RNA remained persistently undetectable and without any clinical or biochemical evidence of HBV/HDV recurrence. CONCLUSIONS: We showed for the first time the efficacy of a short, fixed scheme of low-dose HBIG plus NA followed by long-term NA monoprophylaxis against HBV/HDV recurrence after LT, although careful follow-up is needed after HBIG discontinuation, whereas further larger studies are needed to confirm these findings.

Cost-effectiveness of switching from tenofovir disoproxil fumarate to tenofovir alafenamide versus entecavir for chronic hepatitis B patients in Greece.

Aim: This study assessed the clinical impact and cost-effectiveness of switching from tenofovir disoproxil fumarate (TDF) to either tenofovir alafenamide (TAF) or entecavir (ETV) in a Greek chronic hepatitis B (CHB) population. Patients & methods: A Markov model from the perspective of a third-party payer in Greece quantified the health and economic benefits of switching from TDF to either TAF or ETV over a lifetime horizon. Results: Over a lifetime, patients who switch from TDF to TAF versus patients who switch from TDF to ETV had an overall lower incidence of compensated cirrhosis (0.4% lower), decompensated cirrhosis (0.04% lower) and hepatocellular carcinoma (0.25% lower). Chronic kidney disease and end-stage renal disease were also lower in patients who switch to TAF; major osteoporotic fractures were similar for both groups. While total costs were higher for switching from TDF to TAF versus TDF to ETV due to the higher cost of TAF, switching from TDF to TAF versus ETV was cost effective with an incremental cost-effectiveness ratio of €17,113 per quality-adjusted life year. Conclusion: Switching from TDF to TAF in patients living with CHB is a cost effective strategy to reduce adverse liver disease outcomes, while improving bone- and renal-related safety outcomes.

Comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging in patients with type 2 diabetes mellitus: systematic review and network meta-analysis.

PURPOSE: To assess the comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging (MRI) in patients with T2D. METHODS: We searched several databases and grey literature sources. Eligible trials had at least 12 weeks of intervention, included patients with T2D, and assessed the efficacy of glucose-lowering drugs as monotherapies. The primary outcome of interest was absolute reduction in liver fat content (LFC), assessed by means of MRI. Secondary efficacy outcomes were reduction in visceral and subcutaneous adipose tissue. We performed random effects frequentist network meta-analyses to estimate mean differences (MDs) with 95% confidence intervals (CIs). We ranked treatments based on P-scores. RESULTS: We included 29 trials with 1906 patients. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (P-score 0.84) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (0.71) were the most efficacious in terms of liver fat content reduction. Among individual agents, empagliflozin was the most efficacious (0.86) and superior to pioglitazone (MD -5.7, 95% CI -11.2 to -0.3) (very low confidence). GLP-1 RAs had also the most favorable effects on visceral and subcutaneous adipose tissue. CONCLUSIONS: GLP-1 RAs and SGLT-2 inhibitors seem to be the most efficacious glucose-lowering drugs for liver steatosis in patients with T2D. Assessment of their efficacy on NAFLD in patients irrespective of presence of T2D is encouraged.

Impact and management of COVID-19 in liver transplant candidates and recipients.

The COVID-19 outbreak has had severe consequences for global public health, medical communities, and the socioeconomic status of a considerable number of countries. The emergence of COVID-19 has also significantly impacted the world of liver transplantation (LT). Studies from transplantation centers around the world have shown that LTs during the COVID-19 pandemic have been restricted because of the high risk of serious COVID-19 infection in this population. According to the Centers for Disease Control and Prevention, patients with liver disease are considered at higher risk for severe COVID-19 infection. In March 2020, the American Association for the Study of Liver Diseases recommended that LT should be limited to emergency cases. The COVID-19 treatment guidelines published by the National Institutes of Health are being constantly updated according to new epidemiology trends and treatment regimens. Immunocompromised patients have a higher risk of developing severe disease or death from COVID-19 compared with the general population. In this review, we summarize the available evidence regarding treatment guidelines and considerations for the evaluation and management of LT candidates and recipients in the era of COVID-19. In addition, we present data regarding COVID-19 among LT patients in our local transplantation center.

