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Patients with non-alcoholic fatty liver disease (NAFLD) and significant fibrosis (fibrosis stage ≥2) are candidates for pharmacological trials. The aim of this study was to perform a head-to-head comparison of the diagnostic test characteristics of three non-invasive stiffness-based models including MEFIB (magnetic resonance elastography [MRE] plus FIB-4), MAST (magnetic resonance imaging [MRI]-aspartate aminotransferase [AST]), and FAST (FibroScan-AST) for detecting significant fibrosis.This prospective study included 563 patients with biopsy-proven NAFLD undergoing contemporaneous MRE, MRI proton density fat fraction (MRI-PDFF) and FibroScan from two prospective cohorts derived from Southern California and Japan. Diagnostic performances of models were evaluated by area under the receiver-operating characteristic curve (AUC).The mean age of the cohort was 56.5 years (51% were women). Significant fibrosis was observed in 51.2%. To detect significant fibrosis, MEFIB outperformed both MAST and FAST (both p0.001); AUCs for MEFIB, MAST, and FAST were 0.901 (95% CI 0.875-0.928), 0.770 (95% CI 0.730-0.810), and 0.725 (95% CI 0.683-0.767), respectively. Using rule-in criteria, the positive predictive value of MEFIB (95.3%) was significantly higher than that of FAST (83.5%, p = 0.001) and numerically but not statistically greater than that of MAST (90.0%, p = 0.056). Notably, MEFIB's rule-in criteria covered more of the study population than MAST (34.1% vs. 26.6%; p = 0.006). Using rule-out criteria, the negative predictive value of MEFIB (90.1%) was significantly higher than that of either MAST (69.6%) or FAST (71.8%) (both p0.001). Furthermore, to diagnose "at risk" non-alcoholic steatohepatitis defined as NAFLD activity score ≥4 and fibrosis stage ≥2, MEFIB outperformed both MAST and FAST (both p0.05); AUCs for MEFIB, MAST, and FAST were 0.768 (95% CI 0.728-0.808), 0.719 (95% CI 0.671-0.766), and 0.687 (95% CI 0.640-0.733), respectively.MEFIB was better than MAST and FAST for detection of significant fibrosis as well as "at risk" NASH. All three models provide utility for the risk stratification of NAFLD.Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the general population worldwide and is one of the main causes of chronic liver disease. Because so many individuals have NAFLD, it is not practical to perform liver biopsies to identify those with more severe disease who may require pharmacological interventions. Therefore, accurate non-invasive tests are crucial. Herein, we compared three such tests and found that a test called MEFIB was the best at detecting patients who might require treatment.

There is an unmet need for development of non-invasive tests for the diagnostic assessment and monitoring of nonalcoholic fatty liver disease (NAFLD).Using modified-aptamer proteomics, we assayed 5220 proteins in each of 2852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models for clinically relevant severity of steatosis (grade 0 vs 1-3), hepatocellular ballooning (0 vs 1 or 2), lobular inflammation (0-1 versus 2-3) and fibrosis (stages 0-1 vs 2-4).Results for the 4 protein models, based on 37 analytes (18 not previously linked to NAFLD), in training/paired validation 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 NAS ≥ 4 with one or more points in each of the components and fibrosis stage 2 or higher, was created 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 (OCA). Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and OCA were identified.Serum 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.Individuals with NASH may have liver inflammation and scarring, along with fat in their liver, all of which are assessed by liver biopsy. In this study, we use an innovative protein scanning technology to develop and validate blood-based signatures of liver damage that have the potential to replace liver biopsy for NASH diagnosis and monitoring response to treatment. These signatures can also provide NASH drug developers with insights into treatment-mediated responses and mechanisms of action.An aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of nonalcoholic steatohepatitis for which there are no approved non-invasive diagnostic tools currently available. Specific protein signatures related to presence and severity of NASH and its histological components that were also sensitive to change over time were identified. These are fundamental initial steps in establishing a serum-proteome based diagnostic signature of NASH and provide a rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NASH.Not applicable.

