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The gut microbiome has shown promise as a predictive biomarker for various diseases. However, the potential of gut microbiota for prospective risk prediction of liver disease has not been assessed. Here, we utilized shallow shotgun metagenomic sequencing of a large population-based cohort (N > 7,000) with ∼15 years of follow-up in combination with machine learning to investigate the predictive capacity of gut microbial predictors individually and in conjunction with conventional risk factors for incident liver disease. Separately, conventional and microbial factors showed comparable predictive capacity. However, microbiome augmentation of conventional risk factors using machine learning significantly improved the performance. Similarly, disease-free survival analysis showed significantly improved stratification using microbiome-augmented models. Investigation of predictive microbial signatures revealed previously unknown taxa for liver disease, as well as those previously associated with hepatic function and disease. This study supports the potential clinical validity of gut metagenomic sequencing to complement conventional risk factors for prediction of liver diseases.

BACKGROUND Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODS In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTS A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P=0.007; 800-mg dose vs. placebo, 48% vs. 33%, P=0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibran

Nonalcoholic fatty liver disease (NALFD) is now a leading cause of chronic liver disease worldwide, in part, as a consequence of rapidly rising levels of obesity and metabolic syndrome and is a major risk factor for cirrhosis, hepatocellular carcinoma, and liver-related mortality. From NAFLD stems a myriad of clinical challenges related to both diagnosis and management. A growing body of evidence suggests an intricate linkage between the gut microbiome and the pathogenesis of NAFLD. We highlight how our current knowledge of the gut-liver axis in NAFLD may be leveraged to develop gut microbiome-based personalized approaches for disease management, including its use as a non-invasive biomarker for diagnosis and staging, as a target for therapeutic modulation, and as a marker of drug response. We will also discuss current limitations of these microbiome-based approaches. Ultimately, a better understanding of microbiota-host interactions in NAFLD will inform the development of novel preventative strategies and precise therapeutic targets.

Fatty liver disease is the most common liver disease in the world. Its connection with the gut microbiome has been known for at least 80 y, but this association remains mostly unstudied in the general population because of underdiagnosis and small sample sizes. To address this knowledge gap, we studied the link between the Fatty Liver Index (FLI), a well-established proxy for fatty liver disease, and gut microbiome composition in a representative, ethnically homogeneous population sample of 6,269 Finnish participants. We based our models on biometric covariates and gut microbiome compositions from shallow metagenome sequencing. Our classification models could discriminate between individuals with a high FLI (≥60, indicates likely liver steatosis) and low FLI (<60) in internal cross-region validation, consisting of 30% of the data not used in model training, with an average AUC of 0.75 and AUPRC of 0.56 (baseline at 0.30). In addition to age and sex, our models included differences in 11 microbial groups from class Clostridia, mostly belonging to orders Lachnospirales and Oscillospirales. Our models were also predictive of the high FLI group in a different Finnish cohort, consisting of 258 participants, with an average AUC of 0.77 and AUPRC of 0.51 (baseline at 0.21). Pathway analysis of representative genomes of the positively FLI-associated taxa in (NCBI) Clostridium subclusters IV and XIVa indicated the presence of, e.g., ethanol fermentation pathways. These results support several findings from smaller case-control studies, such as the role of endogenous ethanol producers in the development of the fatty liver.

Nonalcoholic fatty liver disease (NALFD) is now a leading cause of chronic liver disease worldwide, in part, as a consequence of rapidly rising levels of obesity and metabolic syndrome and is a major risk factor for cirrhosis, hepatocellular carcinoma, and liver-related mortality. From NAFLD stems a myriad of clinical challenges related to both diagnosis and management. A growing body of evidence suggests an intricate linkage between the gut microbiome and the pathogenesis of NAFLD. We highlight how our current knowledge of the gut-liver axis in NAFLD may be leveraged to develop gut microbiome-based personalized approaches for disease management, including its use as a non-invasive biomarker for diagnosis and staging, as a target for therapeutic modulation, and as a marker of drug response. We will also discuss current limitations of these microbiome-based approaches. Ultimately, a better understanding of microbiota-host interactions in NAFLD will inform the development of novel preventative strategies and precise therapeutic targets.

