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Background: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established., Methods: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed., Results: Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea., Conclusions: In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.)., (Copyright © 2023 Massachusetts Medical Society.)

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is associated independently with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in nondiabetic patients with histologically proven NAFLD., Methods: We performed a case-control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 nondiabetic subjects with histologically confirmed NAFLD vs lean (N = 81) and obese (N = 81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or from a tissue repository., Results: Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B; increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein (LDL) particles and small dense LDL (sdLDL) cholesterol, and an increased percentage of sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, triglyceride and apolipoprotein B levels, concentrations of LDL particles and LDL cholesterol, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased the development of cirrhosis., Conclusions: Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Priority for "sickest first" liver transplantation (LT) in the United States is determined by the model for end-stage liver disease (MELD). MELD is a good predictor of short-term mortality in cirrhosis, but it can overestimate risk when international normalized ratio (INR) is artificially elevated by anticoagulation. An alternate prognostic index omitting INR is needed in this situation. We retrospectively analyzed survival data for 554 cirrhotic veterans referred for consideration of LT prior to December 1, 2003 (training group). Using logistic regression we derived a predictive formula for 90-day pretransplant mortality incorporating bilirubin and creatinine but omitting INR. We normalized this formula to the same scale as MELD using linear regression. This yielded MELD-XI (for MELD excluding INR) = 5.11 Ln(bilirubin) + 11.76 Ln(creatinine) + 9.44. Accuracy of MELD-XI was validated in a holdout group of 278 cirrhotic veterans referred after December 1, 2003, and in an independent validation dataset of 7,203 cirrhotic adults listed for LT in the United States between May 1, 2001, and October 31, 2001. MELD-XI and MELD correlated well in training, holdout, and independent validation cohorts (r = 0.930, 0.954, and 0.902, respectively). In the holdout cohort, c-statistics of MELD vs. MELD-XI for mortality were, respectively, 0.939 vs. 0.906 at 30 days;0.860 vs. 0.841 at 60 days; 0.842 vs. 0.829 at 90 days; and 0.795 vs. 0.797 at 180 days. In the independent validation dataset, c-statistics for MELD vs. MELD-XI as predictors of 90-day survival were, respectively, 0.857 vs. 0.843 in noncholestatic liver diseases and 0.905 vs. 0.894 in cholestatic liver diseases. Comparable MELD and MELD-XI scores were associated with comparable prognosis. In conclusion, MELD-XI, despite omission of INR, is nearly as accurate as MELD in predicting short-term survival in cirrhosis. In patients treated with oral anticoagulants, substitution of MELD-XI for MELD may permit more accurate assessment of risk and more rational assignment of "sickest first" priority for LT., ((c) 2006 AASLD.)

Background There is a need for reliable noninvasive methods for diagnosing and monitoring nonalcoholic fatty liver disease (NAFLD). Thus, the multidisciplinary Non-invasive Biomarkers of Metabolic Liver disease (NIMBLE) consortium was formed to identify and advance the regulatory qualification of NAFLD imaging biomarkers. Purpose To determine the different-day same-scanner repeatability coefficient of liver MRI biomarkers in patients with NAFLD at risk for steatohepatitis. Materials and Methods NIMBLE 1.2 is a prospective, observational, single-center short-term cross-sectional study (October 2021 to June 2022) in adults with NAFLD across a spectrum of low, intermediate, and high likelihood of advanced fibrosis as determined according to the fibrosis based on four factors (FIB-4) index. Participants underwent up to seven MRI examinations across two visits less than or equal to 7 days apart. Standardized imaging protocols were implemented with six MRI scanners from three vendors at both 1.5 T and 3 T, with central analysis of the data performed by an independent reading center (University of California, San Diego). Trained analysts, who were blinded to clinical data, measured the MRI proton density fat fraction (PDFF), liver stiffness at MR elastography (MRE), and visceral adipose tissue (VAT) for each participant. Point estimates and CIs were calculated using χ2 distribution and statistical modeling for pooled repeatability measures. Results A total of 17 participants (mean age, 58 years ± 8.5 [SD]; 10 female) were included, of which seven (41.2%), six (35.3%), and four (23.5%) participants had a low, intermediate, or high likelihood of advanced fibrosis, respectively. The different-day same-scanner mean measurements were 13%-14% for PDFF, 6.6 L for VAT, and 3.15 kPa for two-dimensional MRE stiffness. The different-day same-scanner repeatability coefficients were 0.22 L (95% CI: 0.17, 0.29) for VAT, 0.75 kPa (95% CI: 0.6, 0.99) for MRE stiffness, 1.19% (95% CI: 0.96, 1.61) for MRI PDFF using magnitude reconstruction, 1.56% (95% CI: 1.26, 2.07) for MRI PDFF using complex reconstruction, and 19.7% (95% CI: 15.8, 26.2) for three-dimensional MRE shear modulus. Conclusion This preliminary study suggests that thresholds of 1.2%-1.6%, 0.22 L, and 0.75 kPa for MRI PDFF, VAT, and MRE, respectively, should be used to discern measurement error from real change in patients with NAFLD. ClinicalTrials.gov registration no. NCT05081427 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kozaka and Matsui in this issue.

Background & aimsDespite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD.MethodsUsing modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4).ResultsThe AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified.ConclusionsSerum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Clinical trial numberNot applicable.Impact and implicationsAn aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of non-alcoholic fatty liver disease (NAFLD), for which no approved non-invasive diagnostic tools are currently available. We also identified specific protein signatures related to the presence and severity of NAFLD and its histological components that were also sensitive to change over time. These are fundamental initial steps in establishing a serum proteome-based diagnostic signature of NASH and provide the rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NAFLD.

