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ObjectivesRecent studies show two-dimensional (2D)-magnetic resonance elastography (MRE) is accurate in diagnosing advanced fibrosis (stages 3 and 4) in nonalcoholic fatty liver disease (NAFLD) patients. Three-dimensional (3D)-MRE is a more advanced version of the technology that can image shear-wave fields in 3D of the entire liver. The aim of this study was to prospectively compare the diagnostic accuracy of 3D-MRE and 2D-MRE for diagnosing advanced fibrosis in patients with biopsy-proven NAFLD.MethodsThis cross-sectional analysis of a prospective study included 100 consecutive patients (56% women) with biopsy-proven NAFLD who also underwent MRE. Area under the receiver operating characteristic (AUROC) analysis was performed to assess the accuracy of 2D- and 3D-MRE in diagnosing advanced fibrosis.ResultsThe mean (±s.d.) of age and body mass index were 50.2 (±13.6) years and 32.1 (±5.0) kg/m(2), respectively. The AUROC for diagnosing advanced fibrosis was 0.981 for 3D-MRE at 40 Hz, 0.927 for 3D-MRE at 60 Hz (standard shear-wave frequency), and 0.921 for 2D-MRE at 60 Hz (standard shear-wave frequency). At a threshold of 2.43 kPa, 3D-MRE at 40 Hz had sensitivity 1.0, specificity 0.94, positive predictive value 0.72, and negative predictive value 1.0 for diagnosing advanced fibrosis. 3D-MRE at 40 Hz had significantly higher AUROC (P

© 2015 by the American Association for the Study of Liver Diseases. Magnetic resonance elastography (MRE), an advanced magnetic resonance-based imaging technique, and acoustic radiation force impulse (ARFI), an ultrasound-based imaging technique, have been shown to be accurate for diagnosing nonalcoholic fatty liver disease (NAFLD) fibrosis. However, no head-to-head comparisons between MRE and ARFI for diagnosing NAFLD fibrosis have been performed. We compared MRE versus ARFI head-to-head for diagnosing fibrosis in well-characterized patients with biopsy-proven NAFLD. This cross-sectional analysis of a prospective cohort involved 125 patients (54.4% female) who underwent MRE, ARFI, and contemporaneous liver biopsies scored using the Nonalcoholic Steatohepatitis Clinical Research Network histological scoring system. The performances of MRE versus ARFI for diagnosing fibrosis were evaluated using area under the receiver operating characteristic curves (AUROCs). The mean (± standard deviation) age and body mass index were 48.9 (±15.4) years and 31.8 (±7.0) kg/m2, respectively. For diagnosing any fibrosis (≥ stage 1), the MRE AUROC was 0.799 (95% confidence interval [CI] 0.723-0.875), significantly (P=0.012) higher than the ARFI AUROC of 0.664 (95% CI 0.568-0.760). In stratified analysis by presence or absence of obesity, MRE was superior to ARFI for diagnosing any fibrosis in obese patients (P

© 2015 John Wiley & Sons Ltd. Background Two-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. Aim To 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. Methods This 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. Results The mean (±s.d.) age and BMI were 51.3 (±14.0) years and 31.7 (±5.5) kg/m2respectively. 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. Conclusion Compared to clinical prediction rules, 2D-MRE provides significantly higher accuracy for the diagnosis of advanced fibrosis in NAFLD patients.

Author(s): Caussy, Cyrielle; Soni, Meera; Cui, Jeffrey; Bettencourt, Ricki; Schork, Nicholas; Chen, Chi-Hua; Ikhwan, Mahdi Al; Bassirian, Shirin; Cepin, Sandra; Gonzalez, Monica P; Mendler, Michel; Kono, Yuko; Vodkin, Irine; Mekeel, Kristin; Haldorson, Jeffrey; Hemming, Alan; Andrews, Barbara; Salotti, Joanie; Richards, Lisa; Brenner, David A; Sirlin, Claude B; Loomba, Rohit; Familial NAFLD Cirrhosis Research Consortium | Abstract: BackgroundThe risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis.MethodsThis is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE).ResultsThe prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8-126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1-146.1, P = 0.0438).ConclusionUsing a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients.Trial registrationUcsd irb140084.FundingNational Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.

Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and non-invasively in blood. Twenty-one patients with suspected NAFLD ingested heavy water (2H2O, 50 ml aliquots) 2-3 times daily for 3 to 5 weeks prior to a clinically indicated liver-biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on 2H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0-F4) and as having non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advancing disease stage (e.g. higher in NASH than NAFL, positive correlation with fibrosis score and liver stiffness) and correlated with hemoglobin A1C. In addition, plasma lumican FSR demonstrated a significant correlation with hepatic collagen FSR. Conclusion: Utilizing a well-characterized cohort of patients with biopsy-proven NAFLD, this study demonstrates that hepatic scar in NASH is actively remodeled even in advanced fibrosis, a disease that is generally regarded as static and slowly progressive. Moreover, hepatic collagen FSR correlates with established risks for fibrotic disease progression in NASH and plasma lumican FSR correlates with hepatic collagen FSR, suggesting applications as direct or surrogate markers, respectively, of hepatic fibrogenesis in humans. This article is protected by copyright. All rights reserved.