Background: In NASH, disease progression results from a complex interplay of intra- and extra-hepatic processes encompassing metabolic (adipose tissue dysfunction, insulin resistance), inflammatory and fibrogenic pathways. Successful treatment most likely needs a multi-targeted approach Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors with key regulatory functions in metabolism, inflammation and fibrogenesis. Lanifibranor is a well-balanced agonist of the 3 PPAR isotypes with a broader and superior efficacy over single and dual PPAR agonists in various pre-clinical models Methods: NATIVE (NCT03008070) was a phase 2b double-blind randomisedcontrolled trial of lanifibranor in patients with biopsy proven, non-cirrhotic, highly active NASH (a SAF Activity score of 3-4) Patients were randomised 1:1:1 to receive once daily placebo, 800 or 1200 mg of lanifibranor for 24 weeks. The primary endpoint was a >=2 point reduction in SAF Activity score. Secondary endpoints were NASH resolution and fibrosis regression Results: 247 patients were randomised: mean age 54y, mean BMI 32 9 kg/m2, 42% males, 42% diabetes, 76% F2/F3 and 73% NAFLD Activity Score (NASH CRN) >=6. Lanifibranor met the primary endpoint at 1200 mg/day and also all key secondary endpoints including: NASH resolution without worsening of fibrosis and regression of >=1 stage of fibrosis without worsening of NASH (Table). The combined endpoint of resolution of NASH plus regression of fibrosis was also significantly met for both treatment arms. Both doses significantly and sustainably improved liver enzymes starting at week 4. In diabetics, both doses significantly reduced HbA1c by > 0.5%. Both doses also equally and significantly increased HDL cholesterol and decreased serum triglycerides Lanifibranor showed a favourable safety profile with a low dropout rate (<5%) of for adverse events comparable to placebo A mean weight increase of 2 4 and 2 7 kg in the 800 and 1200 mg arms respectively was

Background: Biopsy remains the gold standard for assessment of NAFLD severity and treatment efficacy. Semi-quantitative scoring of steatosis, ballooning, lobular inflammation and fibrosis are the most discriminative characteristics NAFLD Activity Score (NAS) by NASH CRN is most frequently used to describe steatohepatitis severity but combines steatosis and activity SAF scoring separately reports steatosis and activity, gives equal weight to ballooning and lobular inflammation and defines ballooning based on cell size, thereby potentially more accurately and reproducibly scoring activity. Lanifibranor is a panPPAR agonist tested in Phase 2b (NATIVE, NCT03008070) for non-cirrhotic NASH with highly significant results on resolution of NASH without worsening of fibrosis, regression of fibrosis of >=1 point without worsening of fibrosis, and on the combination of resolution of NASH and fibrosis regression. Main inclusion criterion was a SAF activity score (A) >=3 (with a SAF A reduction of >=2 as primary efficacy endpoint). We here report the histological characteristics of the patients screened for NATIVE based on this innovative inclusion criterion Methods: Liver biopsies of patients screened for NATIVE were centrally scored by a single experienced pathologist Biopsy could be performed up to 6 months before screening on the condition of metabolic stability or was obtained during screening Results: Out of 868 patients screened, 554 had biopsies of sufficient quality for reading Results are summarised in the table 284 corresponded to the SAF inclusion criteria A>=3 and F<4, all of whom had NASH and NAS>=4; 94 had NASH with NAS>=4 but SAF A<3. In the 284 patients with A>=3, the % of NAS>5 was high (75%) with a mean NAS of 5 9 +/- 1 0 compared to those with A<3, in whom there was no patient with NAS >5 and mean NAS was 4.5 +/- 0.5. Mean fibrosis score was 2.1+/-0.8 vs. 1.1+/-0.8, with 78% F2-F3 vs. only 29% in A>=3 vs. A<3 respectively Mean steatosis score was comparable