The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS).Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87.After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.

Background & aimsA two-step strategy combining a serum marker and magnetic resonance elastography (MRE) for detecting advanced fibrosis (stage 3-4) among patients with nonalcoholic fatty liver disease (NAFLD) has been proposed, but its diagnostic accuracy has not been evaluated. In this multicenter study, we aimed to investigate the diagnostic accuracy of a two-step strategy including Fibrosis-4 (FIB-4) followed by MRE.MethodsIn this multicenter study, 806 patients with biopsy-proven NAFLD who underwent contemporaneous MRE were enrolled and randomly assigned to training and validation cohorts. As a first step, patients with FIB-4

Background/Aims Glycogen synthesis and storage are normal hepatocyte functions. However, glycogenosis, defined as excess hepatocyte glycogen visible by routine H&E light microscopy, has not been well characterized in nonalcoholic fatty liver disease (NAFLD). Methods Glycogenosis in NAFLD liver biopsies was graded as “none”, “focal” (in

ObjectiveEmerging data suggest that a 30% relative decline in liver fat, as assessed by MRI-proton density fat fraction (MRI-PDFF), may be associated with Non-Alcoholic Fatty Liver Disease Activity Score improvement, but the association between decline in MRI-PDFF and fibrosis regression is not known. Therefore, we aimed to examine the association between ≥30% relative decline in MRI-PDFF and fibrosis regression in non-alcoholic fatty liver disease (NAFLD).DesignThis prospective study included 100 well-characterised patients with biopsy-proven NAFLD with paired contemporaneous MRI-PDFF assessment at two time points. MRI-PDFF response was defined as ≥30% relative decline in MRI-PDFF. Theprimary outcomewas ≥1 stage histological fibrosis regression.ResultsThe median (IQR) age was 54 (43–62) years and body mass index was 31.9 (29–36) kg/m2. In multivariable-adjusted logistic regression analysis (adjusted for age, gender, diabetes status, race/ethnicity, interval between biopsies, gamma-glutamyl transferase, liver stiffness by magnetic resonance elastography and change in platelet counts), MRI-PDFF response was an independent predictor of fibrosis regression with an adjusted OR of 6.46 (95% CI 1.1 to 37.0, p=0.04). The proportion of patients with MRI-PDFF response with fibrosis regression, no change in fibrosis and fibrosis progression was 40.0%, 24.6% and 13.0%, respectively, and the proportion of patients with MRI-PDFF response increased with fibrosis regression (p=0.03).Conclusion≥30% reduction in MRI-PDFF in early phase trials can provide a useful estimate of odds of ≥1 stage improvement in fibrosis. These data may be helpful in sample size estimation in non-alcoholic steatohepatitis trials.

BACKGROUND AND AIMS Predictive, noninvasive tools are needed to monitor key features of nonalcoholic fatty liver disease (NAFLD) in children that relate to improvement in liver histology. The purpose of this study was to evaluate the relationship between liver chemistries and liver histology using data from the CyNCh (Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children) clinical trial. APPROACH AND RESULTS This study included 146 children. Improvement in liver histology, defined as decrease in nonalcoholic fatty liver disease (NAFLD) Activity Score ≥2 points without worsening of fibrosis, occurred in 43 participants (30%). There were 46 participants with borderline zone 1 nonalcoholic steatohepatitis (NASH) at baseline, with resolution in 28% (12 of 46). Multivariate models were constructed using baseline and change in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at 52 weeks, for improvement in (1) liver histology primary outcome, (2) borderline zone 1 NASH, and (3) fibrosis. For improvement in histology, the model (P