Assessment of histologic risk factors for hepatocellular carcinoma in patients with chronic hepatitis B of advanced stage.

Histologic markers of increased risk for hepatocellular carcinoma can provide useful information for the management of patients with chronic hepatitis B. The expression of epithelial cell adhesion molecule (EpCAM, a marker of hepatic progenitor cells), p21 (a marker of hepatocyte senescence), glutamine synthetase (a marker of perivenular hepatocytes) and CD34 (a marker of sinusoidal capillarization) were assessed by immunohistochemistry in 52 liver biopsy specimens from patients with advanced stage chronic hepatitis B. Nineteen patients developed hepatocellular carcinoma during a follow-up period of 133 months. The findings were compared with those of 18 liver biopsy specimens from patients with early-stage chronic hepatitis B and 6 liver biopsy specimens without significant pathologic findings. EpCAM expression in hepatocytes was significantly increased in specimens with advanced stage, as compared with all other specimens. EpCAM positivity in over 30 % of hepatocytes was only seen in 3 specimens from patients who subsequently developed hepatocellular carcinoma. The expression of p21, glutamine synthetase and CD34 was not associated with hepatocellular carcinoma development. Nevertheless, glutamine synthetase immunostains highlighted zonality abnormalities that were useful in chronic hepatitis B staging. In conclusion, extensive immunopositivity of hepatocytes for EpCAM in chronic hepatitis B may represent a marker of increased hepatocellular carcinoma risk. Glutamine synthetase immunostaining represents a useful adjunct in determining the stage of chronic hepatitis B in diagnostic practice.

Plasma Lipids Profile in the Prediction of Non-Alcoholic Steatohepatitis in Adults: A Case-Control Study.

Patients with non-alcoholic steatohepatitis (NASH) show significantly faster progress in the stages of fibrosis compared to those with non-alcoholic fatty liver (NAFL) disease. The non-invasive diagnosis of NASH remains an unmet clinical need. Preliminary data have shown that sphingolipids, especially ceramides, fatty acids, and other lipid classes may be related to the presence of NASH and the histological activity of the disease. The aim of our study was to assess the association of certain plasma lipid classes, such as fatty acids, acylcarnitines, and ceramides, with the histopathological findings in patients with NASH. The study included three groups: patients with NASH (N = 12), NAFL (N = 10), and healthy [non non-alcoholic fatty liver disease (NAFLD)] controls (N = 15). Plasma samples were collected after 12 h of fasting, and targeted analyses for fatty acids, acylcarnitines, and ceramides were performed. Baseline clinical and demographic characteristics were collected. There was no significant difference in baseline characteristics across the three groups or between NAFL and NASH patients. Patients with NASH had increased levels of several fatty acids, including, among others, fatty acid (FA) 14:0, FA 15:0, FA 18:0, FA 18:3n3, as well as Cer(d18:1/16:0), compared to NAFL patients and healthy controls. No significant difference was found between NAFL patients and healthy controls. In conclusion, patients with NASH exhibited a distinctive plasma lipid profile that can differentiate them from NAFL patients and non-NAFLD populations. More data from larger cohorts are needed to validate these findings and examine possible implications for diagnostic and management strategies of the disease.

Effects of an active lifestyle on the physical frailty of liver transplant candidates.