Background: In NASH, disease progression results from a complex interplay of intra- and extra-hepatic processes encompassing metabolic (adipose tissue dysfunction, insulin resistance), inflammatory and fibrogenic pathways. Successful treatment most likely needs a multi-targeted approach Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors with key regulatory functions in metabolism, inflammation and fibrogenesis. Lanifibranor is a well-balanced agonist of the 3 PPAR isotypes with a broader and superior efficacy over single and dual PPAR agonists in various pre-clinical models Methods: NATIVE (NCT03008070) was a phase 2b double-blind randomisedcontrolled trial of lanifibranor in patients with biopsy proven, non-cirrhotic, highly active NASH (a SAF Activity score of 3-4) Patients were randomised 1:1:1 to receive once daily placebo, 800 or 1200 mg of lanifibranor for 24 weeks. The primary endpoint was a >=2 point reduction in SAF Activity score. Secondary endpoints were NASH resolution and fibrosis regression Results: 247 patients were randomised: mean age 54y, mean BMI 32 9 kg/m2, 42% males, 42% diabetes, 76% F2/F3 and 73% NAFLD Activity Score (NASH CRN) >=6. Lanifibranor met the primary endpoint at 1200 mg/day and also all key secondary endpoints including: NASH resolution without worsening of fibrosis and regression of >=1 stage of fibrosis without worsening of NASH (Table). The combined endpoint of resolution of NASH plus regression of fibrosis was also significantly met for both treatment arms. Both doses significantly and sustainably improved liver enzymes starting at week 4. In diabetics, both doses significantly reduced HbA1c by > 0.5%. Both doses also equally and significantly increased HDL cholesterol and decreased serum triglycerides Lanifibranor showed a favourable safety profile with a low dropout rate (<5%) of for adverse events comparable to placebo A mean weight increase of 2 4 and 2 7 kg in the 800 and 1200 mg arms respectively was

Background: Biopsy remains the gold standard for assessment of NAFLD severity and treatment efficacy. Semi-quantitative scoring of steatosis, ballooning, lobular inflammation and fibrosis are the most discriminative characteristics NAFLD Activity Score (NAS) by NASH CRN is most frequently used to describe steatohepatitis severity but combines steatosis and activity SAF scoring separately reports steatosis and activity, gives equal weight to ballooning and lobular inflammation and defines ballooning based on cell size, thereby potentially more accurately and reproducibly scoring activity. Lanifibranor is a panPPAR agonist tested in Phase 2b (NATIVE, NCT03008070) for non-cirrhotic NASH with highly significant results on resolution of NASH without worsening of fibrosis, regression of fibrosis of >=1 point without worsening of fibrosis, and on the combination of resolution of NASH and fibrosis regression. Main inclusion criterion was a SAF activity score (A) >=3 (with a SAF A reduction of >=2 as primary efficacy endpoint). We here report the histological characteristics of the patients screened for NATIVE based on this innovative inclusion criterion Methods: Liver biopsies of patients screened for NATIVE were centrally scored by a single experienced pathologist Biopsy could be performed up to 6 months before screening on the condition of metabolic stability or was obtained during screening Results: Out of 868 patients screened, 554 had biopsies of sufficient quality for reading Results are summarised in the table 284 corresponded to the SAF inclusion criteria A>=3 and F<4, all of whom had NASH and NAS>=4; 94 had NASH with NAS>=4 but SAF A<3. In the 284 patients with A>=3, the % of NAS>5 was high (75%) with a mean NAS of 5 9 +/- 1 0 compared to those with A<3, in whom there was no patient with NAS >5 and mean NAS was 4.5 +/- 0.5. Mean fibrosis score was 2.1+/-0.8 vs. 1.1+/-0.8, with 78% F2-F3 vs. only 29% in A>=3 vs. A<3 respectively Mean steatosis score was comparable