Background The prognoses with respect to mortality and hepatic and nonhepatic outcomes across the histologic spectrum of nonalcoholic fatty liver disease (NAFLD) are not well defined. Methods We prospectively followed a multicenter patient population that included the full histologic spectrum of NAFLD. The incidences of death and other outcomes were compared across baseline histologic characteristics. Results A total of 1773 adults with NAFLD were followed for a median of 4 years. All-cause mortality increased with increasing fibrosis stages (0.32 deaths per 100 person-years for stage F0 to F2 [no, mild, or moderate fibrosis], 0.89 deaths per 100 persons-years for stage F3 [bridging fibrosis], and 1.76 deaths per 100 person-years for stage F4 [cirrhosis]). The incidence of liver-related complications per 100 person-years increased with fibrosis stage (F0 to F2 vs. F3 vs. F4) as follows: variceal hemorrhage (0.00 vs. 0.06 vs. 0.70), ascites (0.04 vs. 0.52 vs. 1.20), encephalopathy (0.02 vs. 0.75 vs. 2.39), and hepatocellular cancer (0.04 vs. 0.34 vs. 0.14). As compared with patients with stage F0 to F2 fibrosis, patients with stage F4 fibrosis also had a higher incidence of type 2 diabetes (7.53 vs. 4.45 events per 100 person-years) and a decrease of more than 40% in the estimated glomerular filtration rate (2.98 vs. 0.97 events per 100 person-years). The incidence of cardiac events and nonhepatic cancers were similar across fibrosis stages. After adjustment for age, sex, race, diabetes status, and baseline histologic severity, the incidence of any hepatic decompensation event (variceal hemorrhage, ascites, or encephalopathy) was associated with increased all-cause mortality (adjusted hazard ratio, 6.8; 95% confidence interval, 2.2 to 21.3). Conclusions In this prospective study involving patients with NAFLD, fibrosis stages F3 and F4 were associated with increased risks of liver-related complications and death. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; NAFLD DB2 ClinicalTrials.gov number, NCT01030484.).

BACKGROUND AND AIMS: Patients with NAFLD with significant hepatic fibrosis (Stage ≥ 2) are at increased risk of liver-related morbidity and are candidates for pharmacologic therapies. In this study, we compared the diagnostic accuracy of MEFIB (the combination of magnetic resonance elastography [MRE] and Fibrosis-4 [FIB-4]) and FAST (FibroScan–aspartate aminotransferase; combined liver stiffness measurement by vibration-controlled transient elastography, controlled attenuation parameter, and aspartate aminotransferase) for detecting significant fibrosis. APPROACH AND RESULTS: This prospective cohort study included 234 consecutive patients with NAFLD who underwent liver biopsy, MRE, and FibroScan at the University of California San Diego (UCSD cohort) and an independent cohort (N = 314) from Yokohama City University, Japan. The primary outcome was diagnostic accuracy for significant fibrosis (Stage ≥ 2). The proportions of significant fibrosis in the UCSD and Yokohama cohorts were 29.5% and 66.2%, respectively. Area under the receiver operating characteristic curve (95% CI) of MEFIB (0.860 [0.81–0.91]) was significantly higher than that of FAST (0.757 [0.69–0.82]) in the UCSD cohort (p = 0.005), with consistent results in the Yokohama cohort (AUROC, 0.899 [MEFIB] versus 0.724 [FAST]; p < 0.001). When used as the rule-in criteria (MEFIB, MRE ≥ 3.3 kPa and FIB-4 ≥ 1.6; FAST ≥ 0.67), the positive predictive value for significant fibrosis was 91.2%–96.0% for MEFIB and 74.2%–89.2% for FAST. When used as the rule-out criteria (MEFIB, MRE < 3.3 kPa and FIB-4 < 1.6; FAST ≤ 0.35), the negative predictive value for significant fibrosis was 85.6%–92.8% for MEFIB and 57.8%–88.3% for FAST. CONCLUSIONS: MEFIB has higher diagnostic accuracy than FAST for significant fibrosis in NAFLD, and our results support the utility of a two-step strategy for detecting significant fibrosis in NAFLD.