Background: Magnetic resonance imaging-estimated proton-density-fat-fraction (MRI-PDFF) has been shown to be a noninvasive, accurate and reproducible imaging-based biomarker for assessing steatosis and treatment response in nonalcoholic steatohepatitis (NASH) clinical trials. However, there are no data on the magnitude of MRI-PDFF reduction corresponding to histologic response in the setting of a NASH clinical trial. The aim of this study was to quantitatively compare the magnitude of MRI-PDFF reduction between histologic responders versus histologic nonresponders in NASH patients. Methods: This study is a secondary analysis of the MOZART trial, which included 50 patients with biopsy-proven NASH randomized to ezetimibe 10 mg/day orally or placebo for 24 weeks. The primary aim was to perform a head-to-head comparative analysis of histologic responders [defined as a ⩾2-point reduction in the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) without worsening fibrosis] versus nonresponders, and the corresponding quantitative change in liver fat content measured via MRI-PDFF. Results: Of the 35 patients who underwent paired liver biopsy and MRI-PDFF assessment at the beginning and end of treatment, 10 demonstrated a histologic response. Compared with histologic nonresponders, histologic responders had a statistically significant reduction in MRI-PDFF of −4.1% ± 4.9 versus −0.6 ± 4.1 ( p < 0.04) with a mean relative percent change of −29.3% ± 33.0 versus +2.0% ± 24.0 ( p < 0.004), respectively. Conclusions: Utilizing paired MRI-PDFF and liver histology data, we demonstrate that a relative reduction of 29% in liver fat on MRI-PDFF is associated with a histologic response in NASH. After external validation by independent research groups, these results can be incorporated into designing future NASH clinical trials, especially those utilizing change in hepatic fat quantified by MRI-PDFF, as a treatment endpoint.

Background & aimsUncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin vs. the efficacy of a placebo in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF).MethodsThis randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with prediabetes or early diabetes randomized to sitagliptin orally 100mg/day or placebo for 24weeks. Primary outcome was liver fat change measured by MRI-PDFF in colocalized regions of interest within each of nine liver segments. Additional advanced assessments included MR spectroscopy (MRS) for internal validation of MRI-PDFF's accuracy, and magnetic resonance elastography (MRE) and FIBROSpect® II to assess liver fibrosis.ResultsSitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF (mean difference between sitagliptin and placebo arms: -1.3%, p=0.4). Compared to baseline, there were no significant differences in end-of-treatment MRI-PDFF for sitagliptin (18.1% to 16.9%, p=0.27) or placebo (16.6% to 14.0%, p=0.07). The groups had no significant differences for changes in alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, homeostatic model assessment insulin resistance, and MRE-derived liver stiffness. In both groups at baseline and post-treatment, MRI-PDFF and MRS showed robust correlation coefficients ranging from r(2)=0.96 to r(2)=0.99 (p

Author(s): Cui, Jeffrey; Chen, Chi-Hua; Lo, Min-Tzu; Schork, Nicholas; Bettencourt, Ricki; Gonzalez, Monica P; Bhatt, Archana; Hooker, Jonathan; Shaffer, Katherine; Nelson, Karen E; Long, Michelle T; Brenner, David A; Sirlin, Claude B; Loomba, Rohit; For The Genetics Of Nafld In Twins Consortium | Abstract: Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging-proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m2 , respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging-proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716-1, P l 0.0001).ConclusionsGenes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547-1558).

Mitochondrial dysfunction is intimately involved in cardiovascular diseases. Mitochondrial membrane potential (DeltaPsi(m)) is coupled with oxidative phosphorylation to drive ATP synthesis. In this study, we examined the effect of physiological pulsatile shear stress (PSS) on DeltaPsi(m) and the role of Mn-SOD expression on DeltaPsi(m). Confluent human aortic endothelial cells (HAEC) were exposed to PSS, and DeltaPsi(m) was monitored using tetramethylrhodamine methyl ester (TMRM(+)), a mitochondrial membrane potential probe. PSS significantly increased DeltaPsi(m) and the change in DeltaPsi(m) was a dynamic process. DeltaPsi(m) returned to baseline level after PSS for 2h followed by static state for 4h. Mitochondrial Mn-SOD expression and activities were also significantly up-regulated in response to PSS. Silencing Mn-SOD attenuated PSS-mediated DeltaPsi(m) increase while adding Mn-SOD mimetic, MnTMPyP, increased DeltaPsi(m) to the similar extent as induced by PSS. Our findings suggest that PSS-increased mitochondrial DeltaPsi(m), in part, via Mn-SOD up-regulation.

© 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.

Introduction: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined. Materials and Methods: We conducted a retrospective analysis of 4019 patients treated with intravenous bisphosphonates between 1996 and 2004. Our goals were to estimate the frequency, understand the clinical presentation, and identify risk factors associated with ONJ development. Results: Sixteen of 1338 patients with breast cancer (1.2%) and 13 of 548 patients with multiple myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were significantly higher in patients with ONJ (p < 0.0001). Multivariate Cox proportional hazards regression analysis identified treatment with zoledronic acid (hazards ratio [HR], 15.01; 95% CI: 2.41–93.48; p = 0.0037), treatment with pamidronate followed by zoledronic acid (HR, 4.00; 95% CI: 0.86–18.70; p = 0.078), and dental extractions (HR, 53.19; 95% CI: 18.20–155.46; p < 0.0001) as significant risks for ONJ in breast cancer. In multiple myeloma, dental extractions (HR, 9.78; 95% CI: 3.07–31.14; p = 0.0001) and osteoporosis (HR, 6.11; 95% CI: 1.56–23.98; p = 0.0095) were significant risk factors while controlling for bisphosphonate therapy. Thirteen of 29 patients were followed for a median of 17.1 mo (range, 7–67 mo); lesions healed in 3 patients during this period. Conclusions: ONJ is an uncommon but long-lasting disorder that occurs mainly in breast cancer and multiple myeloma patients treated with intravenous bisphosphonates. High cumulative doses of bisphosphonates, poor oral health, and dental extractions may be significant risk factors for ONJ development. ONJ resolved in 23% of patients with conservative therapy.