BACKGROUND:In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. AIMS:Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. METHODS:The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies. Weight loss was defined as a relative decline from baseline of 2% or more at treatment end. RESULTS:Weight loss occurred in 44% (45/102) of OCA and 32% (31/98) of placebo-treated patients (P = 0.08). The NAFLD Activity score (NAS) improved more in those with than without weight loss in both the OCA- (-2.4 vs -1.2, P<0.001) and placebo-treated patients (-1.2 vs -0.5, P = 0.03). ALT levels also improved in those with vs without weight loss in OCA- (-43 vs -34 U/L, P = 0.12) and placebo-treated patients (-29 vs -10 U/L, P = 0.02). However, among those who lost weight, OCA was associated with opposite effects from placebo on changes in alkaline phosphatase (+21 vs -12 U/L, P<0.001), total (+13 vs -14 mg/dL, P = 0.02) and LDL cholesterol (+18 vs -12 mg/dL, P = 0.01), and HbA1c (+0.1 vs -0.4%, P = 0.01). CONCLUSIONS:OCA leads to weight loss in up to 44% of patients with NASH, and OCA therapy and weight loss have additive benefits on serum aminotransferases and histology. However, favourable effects of weight loss on alkaline phosphatase, lipids and blood glucose seen in placebo-treated patients were absent or reversed on OCA treatment. These findings stress the importance of assessing concomitant metabolic effects of new therapies of NASH. Clinical trial number: NCT01265498.

Chronic liver disease is rising in western countries and liver cirrhosis is the 12th leading cause of death worldwide. Simultaneously, use of gastric acid suppressive medications is increasing. Here, we show that proton pump inhibitors promote progression of alcoholic liver disease, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis in mice by increasing numbers of intestinal Enterococcus spp. Translocating enterococci lead to hepatic inflammation and hepatocyte death. Expansion of intestinal Enterococcus faecalis is sufficient to exacerbate ethanol-induced liver disease in mice. Proton pump inhibitor use increases the risk of developing alcoholic liver disease among alcohol-dependent patients. Reduction of gastric acid secretion therefore appears to promote overgrowth of intestinal Enterococcus, which promotes liver disease, based on data from mouse models and humans. Recent increases in the use of gastric acid-suppressive medications might contribute to the increasing incidence of chronic liver disease.

Chronic liver disease is rising in western countries and liver cirrhosis is the 12th leading cause of death worldwide. Simultaneously, use of gastric acid suppressive medications is increasing. Here, we show that proton pump inhibitors promote progression of alcoholic liver disease, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis in mice by increasing numbers of intestinal Enterococcus spp. Translocating enterococci lead to hepatic inflammation and hepatocyte death. Expansion of intestinal Enterococcus faecalis is sufficient to exacerbate ethanol-induced liver disease in mice. Proton pump inhibitor use increases the risk of developing alcoholic liver disease among alcohol-dependent patients. Reduction of gastric acid secretion therefore appears to promote overgrowth of intestinal Enterococcus, which promotes liver disease, based on data from mouse models and humans. Recent increases in the use of gastric acid-suppressive medications might contribute to the increasing incidence of chronic liver disease.

BackgroundLimited data exist on the clinical presentation and non-invasive detection of liver fibrosis in adults with homozygous Z genotype alpha-1 antitrypsin (AAT) deficiency.AimsTo compare demographic, biochemical, histological and imaging data of AAT deficient patients to normal-control and biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients, and to assess the diagnostic accuracy of magnetic resonance elastography (MRE) in detecting fibrosis in AAT deficiency.MethodsStudy includes 33 participants, 11 per group, who underwent clinical research evaluation, liver biopsy (AAT and NAFLD groups), and MRE. Histological fibrosis was quantified using a modified Ishak 6-point scale and liver stiffness by MRE. Diagnostic performance of MRE in detecting fibrosis was assessed by receiver operating characteristic (ROC) analysis.ResultsMean (±s.d.) of age and BMI of normal-control, AAT and NAFLD groups was 57 (±19), 57 (±18), and 57 (±13) years, and 22.7 (±2.5), 24.8 (±4.0) and 31.0 (±5.1) kg/m(2) respectively. Serum ALT [mean ± s.d.] was similar within normal-control [16.4 ± 4.0] and AAT groups [23.5 ± 10.8], but was significantly lower in AAT than NAFLD even after adjustment for stage of fibrosis (P < 0.05, P = 0.0172). For fibrosis detection, MRE-estimated stiffness had an area under the ROC curve of 0.90 (P < 0.0001); an MRE threshold of ≥3.0 kPa provided 88.9% accuracy, with 80% sensitivity and 100% specificity to detect presence of any fibrosis (stage ≥1).ConclusionsThis pilot prospective study suggests magnetic resonance elastography may be accurate for identifying fibrosis in patients with alpha-1 antitrypsin deficiency. Larger validation studies are warranted.