BACKGROUND: Liver transplantation is the most important therapeutic intervention for end-stage liver disease (ELD). The prioritization of these patients is based on the model for end-stage liver disease (MELD), which can successfully predict short-term mortality. However, despite its great validity and value, it cannot fully incor porate several comorbidities of liver disease, such as sarcopenia and physical frailty, variables that can sufficiently influence the survival of such patients. Subsequently, there is growing interest in the importance of physical frailty in regard to mortality in liver transplant candidates and recipients, as well as its role in improving their survival rates. AIM: To evaluate the effects of an active lifestyle on physical frailty on liver transplant candidates. METHODS: An observational study was performed within the facilities of the Department of Transplant Surgery of Aristotle University of Thessaloniki. Twenty liver tran splant candidate patients from the waiting list of the department were included in the study. Patients that were bedridden, had recent cardiovascular incidents, or had required inpatient treatment for more than 5 d in the last 6 mo were excluded from the study. The following variables were evaluated: Activity level via the International Physical Activity Questionnaire (IPAQ); functional capacity via the 6-min walking test (6MWT) and cardiopulmonary exercise testing; and physical frailty via the Liver Frailty Index (LFI). RESULTS: According to their responses in the IPAQ, patients were divided into the following two groups based on their activity level: Active group (A, 10 patients); and sedentary group (S, 10 patients). Comparing mean values of the recorded variables showed the following results: MELD (A: 12.05 ± 5.63 vs S: 13.99 ± 3.60; P > 0.05); peak oxygen uptake (A: 29.78 ± 6.07 mL/kg/min vs S: 18.11 ± 3.39 mL/kg/min; P < 0.001); anaerobic threshold (A: 16.71 ± 2.17 mL/kg/min vs S: 13.96 ± 1.45 mL/kg/min; P < 0.01); 6MWT (A: 458.2 ± 57.5 m vs S: 324.7 ± 55.8 m; P < 0.001); and LFI (A: 3.75 ± 0.31 vs S: 4.42 ± 0.32; P < 0.001). CONCLUSION: An active lifestyle can be associated with better musculoskeletal and functional capacity, while simultaneously preventing the evolution of physical frailty in liver transplant candidates. This effect appears to be independent of the liver disease severity.

Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation.

Hepatocellular carcinoma (HCC) is an aggressive primary liver neoplasm that, according to tumor stage, can be treated with resection, transplantation, locoregional treatment options, or systemic therapy. Although interventions only in early-stage disease can offer complete tumor regression, systemic therapy in advanced disease can significantly prolong overall survival, according to pub lished clinical trials. The emergence of immunotherapy in the field of cancer therapy has had a positive impact on patients with HCC, resulting in atezolizumab-bevacizumab currently being the first-line option for treatment of advanced HCC. In light of this, application of immunotherapy in the preoperative process could increase the number of patients fulfilling the criteria for liver transplantation (LT). Implementation of this approach is faced with challenges regarding the safety of immunotherapy and the possibly increased risk of re jection in the perioperative period. Case reports and clinical trials assessing the safety profile and effectiveness of neoadjuvant immunotherapy, highlight important aspects regarding this newly evolving approach to HCC management. More studies need to be conducted in order to reach a consensus regarding the optimal way to administer immunotherapy prior to LT. In this review, we sum marize the role, safety profile and future considerations regarding the use of neoadjuvant immunotherapy prior to LT in patients with HCC.

Liver Imaging Reporting and Data System criteria for the diagnosis of hepatocellular carcinoma in clinical practice: A pictorial minireview.

Hepatocellular carcinoma (HCC) is the sixth most common cancer. The main risk factors associated with HCC development include hepatitis B virus, hepatitis C virus, alcohol consumption, aflatoxin B1, and nonalcoholic fatty liver disease. However, hepatocarcinogenesis is a complex multistep process. Various factors lead to hepatocyte malignant transformation and HCC development. Diagnosis and surveillance of HCC can be made with the use of liver ultrasound (US) every 6 mo. However, the sensitivity of this imaging method to detect HCC in a cirrhotic liver is limited, due to the abnormal liver parenchyma. Computed tomography (CT) and magnetic resonance imaging (MRI) are considered to be most useful tools for at-risk patients or patients with inadequate US. Liver biopsy is still used for diagnosis and prognosis of HCC in specific nodules that cannot be definitely characterized as HCC by imaging. Recently the American College of Radiology designed the Liver Imaging Reporting and Data System (LI-RADS), which is a comprehensive system for standardized interpretation of CT and MRI liver examinations that was first proposed in 2011. In 2018, it was integrated into the American Association for the Study of Liver Diseases guidance statement for HCC. LI-RADS is designed to ensure high sensitivity, precise categorization, and high positive predictive value for the diagnosis of HCC and is applied to "high-risk populations" according to specific criteria. Most importantly LI-RADS criteria achieved international collaboration and consensus among liver experts around the world on the best practices for caring for patients with or at risk for HCC.