ObjectiveIn retrospective studies, liver stiffness (LS) by vibration-controlled transient elastography (VCTE) is associated with the risk of liver decompensation in patients with non-alcoholic steatohepatitis (NASH), but prospective data in biopsy-confirmed cohorts with advanced fibrosis are limited. We aimed to establish thresholds for LS by VCTE that predict progression to cirrhosis among patients with bridging fibrosis and hepatic decompensation among patients with cirrhosis due to NASH.DesignWe used data from four randomised placebo-controlled trials of selonsertib and simtuzumab in participants with advanced fibrosis (F3-F4). The trials were discontinued due to lack of efficacy. Liver fibrosis was staged centrally at baseline and week 48 (selonsertib study) or week 96 (simtuzumab study). Associations between LS by VCTE with disease progression were determined using Cox proportional hazards regression analysis.ResultsProgression to cirrhosis occurred in 16% (103/664) of participants with bridging fibrosis and adjudicated liver-related events occurred in 4% (27/734) of participants with baseline cirrhosis. The optimal baseline LS thresholds were ≥16.6 kPa for predicting progression to cirrhosis, and ≥30.7 kPa for predicting liver-related events. Baseline LS ≥16.6 kPa (adjusted HR 3.99; 95% CI 2.66 to 5.98, p

Background & aimsNon-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement.MethodsAdult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76). Adipose tissue compartment volumes were obtained using MRI.ResultsTreatment and placebo groups did not differ in baseline adipose tissue volumes, or in change in adipose tissue volumes longitudinally (p = 0.107 to 0.745). Deep subcutaneous adipose tissue (dSAT) and visceral adipose tissue volume reductions were associated with histologic improvement in NASH (i.e., NAS [non-alcoholic fatty liver disease activity score] reductions of ≥2 points, at least 1 point from lobular inflammation and hepatocellular ballooning, and no worsening of fibrosis) (p = 0.031, and 0.030, respectively). In a stepwise logistic regression procedure, which included demographics, treatment group, baseline histology, baseline and changes in adipose tissue volumes, MRI hepatic proton density fat fraction (PDFF), and serum aminotransferases as potential predictors, reductions in dSAT and PDFF were associated with histologic improvement in NASH (regression coefficient = -2.001 and -0.083, p = 0.044 and 0.033, respectively).ConclusionsIn adults with NASH in the FLINT trial, those with greater longitudinal reductions in dSAT and potentially visceral adipose tissue volumes showed greater hepatic histologic improvements, independent of reductions in hepatic PDFF.Clinical trial numberNCT01265498.Impact and implicationsAlthough central obesity has been identified as a risk factor for obesity-related disorders including insulin resistance and cardiovascular disease, the role of central obesity in non-alcoholic steatohepatitis (NASH) warrants further clarification. Our results highlight that a reduction in central obesity, specifically deep subcutaneous adipose tissue and visceral adipose tissue, may be related to histologic improvement in NASH. The findings from this analysis should increase awareness of the importance of lifestyle intervention in NASH for clinical researchers and clinicians. Future studies and clinical practice may design interventions that assess the reduction of deep subcutaneous adipose tissue and visceral adipose tissue as outcome measures, rather than simply weight reduction.

Background and aimsPatients with nonalcoholic fatty liver disease (NAFLD) cirrhosis benefit from referral to subspecialty care. While several clinical prediction rules exist to identify advanced fibrosis, the cutoff for excluding cirrhosis due to NAFLD is unclear. This analysis compared clinical prediction rules for excluding biopsy-proven cirrhosis in NAFLD.MethodsAdult patients were enrolled in the NASH Clinical Research Network (US) and the Newcastle Cohort (UK). Clinical and laboratory data were collected at enrolment, and a liver biopsy was taken within 1 year of enrolment. Optimal cutoffs for each score (eg, FIB-4) to exclude cirrhosis were derived from the US cohort, and sensitivity, specificity, positive predictive value, negative predictive value and AUROC were calculated. The cutoffs were evaluated in the UK cohort.Results147/1483 (10%) patients in the US cohort had cirrhosis. All prediction rules had similarly high NPV (0.95-0.97). FIB-4 and NAFLD fibrosis scores were the most accurate in characterising patients as having cirrhosis (AUROC 0.84-0.86). 59/494 (12%) patients in the UK cohort had cirrhosis. Prediction rules had high NPV (0.92-0.96), and FIB-4 and NAFLD fibrosis score the most accurate in the prediction of cirrhosis in the UK cohort (AUROC 0.87-0.89).ConclusionsThis cross-sectional analysis of large, multicentre international datasets shows that current clinical prediction rules perform well in excluding cirrhosis with appropriately chosen cutoffs. These clinical prediction rules can be used in primary care to identify patients, particularly those who are white, female, and

Background and aimsManagement of patients with NASH who are at elevated risk of progressing to complications of cirrhosis (at-risk NASH) would be enhanced by an accurate, noninvasive diagnostic test. The new FAST™ score, a combination of FibroScan® parameters liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and aspartate aminotransferase (AST), has shown good diagnostic accuracy for at-risk NASH (area-under-the-Receiver-Operating-Characteristic [AUROC] = 0.80) in European cohorts. We aimed to validate the FAST™ score in a North American cohort and show how its diagnostic accuracy might vary by patient mix. We also compared the diagnostic performance of FAST™ to other non-invasive algorithms for the diagnosis of at-risk NASH.MethodsWe studied adults with biopsy-proven non-alcoholic fatty liver disease (NAFLD) from the multicenter NASH Clinical Research Network (CRN) Adult Database 2 (DB2) cohort study. At-risk-NASH was histologically defined as definite NASH with a NAFLD Activity Score (NAS) ≥ 4 with at least 1 point in each category and a fibrosis stage ≥ 2. We used the Echosens® formula for FAST™ from LSM (kPa), CAP (dB/m), and AST (U/L), and the FAST™-based Rule-Out (FAST™ ≤ 0.35, sensitivity = 90%) and Rule-In (FAST™ ≥ 0.67, specificity = 90%) zones. We determined the following diagnostic performance measures: AUROC, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV); these were calculated for the total sample and by subgroups of patients and by FibroScan® exam features. We also compared the at-risk NASH diagnostic performance of FAST™ to other non-invasive algorithms: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, and AST to platelet ratio index (APRI).ResultsThe NASH CRN population of 585 patients was 62% female, 79% white, 14% Hispanic, and 73% obese; the mean age was 51 years. The mean (SD) AST and ALT were 50 (37) U/L and 66 (45) U/L, respectively. 214 (37%) had at-risk NASH. The AUROC of FAST™ for at-risk NASH in the NASH CRN study population was 0.81 (95% CI: 0.77, 0.84. Using FAST™-based cut-offs, 35% of patients were ruled-out with corresponding NPV = 0.90 and 27% of patients were ruled-in with corresponding PPV = 0.69. The diagnostic accuracy of FAST™ was higher in non-whites vs. whites (AUROC: 0.91 vs 0.78; p = 0.001), and in patients with a normal BMI vs. BMI > 35 kg/m2 (AUROC: 0.94 vs 0.78, p = 0.008). No differences were observed by other patient characteristics or FibroScan® exam features. The FAST™ score had higher diagnostic accuracy than other non-invasive algorithms for the diagnosis of at-risk NASH (AUROC for NFS, FIB-4, and APRI 0.67, 0.73, 0.74, respectively).ConclusionWe validated the FAST™ score for the diagnosis of at-risk NASH in a large, multi-racial population in North America, with a prevalence of at-risk NASH of 37%. Diagnostic performance varies by subgroups of NASH patients defined by race and obesity. FAST™ performed better than other non-invasive algorithms for the diagnosis of at-risk NASH.