BackgroundCurrent guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis.AimTo assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness.MethodsWe performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE.ResultsMean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m(2) , respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger (P = 0.028) and had higher mean BMI (P = 0.0008), waist circumference (P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase.ConclusionsThis proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort.

BackgroundCurrent guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis.AimTo assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness.MethodsWe performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE.ResultsMean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m(2) , respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger (P = 0.028) and had higher mean BMI (P = 0.0008), waist circumference (P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase.ConclusionsThis proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort.

BackgroundLimited data exist on the clinical presentation and non-invasive detection of liver fibrosis in adults with homozygous Z genotype alpha-1 antitrypsin (AAT) deficiency.AimsTo compare demographic, biochemical, histological and imaging data of AAT deficient patients to normal-control and biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients, and to assess the diagnostic accuracy of magnetic resonance elastography (MRE) in detecting fibrosis in AAT deficiency.MethodsStudy includes 33 participants, 11 per group, who underwent clinical research evaluation, liver biopsy (AAT and NAFLD groups), and MRE. Histological fibrosis was quantified using a modified Ishak 6-point scale and liver stiffness by MRE. Diagnostic performance of MRE in detecting fibrosis was assessed by receiver operating characteristic (ROC) analysis.ResultsMean (±s.d.) of age and BMI of normal-control, AAT and NAFLD groups was 57 (±19), 57 (±18), and 57 (±13) years, and 22.7 (±2.5), 24.8 (±4.0) and 31.0 (±5.1) kg/m(2) respectively. Serum ALT [mean ± s.d.] was similar within normal-control [16.4 ± 4.0] and AAT groups [23.5 ± 10.8], but was significantly lower in AAT than NAFLD even after adjustment for stage of fibrosis (P < 0.05, P = 0.0172). For fibrosis detection, MRE-estimated stiffness had an area under the ROC curve of 0.90 (P < 0.0001); an MRE threshold of ≥3.0 kPa provided 88.9% accuracy, with 80% sensitivity and 100% specificity to detect presence of any fibrosis (stage ≥1).ConclusionsThis pilot prospective study suggests magnetic resonance elastography may be accurate for identifying fibrosis in patients with alpha-1 antitrypsin deficiency. Larger validation studies are warranted.

BackgroundNon-alcoholic fatty liver disease (NAFLD) can lead to non-alcoholic steatohepatitis (NASH) and cirrhosis. Fibrosis predicts worse outcomes and mortality. New treatments targeting fibrosis are being investigated to reverse disease progression.AimTo review the new pipeline therapeutic agents targeting fibrosis in NASH patients, with particular focus on clinical trials in which reversing fibrosis and portal hypertension are the primary outcomes.MethodsThe literature was searched in PubMed between January 2000 and January 2016 using search terms non-alcoholic fatty liver disease and NASH, with filters of 'English language'. We focused on fibrosis improvement as the key outcome. We also searched the ClinicalTrials.gov for promising agents that target fibrosis in NASH patients.ResultsSignificant advances have been made on approaches targeting fibrosis in NASH patients. Many therapeutic agents are already in development, some of which have shown promising results in preclinical and phase I studies. Novel therapies have entered phase II and III studies targeting fibrosis reversal and/or improvement in portal hypertension. Innovative studies have also started looking into combining these agents, aiming at different mechanisms to maximise therapeutic outcomes. We found five clinical trials in phase II and one in phase III focusing on fibrosis in NASH patients as key outcomes. One of the phase II trials is using combination therapy to target fibrosis.ConclusionsOngoing research studies are already investigating new pathways aimed at reversing fibrosis in NASH patients. Novel therapeutic agents are in development and are expected to offer unique options to NASH patients with advanced fibrosis.