Enhanced recovery after surgery in liver transplantation: Challenges and feasibility.

BACKGROUND: Enhanced recovery after surgery (ERAS) started a revolution that changed age-old surgical stereotypical practices regarding the overall management of the surgical patient. In the last decade, ERAS has gained significant acceptance in the community of general surgery, in addition to several other surgical specialties, as the evidence of its advantages continues to grow. One of the last remaining fields, given its significant complexity and intricate nature, is liver transplantation (LT). AIM: To investigate the existing efforts at implementing ERAS in LT. METHODS: We conducted a systematic review of the existing studies that evaluate ERAS in orthotopic LT, with a multimodal approach and focusing on measurable clinical primary endpoints, namely length of hospital stay. RESULTS: All studies demonstrated a considerable decrease in length of hospital stay, with no readmission or negative impact of the ERAS protocol applied to the postoperative course. CONCLUSIONS: ERAS is a well-validated multimodal approach for almost all types of surgical procedures, and its future in selected LT patients seems promising, as the preliminary results advocate for the safety and efficacy of ERAS in the field of LT.

Endothelial and microvascular function in liver cirrhosis: an old concept that needs re-evaluation?

Liver cirrhosis is characterized by significant circulatory dysregulation, related to an imbalance among several vasodilating agents, mainly nitric oxide. In contrast to portal vein and macrovascular hemodynamic alterations, which have been rather well described, the peripheral microcirculatory and endothelial structure and function in this population are less well studied. Endothelial dysfunction is characterized by an imbalance between endothelium-derived relaxing and contracting factors. A number of methods have been used to assess endothelial and microvascular function in human studies. Venous occlusion plethysmography was used for many years as the gold standard for evaluating endothelial function, but flow-mediated dilatation (FMD) of the forearm is currently the most frequently used method. In patients with cirrhosis, the few existing studies have mainly used FMD, but the relevant results are largely contradictory. In recent years, several noninvasive and easily applicable methods, such as near-infrared spectroscopy, laser speckle contrast imaging, peripheral arterial tonometry, optical coherence tomography and nailfold video-capillaroscopy, have been increasingly used to assess peripheral microvascular function and have demonstrated a number of advantages. In this review, we present functional methods to evaluate peripheral microvascular and endothelial function, and we discuss the existing evidence on circulatory dysfunction in patients with liver cirrhosis.

Peripheral endothelial and microvascular damage in liver cirrhosis: A systematic review and meta-analysis.

OBJECTIVE: This is the first systematic review and meta-analysis of studies using any available functional method to examine differences in peripheral endothelial function between cirrhotic and non-cirrhotic individuals. METHODS: Literature search involved PubMed, Web-of-Science, and Scopus databases, as well as gray literature sources. We included studies in adult subjects evaluating endothelial function with any semi-invasive or non-invasive functional method in patients with and without liver cirrhosis. RESULTS: From 3378 records initially retrieved, 15 studies with a total of 570 participants were included in the final quantitative meta-analysis. In six studies examining endothelial function with flow-mediated-dilatation, no differences between patients with cirrhosis and controls were evident (WMD: 1.33, 95%CI [-2.87, 5.53], I2  = 97%, p < .00001). Among studies assessing differences in endothelial-dependent or endothelial-independent vasodilation with venous-occlusion-plethysmography, there were no significant differences between the two groups. When pooling all studies together, regardless of the technique used, no significant difference in endothelial function between cirrhotic patients and controls was observed(SMD: 0.79, 95%CI[-0.04, 1.63], I2  = 94%, p < .00001). CONCLUSIONS: No differences in peripheral endothelial function assessed with semi-invasive or non-invasive functional methods exist between cirrhotic and non-cirrhotic subjects. The increasing co-existence of cardiovascular risk factors leading to impaired vascular reactivity in cirrhotic patients may partly explain these findings.