Background and aimsThe composition of the human gut microbiota is linked to health and disease, and knowledge of the impact of therapeutics on the microbiota is essential to decipher their biological roles and to gain new mechanistic insights. Here we report the effect of aldafermin, an analog of the gut hormone FGF19, versus placebo on the gut microbiota in a prospective, phase 2 study in patients with NASH.Approach and resultsA total of 176 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease activity score ≥ 4), fibrosis (F1-F3 by NASH Clinical Research Network criteria), and elevated liver fat content (≥ 8% by magnetic resonance imaging-proton density fat fraction) received 0.3 mg (n = 23), 1 mg (n = 49), 3 mg (n = 49), and 6 mg (n = 28) aldafermin or placebo (n = 27) for 12 weeks. Stool samples were collected on day 1 and week 12 and profiled using 16S ribosomal RNA gene sequencing; 122 patients had paired stool microbiome profiles at both day 1 and week 12. Overall, the state of the gut microbial community was distinctly stable in patients treated with aldafermin, with all major phyla and genera unaltered during therapy. Patients treated with aldafermin showed a significant, dose-dependent enrichment in the rare genus Veillonella, a commensal microbe known to have lactate-degrading and performance-enhancing properties, which correlated with changes in serum bile acid profile.ConclusionsVeillonella may be a bile acid-sensitive bacteria whose enrichment is enabled by aldafermin-mediated suppression of bile acid synthesis and, in particular, decreases in toxic bile acids. This study provides an integrated analysis of gut microbiome, serum bile acid metabolome, imaging, and histological measurements in clinical trials testing aldafermin for NASH. Our results provide a better understanding of the intricacies of microbiome-host interactions (clinicaltrials.gov trial No. NCT02443116).

Background & aimsNon-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.MethodsIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.ResultsIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P

Background & aimsVibration-controlled transient elastography (VCTE), which measures liver stiffness, has become an important tool for evaluating patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the diagnostic accuracy of VCTE in detection of NAFLD in a multicenter cohort of patients.MethodsWe performed a prospective study of 393 adults with NAFLD who underwent VCTE within 1 year of liver histology analysis (median time, 49 d; interquartile range, 25-78 d), from July 1, 2014, through July 31, 2017. Liver stiffness measurement (LSM) cut-off values for pairwise fibrosis stage and controlled attenuation parameter cut-off values for pairwise steatosis grade were determined using cross-validated area under the receiver operating characteristics curve (AUROC) analyses. Diagnostic statistics were computed at a sensitivity fixed at 90% and a specificity fixed at 90%.ResultsLSM identified patients with advanced fibrosis with an AUROC of 0.83 (95% CI, 0.79- 0.87) and patients with cirrhosis with an AUROC of 0.93 (95% CI, 0.90-0.97). At a fixed sensitivity, a cut-off LSM of 6.5 kPa excluded advanced fibrosis with a negative predictive value of 0.91, and a cut-off LSM of 12.1 kPa excluded cirrhosis with a negative predictive value of 0.99. At a fixed specificity, LSM identified patients with advanced fibrosis with a positive predictive value of 0.71 and patients with cirrhosis with a positive predictive value of 0.41. Controlled attenuation parameter analysis detected steatosis with an AUROC of 0.76 (95% CI, 0.64-0.87). In contrast, the VCTE was less accurate in distinguishing lower fibrosis stages, higher steatosis grades, or the presence of NASH.ConclusionsIn a prospective study of adults with NAFLD, we found VCTE to accurately distinguish advanced vs earlier stages of fibrosis, using liver histology as the reference standard.

AimTo determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.MethodsTransient elastography with controlled attenuation parameter (CAP) was used to assess hepatic steatosis post-sustained virological response (SVR); the CAP technology was not available in the United States at study initiation. Liver stiffness/fibrosis was measured before and 47 wk after treatment completion. Patients with genotype 3 and patients with cirrhosis were excluded.ResultsOne hundred and one patients were included in the study. Post-SVR there were decreases from baseline in alanine aminotransferase (ALT) (63.1 to 17.8 U/L), aspartate aminotransferase (51.8 to 21.5 U/L) and fibrosis score (7.4 to 6.1 kPa) (P < 0.05). Post-SVR, 48 patients (47.5%) had steatosis on CAP; of these, 6.25% had advanced fibrosis. Patients with steatosis had higher body mass index (29.0 vs 26.1 kg/m2), glucose (107.8 vs 96.6 mg/dL), ALT (20.4 vs 15.3 mg/dL), CAP score (296.3 vs 212.4 dB/m) and fibrosis score (7.0 vs 5.3 kPa); P < 0.05. Interestingly, compared to baseline, both patients with and without steatosis had change in fibrosis score post-SVR (7.7 kPa vs 7.0 kPa and 7.0 kPa vs 5.3 kPa); alternatively, (P < 0.05) and therefore patients with steatosis continued to have clinically significant stiffness (≥ 7 kPa).ConclusionFatty liver is very common in hepatitis C virus (HCV) patients post-SVR. These patients continue to have elevated mean fibrosis score (≥ 7 kPa) compared to those without fatty liver; some have advanced fibrosis. Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.