International audience; BACKGROUND AND AIMS: Patients 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. METHODS: Adult 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. RESULTS: 147/1483 (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). CONCLUSIONS: This 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 \textless65, unlikely to have cirrhosis so higher-risk patients maintain access to specialty care.

Background and aims Management 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. Methods We 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). Results The 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). Conclusion We 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.

The Nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) has been applied as a method for evaluating treatment response, and a ≥2-point improvement in NAS has been commonly used as an accepted end point in phase 2b clinical trials in nonalcoholic steatohepatitis.1,2 Although liver fibrosis is the strongest histologic predictor of liver-related outcome and all-cause mortality in NAFLD,3,4 the association between change in NAS and change in fibrosis stage has not been fully verified. Therefore, we aimed to examine the association between change in NAS and change in fibrosis stage in well-characterized patients with NAFLD who had a paired liver biopsy assessment.

ObjectivePatients with non-alcoholic fatty liver disease (NAFLD) with ≥stage 2 fibrosis are at increased risk for liver-related mortality and are candidates for pharmacological therapies for treatment of NAFLD. The aim of this prospective cohort study is to examine the diagnostic accuracy of MR elastography (MRE) combined with fibrosis-4 (FIB-4) in diagnosing ≥stage 2 fibrosis (candidates for pharmacological therapies).DesignThis is a cross-sectional analysis of a prospective cohort (University of California at San Diego (UCSD)-NAFLD) including 238 consecutive patients with contemporaneous MRE and biopsy-proven NAFLD. Non-alcoholic steatohepatitis-Clinical Research Network-Histologic Scoring System was used to assess histology. The radiologist and pathologist were blinded to clinical, pathological and imaging data, respectively. Receiver operating characteristics (ROCs) were determined to examine the diagnostic accuracy of MRE and FIB-4 for diagnosis of ≥stage 2 fibrosis in NAFLD. We then validated these findings in an independent validation cohort derived from Yokohama City University in Japan (Japan-NAFLD Cohort; N=222 patients).ResultsIn the UCSD-NAFLD (training) Cohort, MRE demonstrated a clinically significant diagnostic accuracy for the detection of ≥stage 2 fibrosis with an area under the ROC curve (AUROC) of 0.93 (95% CI 0.90 to 0.97) vs FIB-4 with an AUROC of 0.78 (95% CI 0.71 to 0.85), which was both clinically and statistically significant (pConclusionMRE combined with FIB-4 (MEFIB) index may be used for non-invasive identification of candidates for (≥stage 2 fibrosis) pharmacological therapy among patients with NAFLD with a high PPV.

Context Sex hormones have been linked with presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults, but it is unknown if they affect severity of pediatric NAFLD. Objective To examine associations of circulating SHBG, estrogens, and androgens with key histologic features of pediatric, biopsy-confirmed NAFLD. Design Baseline assessment of longitudinal cohorts and randomized clinical trials. Setting Nonalcoholic Steatohepatitis Clinical Research Network. Patients Children and adolescents ≤18 years with liver biopsy-confirmed NAFLD in the United States. Main Outcome Measures We assayed SHBG, estrone, estradiol, dehydroepiandrosterone (DHEAS), androstenedione, and testosterone in relation to grade/stage of steatosis, portal inflammation, hepatic ballooning, fibrosis, and nonalcoholic steatohepatitis (NASH) severity using linear regression. Results Mean age of 573 children at the time of biopsy was 13.1 years (SD 2.8). Lower SHBG was inversely associated with steatosis severity in boys and girls (P = 0.001), and with portal inflammation in girls only (P for sex interaction Conclusions Largely consistent with findings in adults, sex hormones are associated with distinct histologic features of NAFLD in children and adolescents. These hormone levels relate to differences with gender and pubertal change.