Purpose: Determine intra- and inter-examination repeatability of magnitude-based magnetic resonance imaging (MRI-M), complex-based magnetic resonance imaging (MRI-C), and magnetic resonance spectroscopy (MRS) at 3T for estimating hepatic proton density fat fraction (PDFF), and using MRS as a reference, confirm MRI-M and MRI-C accuracy. Methods: Twenty-nine overweight and obese pediatric (n = 20) and adult (n = 9) subjects (23 male, 6 female) underwent three same-day 3T MR examinations. In each examination MRI-M, MRI-C, and single-voxel MRS were acquired three times. For each MRI acquisition, hepatic PDFF was estimated at the MRS voxel location. Intra- and inter-examination repeatability were assessed by computing standard deviations (SDs) and intra-class correlation coefficients (ICCs). Aggregate SD was computed for each method as the square root of the average of first repeat variances. MRI-M and MRI-C PDFF estimation accuracy was assessed using linear regression with MRS as a reference. Results: For MRI-M, MRI-C, and MRS acquisitions, respectively, mean intra-examination SDs were 0.25%, 0.42%, and 0.49%; mean intra-examination ICCs were 0.999, 0.997, and 0.995; mean inter-examination SDs were 0.42%, 0.45%, and 0.46%; and inter-examination ICCs were 0.995, 0.992, and 0.990. Aggregate SD for each method was <0.9%. Using MRS as a reference, regression slope, intercept, average bias, and R2, respectively, for MRI-M were 0.99%, 1.73%, 1.61%, and 0.986, and for MRI-C were 0.96%, 0.43%, 0.40%, and 0.991. Conclusion: MRI-M, MRI-C, and MRS showed high intra- and inter-examination hepatic PDFF estimation repeatability in overweight and obese subjects. Longitudinal hepatic PDFF change >1.8% (twice the maximum aggregate SD) may represent real change rather than measurement imprecision. Further research is needed to assess whether examinations performed on different days or with different MR technologists affect repeatability of MRS voxel placement an

© 2015 John Wiley & Sons Ltd. Background Current guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis. Aim To assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness. Methods We performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE. Results Mean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m2, respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger (P = 0.028) and had higher mean BMI (P = 0.0008), waist circumference (P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase. Conclusions This proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort.

BackgroundTwo-dimensional magnetic resonance elastography (2D-MRE) is an advanced magnetic resonance method with high diagnostic accuracy for predicting advanced fibrosis in non-alcoholic fatty liver disease (NAFLD) patients. However, no prospective, head-to-head comparisons between 2D-MRE and clinical prediction rules (CPRs) have been performed in patients with biopsy-proven NAFLD.AimTo compare the diagnostic utility of 2D-MRE against that of eight CPRs (AST:ALT ratio, APRI, BARD, FIB-4, NAFLD Fibrosis Score, Bonacini cirrhosis discriminant score, Lok Index and NASH CRN model) for predicting advanced fibrosis in a prospective cohort with paired liver biopsy as the gold standard.MethodsThis is a cross-sectional analysis of a prospective study of 102 patients (58.8% women) with biopsy-proven NAFLD, 2D-MRE and clinical research assessment within 90 days of biopsy. Receiver operating characteristic (ROC) analysis was performed to assess the performance of 2D-MRE and CPRs for predicting advanced fibrosis.ResultsThe mean (±s.d.) age and BMI were 51.3 (±14.0) years and 31.7 (±5.5) kg/m(2) respectively. 48, 26, 9, 13 and 6 patients had stage 0, 1, 2, 3 and 4 fibrosis respectively. The area under ROC curve (AUROC) was 0.957 for 2D-MRE and between 0.796 and 0.861 for the CPRs. FIB-4 was the best-performing CPR at predicting advanced fibrosis with AUROC of 0.861. In head-to-head comparisons using the DeLong test, 2D-MRE had significantly better AUROC (P < 0.05) than each CPR for predicting advanced fibrosis.ConclusionCompared to clinical prediction rules, 2D-MRE provides significantly higher accuracy for the diagnosis of advanced fibrosis in NAFLD patients.