Background & aimsSex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation.MethodsWe collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress.ResultsPremenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory-Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05).ConclusionsBeing a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

BACKGROUND Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear. METHODS In this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage Fl through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage. RESULTS A total of293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo. CONCLUSIONS Survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. [ABSTRACT FROM AUTHOR]

Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. [Display omitted] • OCA was superior to placebo in improving fibrosis by ≥1 stage with no worsening of NASH. • OCA treatment resulted in dose-dependent reductions of serum ALT levels. • OCA reduced liver stiffness compared to placebo regardless of histologic response. • OCA was generally well tolerated and demonstrated a favorable safety profile. [ABSTRACT FROM AUTHOR]

• Nonalcoholic fatty liver disease (NAFLD) severity on liver biopsy has an inverse relationship with Lp(a) level. Patients with non-alcoholic steatohepatitis (NASH) on histology had 50% lower Lp(a) compared to patients with nonalcoholic fatty liver (NAFL). • Conversely, NAFLD severity has a direct relationship with other markers of atherogenic dyslipidemia, including HDL-C, triglycerides, apolipoprotein-B (ApoB), and low-density lipoprotein particle concentration (LDL-P). • This relationship may have implications for prognosticating cardiovascular disease risk in patients with NAFLD. Nonalcoholic fatty liver disease (NAFLD) is associated with atherogenic dyslipidemia and an increased risk of cardiovascular events. Previous studies have suggested an inverse relationship between NAFLD severity and lipoprotein(a) [Lp(a)] level, but contemporary data from the U.S. are lacking. Lp(a), lipid profile, apolipoproteins, and nuclear magnetic resonance-based lipoprotein particle concentrations were measured in 151 patients with biopsy-proven NAFLD. Levels were compared between those with nonalcoholic fatty liver (NAFL) on histology and non-alcoholic steatohepatitis (NASH). Median age was 55 [48, 62] years, 67% of patients were women, 83% were White, 43% had NAFL, and 57% had NASH. Triglyceride level was higher and high-density lipoprotein-cholesterol (HDL-C) was lower among those with NASH as compared with NAFL. Circulating apolipoprotein-B (ApoB) and low-density lipoprotein particle concentration (LDL-P) were 9% and 17% higher in the NASH group as compared with NAFL, respectively. Contrastingly, Lp(a) concentration was 50% lower in NASH relative to NAFL group. Hepatocyte ballooning, lobular inflammation, and fibrosis on histology were inversely associated with Lp(a) concentration. NAFLD severity has a discordant association with Lp(a) and other markers of atherogenic dyslipidemia. This relationship may have implications for prognosticating cardiovascular disease risk in patients with NAFLD. [ABSTRACT FROM AUTHOR]

The purpose of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review is to provide clinicians with guidance on the use of noninvasive tests (NITs) in the evaluation and management of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD affects nearly 30% of the global population and is a growing cause of end-stage liver disease and liver-related health care resource utilization. However, only a minority of all patients with NAFLD experience a liver-related outcome. It is therefore critically important for clinicians to assess prognosis and identify those with increased risk of disease progression and negative clinical outcomes at the time of initial assessment. It is equally important to assess disease trajectory over time, particularly in response to currently available therapeutic approaches. The reference standard for assessment of prognosis and disease monitoring is histologic examination of liver biopsy specimens. There are, however, many limitations of liver biopsies and their reading that have limited their use in routine practice. The utilization of NITs facilitates risk stratification of patients and longitudinal assessment of disease progression for patients with NAFLD. This clinical update provides best practice advice based on a review of the literature on the utilization of NITs in the management of NAFLD for clinicians. Accordingly, a combination of available evidence and consensus-based expert opinion, without formal rating of the strength and quality of the evidence, was used to develop these best practice advice statements. This Expert Review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements NITs can be used for risk stratification in the diagnostic evaluation of patients with NAFLD. A Fibrosis 4 Index score <1.3 is associated with strong negative predictive value for advanced hepatic fibrosis and may be useful for exclusion of advanced hepatic fibrosis in patients with NAFLD. A combination of 2 or more NITs combining serum biomarkers and/or imaging-based biomarkers is preferred for staging and risk stratification of patients with NAFLD whose Fibrosis 4 Index score is >1.3. Use of NITs in accordance with manufacturer's specifications (eg, not in patients with ascites or pacemakers) can minimize risk of discordant results and adverse events. NITs should be interpreted with context and consideration of pertinent clinical data (eg, physical examination, biochemical, radiographic, and endoscopic) to optimize positive predictive value in the identification of patients with advanced fibrosis. Liver biopsy should be considered for patients with NIT results that are indeterminate or discordant; conflict with other clinical, laboratory, or radiologic findings; or when alternative etiologies for liver disease are suspected. Serial longitudinal monitoring using NITs for assessment of disease progression or regression may inform clinical management (ie, response to lifestyle modification or therapeutic intervention). Patients with NAFLD and NITs results suggestive of advanced fibrosis (F3) or cirrhosis (F4) should be considered for surveillance of liver complications (eg, hepatocellular carcinoma screening and variceal screening per Baveno criteria). Patients with NAFLD and NITs suggestive of advanced hepatic fibrosis (F3) or (F4), should be monitored with serial liver stiffness measurement; vibration controlled transient elastography; or magnetic resonance elastography, given its correlation with clinically significant portal hypertension and clinical decompensation. [ABSTRACT FROM AUTHOR]

Introduction: The current ordinal fibrosis staging system for nonalcoholic steatohepatitis (NASH) has a limited dynamic range. The goal of this study was to determine if second-harmonic generated (SHG) quantifiable collagen fibrillar properties (qFP) and their derived qFibrosis score capture changes in disease progression and regression in a murine model of NASH, in which disease progression can be induced by a high fat sugar water (HFSW) diet and regression by reversal to chow diet (CD). Methods: DIAMOND mice were fed a CD or HFSW diet for 40 to 52 weeks. Regression related changes were studied in mice with diet reversal for 4 weeks after 48 to 60 weeks of a HFSW diet. Results: As expected, mice on HFSW developed steatohepatitis with stage 2 to 3 fibrosis between weeks 40 and 44. Both the collagen proportionate area and the qFibrosis score based on 15 SHG-quantified collagen fibrillar properties in humans were significantly higher in mice on HFSW for 40 to 44 weeks compared to CD fed mice. These changes were greatest in the sinusoids (Zone 2) with further increase in septal and portal fibrosis related scores between weeks 44 and 48. Diet reversal led to decrease in qFibrosis, septal thickness, and cellularity with greatest changes in Zone 2. Specific qFPs associated with progression only, regression only, or both processes were identified and categorized based on direction of fibrosis change. Conclusion: Complementing recent human studies, these findings support the concept that changes of disease progression and regression can be assessed using SHG-based image quantification of fibrosis related parameters. [ABSTRACT FROM AUTHOR]

Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics. This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM. Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF. The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population. Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved. [Display omitted] • Non-invasive tests' ability to rule-in advanced fibrosis and cirrhosis is moderate. • Consequently, two new FibroScan-based scores are proposed: Agile 3+ and Agile 4. • They demonstrate fewer indeterminate results and higher positive predictive value. • Clinical performances are globally validated in two large independent cohorts. • Use of these scores in clinical practice could reduce the need for liver biopsy. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Non‐alcoholic steatohepatitis (NASH) is the most common cause of liver disease. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta‐analysis evaluating drug classes through comparing histological outcomes and targets of drugs. Approach and Results: Medline, EMBASE and CENTRAL were searched for randomised controlled trials evaluating NASH drugs in biopsy‐proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, at least 2‐point reduction in Non‐alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and at least 1‐point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. Among 49 included trials, treatments modulating energy (Risk ratio (RR): 1.92, Credible intervals (Crl): 1.59‐2.34) were most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.66, Crl: 0.65‐4.50), bile acids (RR: 1.37, Crl: 0.99‐1.92) and inflammation (RR: 1.00, Crl: 0.75‐1.33). Energy and bile acids modulation were effective in at least 2‐point NAS reduction without worsening of fibrosis (RR: 1.52, Crl 1.30‐1.77; RR: 1.69, Crl 1.41‐2.03) and at least 1‐point reduction in fibrosis (RR: 1.26, Crl:1.05‐1.49; RR: 1.54, Crl: 1.20‐1.97). Conclusions: This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies. [ABSTRACT FROM AUTHOR]

Simple tests of routine data are needed for those with severe acute respiratory syndrome coronavirus 2, which causes corona virus disease 2019 (COVID‐19), to help identify those who may need mechanical ventilation (MV). In this study, we aimed to determine if fibrosis‐4 (FIB‐4) is associated with the need for MV in patients with COVID‐19 and if there is an association to determine the optimal FIB‐4 cutoff. This was a retrospective, national, multiethnic cohort study of adults seen in an ambulatory or emergency department setting who were diagnosed with COVID‐19. We used the TriNetX platform for analysis. Measures included demographics, comorbid diseases, and routine laboratory tests. A total of 4,901 patients with COVID‐19 were included. Patients had a mean age of 56, 48% were women, 42% were obese, 38% were white, 40% were black, 15% had cardiac disease, 39% had diabetes mellitus, 20% had liver disease, and 50% had respiratory disease. The need for MV was 6%. The optimal FIB‐4 cutoff for the need for MV was 3.04 (area under the curve, 0.735), which had sensitivity, specificity, and positive and negative predictive values of 42%, 77%, 11%, and 95%, respectively, with 93% accuracy. When stratified by race, increased FIB‐4 remained associated with the need for MV in both white and black patients. Conclusion: FIB‐4 can be used by frontline providers to identify patients that may require MV. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is a major cause of liver‐related morbidity and mortality worldwide. Liver fibrosis stage, a key component of NASH, has been linked to the risk of mortality and liver‐related clinical outcomes. Currently there are no validated noninvasive diagnostics that can differentiate between fibrosis stages in patients with NASH; many existing tests do not reflect underlying disease pathophysiology. Noninvasive biomarkers are needed to identify patients at high‐risk of NASH with advanced fibrosis. This was a retrospective study of patients with histologically proven NASH with fibrosis stages 0‐4. The SOMAscan proteomics platform was used to quantify 1,305 serum proteins in a discovery cohort (n = 113). In patients with advanced (stages 3‐4) versus early fibrosis (stages 0‐2), 97 proteins with diverse biological functions were differentially expressed. Next, fibrosis‐stage classification models were explored using a machine learning–based approach to prioritize the biomarkers for further evaluation. A four‐protein model differentiated patients with stage 0‐1 versus stage 2‐4 fibrosis (area under the receiver operating characteristic curve [AUROC] = 0.74), while a 12‐protein classifier differentiated advanced versus early fibrosis (AUROC = 0.83). Subsequently, the model's performance was validated in two independent cohorts (n = 71 and n = 32) with similar results (AUROC = 0.74‐0.78). Our advanced fibrosis model performed similarly to or better than Fibrosis‐4 index, aspartate aminotransferase–to‐platelet ratio index, and nonalcoholic fatty liver disease (NAFLD) fibrosis score–based models for all three cohorts. Conclusion: A SOMAscan proteomics‐based exploratory classifier for advanced fibrosis, consisting of biomarkers that reflect the complexity of NASH pathophysiology, demonstrated similar performance in independent validation cohorts and performed similarly or better than Fibrosis‐4 index, aspartate aminotransferase–to‐platelet ratio index, and NAFLD fibrosis score. Further studies are warranted to evaluate the clinical utility of these biomarker panels in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) has now become a worldwide health issue due to the obesity epidemic, affecting approximately 90% of the obese population and 15–40% of the general population. It is the most common form of chronic liver disease in the United States. NAFLD constitutes a spectrum of diseases ranging in severity from mild, such as fatty liver, progressing into nonalcoholic steatohepatitis (NASH), then fibrosis, and ending with cirrhosis. NASH and increasing fibrosis stage are associated with increased morbidity and mortality; the fibrosis stage is therefore a critical element of risk stratification needed to determine therapeutic approach and also the response to treatment. Liver biopsy is considered the 'gold standard' in the diagnosis of NAFLD. However, it is not practical for widespread clinical use because it is invasive, costly, and associated with complications including occasional death. These limitations have driven the development of noninvasive tests that can accurately predict the fibrosis stage in those with NAFLD. In this review, we provide a concise overview of different non-invasive measurements used for NAFLD/NASH. [ABSTRACT FROM AUTHOR]

Abstract: Non‐alcoholic fatty liver disease is a leading cause of chronic liver disease and can lead to cirrhosis, hepatocellular cancer and end stage liver disease. It is also associated with increased cardiovascular and cancer related morbidity and mortality. The pathogenesis of non‐alcoholic fatty liver disease includes metabolic stress to the liver associated with insulin resistance with downstream cell stress from reactive oxygen species and unfolded protein response with activation of inflammatory and fibrotic pathways. There are currently no approved therapies for non‐alcoholic fatty liver disease. This review summarizes ongoing efforts to establish the treatment of non‐alcoholic steatohepatitis the progressive form of non‐alcoholic fatty liver disease. Therapies are currently directed towards improving the metabolic status of the liver, cell stress, apoptosis, inflammation or fibrosis. Several agents are now in pivotal trials and it is expected that the first therapies will be approved in 2‐3 years. [ABSTRACT FROM AUTHOR]