Context.—The adoption of digital capture of pathology slides as whole slide images (WSI) for educational and research applications has proven utility.Objective.—To compare pathologists' primary diagnoses derived from WSI versus the standard microscope. Because WSIs differ in format and method of observation compared with the current standard glass slide microscopy, this study is critical to potential clinical adoption of digital pathology.Design.—The study enrolled a total of 2045 cases enriched for more difficult diagnostic categories and represented as 5849 slides were curated and provided for diagnosis by a team of 19 reading pathologists separately as WSI or as glass slides viewed by light microscope. Cases were reviewed by each pathologist in both modalities in randomized order with a minimum 31-day washout between modality reads for each case. Each diagnosis was compared with the original clinical reference diagnosis by an independent central adjudication review.Results.—The overall major discrepancy rates were 3.64% for WSI review and 3.20% for manual slide review diagnosis methods, a difference of 0.44% (95% CI, −0.15 to 1.03). The time to review a case averaged 5.20 minutes for WSI and 4.95 minutes for glass slides. There was no specific subset of diagnostic category that showed higher rates of modality-specific discrepancy, though some categories showed greater discrepancy than others in both modalities.Conclusions.—WSIs are noninferior to traditional glass slides for primary diagnosis in anatomic pathology.

BACKGROUND AND AIMS Emerging data from a single-center study suggests that a 30% relative reduction in liver fat content as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) from baseline may be associated with histologic improvement in nonalcoholic steatohepatitis (NASH). There are limited multicenter data comparing an active drug versus placebo on the association between the quantity of liver fat reduction assessed by MRI-PDFF and histologic response in NASH. This study aims to examine the association between 30% relative reduction in MRI-PDFF and histologic response in obeticholic acid (OCA) versus placebo-treated patients in the FLINT (farnesoid X receptor ligand obeticholic acid in NASH trial). APPROACH AND RESULTS This is a secondary analysis of the FLINT trial including 78 patients with MRI-PDFF measured before and after treatment along with paired liver histology assessment. Histologic response was defined as a 2-point improvement in nonalcoholic fatty liver disease activity score without worsening of fibrosis. OCA (25 mg orally once daily) was better than placebo in improving MRI-PDFF by an absolute difference of -3.4% (95% confidence interval [CI], -6.5 to -0.2%, P value = 0.04) and relative difference of -17% (95% CI, -34 to 0%, P value = 0.05). The optimal cutoff point for relative decline in MRI-PDFF for histologic response was 30% (using Youden's index). The rate of histologic response in those who achieved less than 30% decline in MRI-PDFF versus those who achieved a 30% or greater decline in MRI-PDFF (MRI-PDFF responders) relative to baseline was 19% versus 50%, respectively. Compared with MRI-PDFF nonresponders, MRI-PDFF responders demonstrated both a statistically and clinically significant higher odds 4.86 (95% CI, 1.4-12.8, P value