© 2015 John Wiley & Sons Ltd. Background Current guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis. Aim To assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness. Methods We performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE. Results Mean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m2, respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger (P = 0.028) and had higher mean BMI (P = 0.0008), waist circumference (P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase. Conclusions This proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort.

Purpose: Determine intra- and inter-examination repeatability of magnitude-based magnetic resonance imaging (MRI-M), complex-based magnetic resonance imaging (MRI-C), and magnetic resonance spectroscopy (MRS) at 3T for estimating hepatic proton density fat fraction (PDFF), and using MRS as a reference, confirm MRI-M and MRI-C accuracy. Methods: Twenty-nine overweight and obese pediatric (n = 20) and adult (n = 9) subjects (23 male, 6 female) underwent three same-day 3T MR examinations. In each examination MRI-M, MRI-C, and single-voxel MRS were acquired three times. For each MRI acquisition, hepatic PDFF was estimated at the MRS voxel location. Intra- and inter-examination repeatability were assessed by computing standard deviations (SDs) and intra-class correlation coefficients (ICCs). Aggregate SD was computed for each method as the square root of the average of first repeat variances. MRI-M and MRI-C PDFF estimation accuracy was assessed using linear regression with MRS as a reference. Results: For MRI-M, MRI-C, and MRS acquisitions, respectively, mean intra-examination SDs were 0.25%, 0.42%, and 0.49%; mean intra-examination ICCs were 0.999, 0.997, and 0.995; mean inter-examination SDs were 0.42%, 0.45%, and 0.46%; and inter-examination ICCs were 0.995, 0.992, and 0.990. Aggregate SD for each method was <0.9%. Using MRS as a reference, regression slope, intercept, average bias, and R2, respectively, for MRI-M were 0.99%, 1.73%, 1.61%, and 0.986, and for MRI-C were 0.96%, 0.43%, 0.40%, and 0.991. Conclusion: MRI-M, MRI-C, and MRS showed high intra- and inter-examination hepatic PDFF estimation repeatability in overweight and obese subjects. Longitudinal hepatic PDFF change >1.8% (twice the maximum aggregate SD) may represent real change rather than measurement imprecision. Further research is needed to assess whether examinations performed on different days or with different MR technologists affect repeatability of MRS voxel placement an

BackgroundTwo-dimensional magnetic resonance elastography (2D-MRE) is an advanced magnetic resonance method with high diagnostic accuracy for predicting advanced fibrosis in non-alcoholic fatty liver disease (NAFLD) patients. However, no prospective, head-to-head comparisons between 2D-MRE and clinical prediction rules (CPRs) have been performed in patients with biopsy-proven NAFLD.AimTo compare the diagnostic utility of 2D-MRE against that of eight CPRs (AST:ALT ratio, APRI, BARD, FIB-4, NAFLD Fibrosis Score, Bonacini cirrhosis discriminant score, Lok Index and NASH CRN model) for predicting advanced fibrosis in a prospective cohort with paired liver biopsy as the gold standard.MethodsThis is a cross-sectional analysis of a prospective study of 102 patients (58.8% women) with biopsy-proven NAFLD, 2D-MRE and clinical research assessment within 90 days of biopsy. Receiver operating characteristic (ROC) analysis was performed to assess the performance of 2D-MRE and CPRs for predicting advanced fibrosis.ResultsThe mean (±s.d.) age and BMI were 51.3 (±14.0) years and 31.7 (±5.5) kg/m(2) respectively. 48, 26, 9, 13 and 6 patients had stage 0, 1, 2, 3 and 4 fibrosis respectively. The area under ROC curve (AUROC) was 0.957 for 2D-MRE and between 0.796 and 0.861 for the CPRs. FIB-4 was the best-performing CPR at predicting advanced fibrosis with AUROC of 0.861. In head-to-head comparisons using the DeLong test, 2D-MRE had significantly better AUROC (P < 0.05) than each CPR for predicting advanced fibrosis.ConclusionCompared to clinical prediction rules, 2D-MRE provides significantly higher accuracy for the diagnosis of advanced fibrosis in NAFLD patients.