A longitudinal molecular model of the development and progression of nonalcoholic fatty liver disease (NAFLD) over time is lacking. We have recently validated a high fat/sugar water-induced animal (an isogenic strain of C57BL/6 J:129S1/SvImJ mice) model of NAFLD that closely mimics most aspects of human disease. The hepatic transcriptome of such mice with fatty liver (8 weeks), steatohepatitis with early fibrosis (16–24 weeks) and advanced fibrosis (52 weeks) after initiation of the diet was evaluated and compared to mice on chow diet. Fatty liver development was associated with transcriptional activation of lipogenesis, FXR-RXR, PPAR-α mediated lipid oxidation and oxidative stress pathways. With progression to steatohepatitis, metabolic pathway activation persisted with additional activation of IL-1/inhibition of RXR, granulocyte diapedesis/adhesion, Fc macrophage activation, prothrombin activation and hepatic stellate cell activation. Progression to advanced fibrosis was associated with dampening of metabolic, oxidative stress and cell stress related pathway activation but with further Fc macrophage activation, cell death and turnover and activation of cancer-related networks. The molecular progression of NAFLD involves a metabolic perturbation which triggers subsequent cell stress and inflammation driving cell death and turnover. Over time, inflammation and fibrogenic pathways become dominant while in advanced disease an inflammatory-oncogenic profile dominates. [ABSTRACT FROM AUTHOR]

Background and Aims Nonalcoholic fatty liver disease ( NAFLD) develops from a complex process, which includes changes in the liver methylome. Betaine plays a pivotal role in the regulation of methylogenesis. We performed a two-stage case-control study, which included patients with biopsy-proven NAFLD to explore circulating levels of betaine and its association with the histological spectrum. We also explored the association between a missense rs1805074, p.Ser646Pro variant in DMGDH (dimethylglycine dehydrogenase mitochondrial) and NAFLD severity (n=390). Results In the discovery phase (n=48), betaine levels were associated with the disease severity ( P=.0030), including liver inflammation (Spearman R:−0.51, P=.001), ballooning degeneration (R: −0.50, P=.01) and fibrosis (R: −0.54, P=.0008). Betaine levels were significantly decreased in nonalcoholic steatohepatitis ( NASH) in comparison with nonalcoholic fatty liver ( NAFL). Further replication (n=51) showed that betaine levels were associated with advanced NAFLD ( P=.0085), and patients with NASH had a 1.26-fold decrease in betaine levels compared with those with NAFL. The rs1805074 was significantly associated with the disease severity ( P=.011). Conclusion NAFLD severity is associated with a state of betaine-insufficiency. [ABSTRACT FROM AUTHOR]

Background & Aims In non-alcoholic fatty liver disease, presence of fibrosis is predictive of long-term liver-related complications. Currently, there are no reliable and non-invasive means of quantifying fibrosis in those with non-alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non-invasive models in predicting fibrosis in non-alcoholic fatty liver disease. Methods The accuracy of FibroMeter non-alcoholic fatty liver disease, fibrosis 4 and four other non-invasive models in predicting fibrosis in those with biopsy proven non-alcoholic fatty liver disease was compared. These models were constructed post hoc in patients who had necessary clinical information collected within 2 months of a liver biopsy. The areas under receiver operating characteristics curves were compared for each model using Delong analysis. Optimum cut-off for each model and fibrosis stage were calculated using the Youden index. Results The area under receiver operating characteristics curves for F ≥ 1 fibrosis for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease was 0.821 and 0.801 respectively. For F ≥ 3, the area under receiver operating characteristics curves was 0.866 for fibrosis 4 and 0.862 for FibroMeter non-alcoholic fatty liver disease. Delong analysis showed the area under receiver operating characteristics curves was statistically different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease compared with BARD, BAAT and aspartate aminotransferase:alanine aminotransferase ratio for F ≥ 1 and F ≥ 3. Area under receiver operating characteristics curves were significantly different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease for F ≥ 3 compared with non-alcoholic fatty liver disease fibrosis score. At a fixed sensitivity of 90%, FibroMeter non-alcoholic fatty liver disease had the highest specificity for F ≥ 1 (52.4%) and F ≥ 3 (63.8%). In contrast, at a fixed specificity of 90%, fibrosis 4 outperformed other models with a sensitivity of 60.2% for F ≥ 1 and 70.6% for F ≥ 3 fibrosis. Conclusion These non-invasive models of fibrosis can predict varying degrees of fibrosis from routinely collected clinical information in non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