Emerging advances in the pharmacologic treatment of nonalcoholic steatohepatitis and related cirrhosis.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly growing throughout the world. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is likely to become the leading cause of cirrhosis and etiology for liver transplantation in future decades in the Western World. Most patients with NAFLD have some components of metabolic syndrome, including obesity, insulin resistance, dyslipidemia, and hypertension. NAFLD encompasses a wide spectrum of liver damage, ranging from simple steatosis to NASH, that can progress to advanced liver disease, as well as hepatocellular carcinoma. Unfortunately, the options for the pharmacological treatment of NASH are still very limited. Nonetheless, several classes of therapies have shown promise, and are currently being evaluated in large phase 2b and phase 3 trials, creating some hope that selected agents will be approved in the coming years. As NASH is a heterogeneous disease, multiple mechanistic pathways are being targeted to achieve optimal treatment response. Combination therapy is also on the horizon, where 2 or more drugs targeting different mechanistic pathways are being used to boost the clinical response. In this review, we first present the current concept of the pathophysiology of NASH, focusing on the pathways currently targeted in clinical trials. We then present the pharmacological agents that are being evaluated in phase IIb of clinical development and beyond, using histological outcomes, and finally we present preliminary results from the combination trials that have already been initiated.

Estimation of glomerular filtration rate in patients with cirrhosis: evaluation of equations currently used in clinical practice and validation of Royal Free Hospital cirrhosis glomerular filtration rate.

OBJECTIVE: Conventional creatinine-based glomerular filtration rate (GFR) equations have been reported to overestimate renal function in patients with cirrhosis. The Royal Free Hospital (RFH) cirrhosis GFR equation was developed to accurately estimate GFR in this population. The aim of this study was to evaluate the ability of widely available equations [Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), Modification of Diet in Renal Disease equations (MDRD-4, MDRD-6)] and the RFH equation to correctly estimate the GFR of patients with cirrhosis. METHODS: We retrospectively analyzed data from patients with cirrhosis who underwent measurement of GFR with the use of 51Cr-EDTA (GFR-M). The CKD-EPI, MDRD-4, MDRD-6 and RFH equations were calculated, while bias, precision and accuracy were estimated for each one of them and then compared with paired t-tests. Bias was defined as the mean difference between the GFR-M and the result of each equation; precision was defined as the SD of the differences and accuracy was defined as the square root of the mean squared error (mean of the squared differences). Higher values are associated with worse bias and better precision/accuracy. RESULTS: One-hundred and thirty-four cirrhotic patients were included. Bias was estimated for CKD-EPI, MDRD-4, MDRD-6 and RFH at -5.91, -3.13, 0.92 and 18.24, respectively. Significant differences were observed between all equations (P < 0.001). Regarding precision, only the comparison between MDRD-4 (20.81) and RFH (16.6) yielded a statistically significant result (P = 0.037). Finally, CKD-EPI (19.32) and MDRD-6 (18.81) exhibited better accuracy than GFR-RFH (24.61) (P = 0.006 and 0.001). CONCLUSION: RFH demonstrates inferior accuracy in predicting renal function in patients with cirrhosis, in comparison to conventional equations.

Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence?

Intrahepatic cholangiocarcinoma (iCCA) is a subgroup of cholangiocarcinoma that accounts for about 10%-20% of the total cases. Infection with hepatitis B virus (HBV) is one of the most important predisposing factors leading to the formation of iCCA. It has been recently estimated based on abundant epidemiological data that the association between HBV infection and iCCA is strong with an odds ratio of about 4.5. The HBV-associated mechanisms that lead to iCCA are under intense investigation. The diagnosis of iCCA in the context of chronic liver disease is challenging and often requires histological confirmation to distinguish from hepatocellular carcinoma. It is currently unclear whether antiviral treatment for HBV can decrease the incidence of iCCA. In terms of management, surgical resection remains the mainstay of treatment. There is a need for effective treatment modalities beyond resection in both first- and second-line treatment. In this review, we summarize the epidemiological evidence that links the two entities, discuss the pathogenesis of HBV-associated iCCA, and present the available data on the diagnosis and management of this cancer.