BackgroundPentraxin-2 (PTX-2), a serum protein, inhibits inflammation and fibrosis, and recombinant PTX-2 is being tested as an anti-fibrotic agent.AimTo evaluate the association between serum PTX-2 levels and fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD).MethodsSerum pentraxin-2 levels were compared between four groups of well-characterised patients including NAFLD with no fibrosis, NAFLD with mild-moderate fibrosis (stage 1-2), NAFLD with advanced fibrosis (stage 3-4), and age-sex matched non-NAFLD controls.ResultsSixty subjects were included in the study. The mean age was 58.9 years, 68% were male and 58% were Caucasian. In univariate analysis, serum PTX-2 levels significantly decreased from non-NAFLD controls to mild NAFLD with no fibrosis, to NAFLD with mild-moderate fibrosis and were lowest in patients with NAFLD and advanced fibrosis, in a dose-dependent manner (P < 0.0001). In multivariable-adjusted analyses controlling for age, sex, albumin, and CRP, the results remained consistent and statistically significant. Serum PTX-2 level had an AUROC of 0.84 (95% CI: 0.71-0.97) for the diagnosis of NAFLD, and an AUROC of 0.77 (95% CI: 0.65-0.90) for the diagnosis of advanced fibrosis in NAFLD. Serum PTX-2 levels also decreased with increasing liver stiffness as estimated by magnetic resonance elastography (r = -0.31, P = 0.02).ConclusionsPTX-2 levels are significantly lower in patients with NAFLD compared to non-NAFLD controls, and decline further in patients with advanced fibrosis. PTX-2 may therefore be both a biomarker of disease and a potential target for anti-fibrotic therapy with the recombinant pentraxin-2.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. It is considered the hepatic manifestation of the metabolic syndrome. Approximately a third of adults in the United States have NAFLD. While the majority of individuals with NAFLD do not develop progressive liver disease and have been classified as having non-alcoholic fatty liver (NAFL), a subset of patients with NAFLD have the progressive form termed non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis, and hepatocellular carcinoma. Liver biopsy evaluation is the gold standard for the detection of NASH. It is impractical, unnecessary and cost prohibitive to subject all patients with NAFLD to a liver biopsy evaluation. Here in this review, we discuss our approach to clinical risk stratification of patients with NAFLD and who should be referred for a liver biopsy based upon the likelihood of finding the presence of NASH and/or advanced fibrosis on liver biopsy.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. It is considered the hepatic manifestation of the metabolic syndrome. Approximately a third of adults in the United States have NAFLD. While the majority of individuals with NAFLD do not develop progressive liver disease and have been classified as having non-alcoholic fatty liver (NAFL), a subset of patients with NAFLD have the progressive form termed non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis, and hepatocellular carcinoma. Liver biopsy evaluation is the gold standard for the detection of NASH. It is impractical, unnecessary and cost prohibitive to subject all patients with NAFLD to a liver biopsy evaluation. Here in this review, we discuss our approach to clinical risk stratification of patients with NAFLD and who should be referred for a liver biopsy based upon the likelihood of finding the presence of NASH and/or advanced fibrosis on liver biopsy.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.