The epidemic of obesity has resulted in a parallel incremental burden of nonalcoholic fatty liver disease (NAFLD) worldwide. Nonalcoholic fatty liver disease includes a spectrum of liver disease that ranges from simple fat accumulation in the liver to necroinflammation, fibrosis, cirrhosis, and hepatocellular carcinoma, which in essence represent the stages of the natural history of NAFLD. The rising prevalence of NAFLD globally may be accounted for by changes in dietary habits and an increase in sedentary lifestyle. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, is currently the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. In the current review, the authors discuss the uncertainty around the progression from NAFL (steatosis) to NASH (steatohepatitis), the undisputed progression of NASH to cirrhosis, and the risk factors that predispose to such progression. The published literature on the long-term cardiovascular complications and liver-related mortality of NAFLD is also discussed. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is a common cause of liver related morbidity and mortality. It is closely linked to underlying insulin resistance. It has recently been shown that bile acids modulate insulin signaling and can improve insulin resistance in cell based and animal studies. These effects are mediated in part by activation of farnesoid x receptors by bile acids. In human studies, FXR agonists improve insulin resistance and have recently been shown to improve NAFLD. The basis for the use of FXR agonists for the treatment of NAFLD and early human experience with such agents is reviewed in this paper. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and aims. The histologic hallmarks of chronic HCV include inflammation and fibrosis. The impact of interferon therapy on liver histology was evaluated. Material and methods. The study population consisted of 348 patients with chronic HCV who underwent a baseline liver biopsy, received either no treatment or a single course of interferon based therapy, were followed for 5 years without any treatment or additional treatment and then underwent a repeat liver biopsy. The patients were divided into 3 groups; deferred treatment (NoTx = 47), received interferon based therapy but failed to achieve SVR (NoSVR = 189) and achieved SVR (SVR = 112). Results. Patients with NoTx and NoSVR had significant increases in mean inflammation scores (from 4.3 to 6.3 and 5.4 to 6.7 respectively; p < 0.001 for both) and fibrosis scores (from 0.9 to 1.8 and 1.9 to 2.5; p < 0.001 for both). The amounts by which inflammation, fibrosis and rate of fibrosis progression increased were not significantly different between the two groups. Increases in total inflammation and the piecemeal necrosis sub-score over time were strongly associated with fibrosis progression. Patients with SVR had a significant decline in mean inflammation and fibrosis scores (from 6.7 to 2.2 and 3.3 to 1.8; p < 0.001 for both); 40% of patients resolved all fibrosis and 50% of patients resolved cirrhosis. Conclusion. Increases in inflammation are associated with fibrosis progression and in the absence of SVR interferon treatment does not appear to affect the long term natural history of this process. Patients with SVR have resolution of inflammation and fibrosis and many resolve cirrhosis. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is a spectrum that ranges from benign steatosis to steatohepatitis. It has become the most common cause of chronic liver disease, and yet there continues to be a lack of effective therapeutic options. This article reviews current concepts underlying the pathophysiological basis of nonalcoholic steatohepatitis from development of insulin resistance to the establishment of fibrosis. Then using a physiology-based approach, specific targeted therapeutics are reviewed along with their drawbacks. The evidence behind current therapies is based predominantly on small trials and, thus, no recommendations can be made until larger randomized trials are conducted. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The objective of this study was to determine the incidence and risk factors associated with new-onset and worsening portal hypertensive gastropathy (PHG) in patients with chronic hepatitis C (CHC).METHODS:A total of 831 CHC patients with bridging fibrosis or cirrhosis at the time of entry were prospectively monitored for clinical and histological liver disease progression while receiving either low-dose peginterferon α2a or no antiviral therapy in the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial. Upper endoscopy with grading of PHG was performed at baseline and at year 4 of the study. The presence and severity of PHG were determined using the NIEC (New Italian Endoscopy Conference) criteria, and worsening PHG was defined as a score increase of ≥1 point.RESULTS:During a median follow-up of 3.85 years, 50% of 514 subjects without PHG developed new-onset PHG, whereas 26% of 317 patients with baseline PHG had worsening PHG. Independent predictors of new-onset PHG included higher alkaline phosphatase and being diabetic, whereas predictors of worsening PHG were Caucasian race, lower albumin, as well as higher serum aspartate transaminase/alanine transaminase ratio and homeostatic model assessment levels. New-onset and worsening PHG were significantly associated with clinical and histological progression. They were also associated with new-onset and worsening gastroesophageal varices.CONCLUSIONS:New-onset and worsening PHG develop at a rate of 12.9% per year and 6.7% per year, respectively, in non-responder CHC patients with advanced fibrosis. If confirmed in other studies, endoscopic surveillance for PHG may need to be tailored to individual patient risk factors. [ABSTRACT FROM AUTHOR]

Hepatitis C is a common cause of chronic viral infection of the liver. It is associated with insulin resistance and the development of type 2 diabetes mellitus. It is also associated with the development of hepatic steatosis. The presence of hepatic steatosis is associated with an increased risk of having hepatic fibrosis. This is also associated with the severity of insulin resistance. These findings are specifically germane for those with genotype1 infection. Genotype 3 infection independently causes steatosis and successful treatment of the virus is followed by resolution of steatosis. In genotype 1 infection, the presence of hepatic steatosis is also a risk factor for failure to respond to pegylated interferon and ribavirin therapy. Unfortunately efforts to treat insulin resistance prior to antiviral therapy have not been very successful. Newer efforts focused on the role of specific micro RNAs in mediating the metabolic effects of hepatitis C virus infection may provide to ameliorate the metabolic risks of HCV infection. [ABSTRACT FROM AUTHOR]

Background & Aims: Fibrosis progression might be accelerated in patients who are coinfected with human immunodeficiency virus (HIV) and HCV (HIV/HCV). However, no studies have directly compared fibrosis progression by paired liver biopsy between patients infected with HIV and HCV versus those infected with only HCV. Methods: Liver biopsy samples were collected from patients with HIV/HCV (n = 306) and those with HCV; biopsies from 59 without a sustained virologic response (SVR) or cirrhosis were matched with those from patients with only HCV (controls) for initial fibrosis stage, demographics, and HCV treatment. For HIV/HCV patients, categorical variables at baseline and the area under the curve of continuous variables per unit time were analyzed for associations with fibrosis progression. Results: Liver biopsies from HIV/HCV patients had more piecemeal necrosis than controls (P = .001) and increased lobular inflammation (P = .002); HIV/HCV patients also had shorter intervals between liver biopsies (4.7 vs 5.9 years, P < .0001). Between the first and second biopsies, fibrosis remained unchanged or progressed 1 or 2 units in 55%, 18%, and 18% of HIV/HCV patients, respectively, compared with 45%, 30%, and 9% of controls. The fibrosis progression rate was similar between HIV/HCV and control patients (0.12 ± 0.40 vs 0.091 ± 0.29 units/y; P = .72). In paired biopsies from 66 patients, including those with SVR, there were no associations between fibrosis progression and demographics; numbers of CD4+ T cells; levels of aspartate aminotransferase or alanine aminotransferase; use of highly active antiretroviral therapy; response to HCV therapy (no treatment, SVR, or non-response); baseline levels of FIB-4; or histologic features including inflammation, fibrosis, or steatosis. Conclusions: On the basis of analysis of liver biopsy samples, fibrosis progression was similar between HIV/HCV-infected and HCV-infected patients; no clinical or laboratory parameters predicted disease progression. [Copyright &y& Elsevier]

OBJECTIVES:Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of metabolic syndrome (MetS) among adults. Emerging data suggest that MetS may be associated with nonalcoholic fatty liver disease (NAFLD) in children as well. We sought to determine whether MetS or its component features are associated with specific histological features or severity of NAFLD.METHODS:Children and adolescents aged 6–17 years enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with clinical data obtained within 6 months of liver biopsy were included. MetS was defined as the presence of three or more of the following features as determined by application of age-adjusted normative values: central obesity, dyslipidemia, impaired fasting glucose, and elevated blood pressure. Liver biopsies were evaluated by the Pathology Committee of the NASH CRN.RESULTS:Two hundred fifty four children were included in the analysis, of whom 65 (26%) met specified criteria for MetS. Among children with MetS, there is a higher proportion of females who were on average older in age and pubertal. The risk of MetS was greatest among those with severe steatosis (odds ratio (OR)=2.58 for grade 3 vs. grade 1 steatosis, P=0.001). The presence of hepatocellular ballooning was also significantly associated with MetS (OR=2.10, P=0.03). Those with advanced fibrosis (stage 3/4) had an OR for MetS of 3.21 (P=0.04) vs. those without fibrosis (stage 0). Borderline zone 1 or definite NASH patterns compared with “not NASH” were strongly associated with MetS (OR=4.44, P=0.005 and OR=4.07, P=0.002, respectively). The mean NAFLD Activity Score (NAS) was greater among children with MetS vs. those without (4.8 ± 1.4 vs. 4.3 ± 1.4, P=0.01). Central obesity was significantly associated with steatosis, fibrosis, hepatocellular ballooning, and NAFLD pattern. Insulin resistance was significantly associated with steatosis, fibrosis, hepatocellular ballooning, NAS, and NAFLD pattern.CONCLUSIONS:MetS is common among children with NAFLD and is associated with severity of steatosis, hepatocellular ballooning, NAS, NAFLD pattern, and the presence of advanced fibrosis. Individual MetS features, particularly central obesity and insulin resistance, were also associated with severity of NAFLD. MetS features should be considered in children with NAFLD as individually and collectively they help identify children with more advanced disease. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Results: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.) N Engl J Med 2010;362:1675-85. [ABSTRACT FROM AUTHOR]

Background & Aims: There is a need for a reliable and inexpensive noninvasive marker of hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We compared the performance of the FIB4 index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) with 6 other non-invasive markers of fibrosis in patients with NAFLD. Methods: Using a nation-wide database of 541 adults with NAFLD, jackknife-validated areas under receiver operating characteristic curves (AUROC) of FIB4 and 7 other markers were compared. The sensitivity at 90% specificity, 80% positive predictive value, and 90% negative predictive values were determined along with cutoffs for advanced fibrosis. Results: The median FIB4 score was 1.11 (interquartile range = 0.74–1.67). The jackknife-validated AUROC for FIB4 was 0.802 (95% confidence interval [CI], 0.758–0.847), which was higher than that of the NAFLD fibrosis score (0.768; 95% CI, 0.720–0.816; P = .09), Goteburg University Cirrhosis Index (0.743; 95% CI, 0.695–0.791; P < .01), AST:ALT ratio (0.742; 95% CI, 0.690–0.794; P < .015), AST:platelet ratio index (0.730; 95% CI, 0.681–0.779; P < .001), AST:platelet ratio (0.720; 95% CI, 0.669–0.770; P < .001), body mass index, AST:ALT, diabetes (BARD) score (0.70; P < .001), or cirrhosis discriminant score (0.666; 95% CI, 0.614–0.718; P < .001). For a fixed specificity of 90% (FIB4 = 1.93), the sensitivity in identifying advanced fibrosis was only 50% (95% CI, 46–55). A FIB4 ≥ 2.67 had an 80% positive predictive value and a FIB4 index ≤ 1.30 had a 90% negative predictive value. Conclusions: The FIB4 index is superior to 7 other noninvasive markers of fibrosis in patients with NAFLD; however its performance characteristics highlight the need for even better noninvasive markers. [Copyright &y& Elsevier]

Background & Aims: Standard treatment for autoimmune hepatitis (AIH) involves immune suppression by using prednisone alone or in combination with azathioprine (AZA). Although this regimen achieves remission in approximately 80%, some patients are intolerant or do not respond. Mycophenolate mofetil (MMF) is a potent immunosuppressant. However, its utility in AIH is not well-defined. Methods: We performed a retrospective longitudinal analysis of patients with AIH. Results: We identified 128 patients with AIH: mean age, 42.8 years; 83% female; 69% white. At presentation, median AST and ALT were 227 and 261 U/L, respectively, and bridging fibrosis and cirrhosis were present in 38% and 22%, respectively. Overall, 29 patients received MMF; 12 were switched to MMF after intolerance or nonresponse to prednisone ± AZA, whereas 17 received MMF ± prednisone as initial therapy. The main reasons for switching to MMF were nausea/vomiting (n = 4) and failure to normalize liver enzymes (n = 3). Ten of the 29 patients who received MMF therapy (34%) discontinued MMF as a result of side effects. Sixteen (84%) of the remaining 19 patients on MMF achieved remission, which closely matched the remission rate of those who remained on prednisone ± AZA (82%). The only independent clinical factor that predicted the eventual need for the use of MMF was absence of cirrhosis (P = .0067). Conclusions: (1) MMF was associated with a high rate of intolerance (34%). (2) In those who could tolerate it, it was associated with a high rate of remission (84%). (3) Absence of cirrhosis on presentation was the only independent factor associated with eventual need for MMF. [Copyright &y& Elsevier]

OBJECTIVES: The clinical significance of portal hypertensive gastropathy (PHG) in patients with compensated liver disease is not well established. The aim of this study was to determine the prevalence and correlates of PHG in a large cohort of patients with chronic hepatitis C virus (HCV) infection and bridging fibrosis/compensated cirrhosis entering the randomized phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial (HALT-C). METHODS: The presence and severity of PHG in 1,016 HCV patients with no prior history of gastrointestinal bleeding was determined at surveillance endoscopy using the New Italian Endoscopy Club criteria. RESULTS: Overall, 37% of HALT-C patients had PHG with 34% having mild and 3% with severe changes. The mucosal mosaic pattern was identified in 33%, red marks in 15%, and gastric antral vascular ectasia (GAVE) features in only 3%. Independent correlates of PHG included biochemical markers of liver disease severity (lower serum albumin, higher bilirubin), portal hypertension (lower platelet count), insulin resistance (higher glucose), and non-African American race. Independent correlates of GAVE included a history of smoking, nonsteroidal anti-inflammatory drugs (NSAIDs) use within the past year, and higher serum bilirubin and glucose levels. There was a strong positive association between the presence of PHG and esophageal varices ( p < 0.0001). CONCLUSIONS: PHG is associated with the histological and biochemical severity of liver disease in patients with HCV and advanced fibrosis but is mild in most patients. The clinical relevance of these findings will be further explored during the randomized phase of the HALT-C study. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH. The Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety. REGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis and ≥1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25 mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events. REGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes. ClinicalTrials.gov with the identifier NCT02548351. [ABSTRACT FROM AUTHOR]