Key Points Question In patients with nonalcoholic fatty liver disease who are not undergoing specific therapeutic interventions, what factors are associated with progression and regression of hepatic fibrosis? Findings In this cohort study of 446 patients, high baseline nonalcoholic fatty liver disease activity score and changes in the score were associated with concordant changes in fibrosis. Weight gain, high baseline aspartate aminotransferase level, and increases in the aspartate aminotransferase level were associated with fibrosis progression. Meaning These data may support the use of therapeutics targeting disease activity in nonalcoholic steatohepatitis and the use of short-term changes in the nonalcoholic fatty liver disease activity score as an end point in such clinical trials; in clinical practice, weight gain and an increasing aspartate aminotransferase level should increase suspicion of increasing fibrosis., Importance The histologic evolution of the full spectrum of nonalcoholic fatty liver disease (NAFLD) and factors associated with progression or regression remain to be definitively established. Objective To evaluate the histologic evolution of NAFLD and the factors associated with changes in disease severity over time. Design, Setting, and Participants A prospective cohort substudy from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database study, a noninterventional registry, was performed at 8 university medical research centers. Masked assessment of liver histologic specimens was performed, using a prespecified protocol to score individual biopsies. Participants included 446 adults with NAFLD enrolled in the NASH CRN Database studies between October 27, 2004, and September 13, 2013, who underwent 2 liver biopsies 1 or more year apart. Data analysis was performed from October 2016 to October 2018. Main Outcomes and Measures Progression and regression of fibrosis stage, using clinical, laboratory, and histologic findings, including the NAFLD activity score (NAS) (sum of scores for steatosis, lobular inflammation, and ballooning; range, 0-8, with 8 indicating more severe disease). Results A total of 446 adults (mean [SD] age, 47 [11] years; 294 [65.9%] women) with NAFLD (NAFL, 86 [19.3%]), borderline NASH (84 [18.8%]), and definite NASH (276 [61.9%]) were studied. Over a mean (SD) interval of 4.9 (2.8) years between biopsies, NAFL resolved in 11 patients (12.8%) and progressed to steatohepatitis in 36 patients (41.9%). Steatohepatitis resolved in 24 (28.6%) of the patients with borderline NASH and 61 (22.1%) of those with definite NASH. Fibrosis progression or regression by at least 1 stage occurred in 132 (30%) and 151 [34%] participants, respectively. Metabolic syndrome (20 [95%] vs 108 [72%]; P = .03), baseline NAS (mean [SD], 5.0 [1.4] vs 4.3 [1.6]; P = .005), and smaller reduction in NAS (−0.2 [2] vs −0.9 [2]; P, This cohort study evaluates the progression and regression of hepatic fibrosis over time in association with the severity of nonalcoholic fatty liver disease.

Background and aimsCross-sectional studies have shown that magnetic resonance elastography (MRE) is accurate in the noninvasive detection of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD). However, there are limited data on the longitudinal association between an increase in liver stiffness on MRE and fibrosis progression in NAFLD. Therefore, using a well-characterized prospective cohort of patients with biopsy-proven NAFLD, we aimed to examine the longitudinal association between a 15% increase in liver stiffness on MRE and fibrosis progression in NAFLD.Approach and resultsThis prospective cohort study included 102 patients (62.7% women) with biopsy-proven NAFLD who underwent contemporaneous MRE and liver biopsy at baseline followed by a repeat paired liver biopsy and MRE assessment. The primary outcome was odds of fibrosis progression by one or more stage as assessed by the Nonalcoholic Steatohepatitis Clinical Research Network histologic scoring system. The mean (±SD) of age and body mass index (BMI) were 52 (±14) years and 32.6 (±5.3) kg/m2 , respectively. The median time interval between the two paired assessments was 1.4years (interquartile range 2.15years). The number of patients with fibrosis stages 0, 1, 2, 3, and 4 was 27, 36, 12, 17, and 10, respectively. In unadjusted analysis, a 15% increase in MRE was associated with increased odds of histologic fibrosis progression (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.17-10.76; P=0.0248). These findings remained clinically and statistically significant even after multivariable adjustment for age, sex, and BMI (adjusted OR, 3.36; 95% CI, 1.10-10.31; P=0.0339). A 15% increase in MRE was the strongest predictor of progression to advanced fibrosis (OR, 4.90; 95% CI, 1.35-17.84; P=0.0159).ConclusionsA 15% increase in liver stiffness on MRE may be associated with histologic fibrosis progression and progression from early fibrosis to advanced fibrosis.

Background Haptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic response to VitE in nonalcoholic steatohepatitis (NASH) is unknown. Goals Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH. Study A post hoc analysis of 228 patients receiving VitE or placebo in 2 clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1-1, 2-1, or 2-2), on histologic features and laboratory markers of nonalcoholic fatty liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype. Results Hp 2-2 patients treated with VitE versus placebo showed significant histologic improvement (51% vs. 20%; OR=4.2; P=0.006), resolution of steatohepatitis (44% vs. 12%; OR=6.2; P=0.009), decrease in nonalcoholic fatty liver disease Activity Score (NAS) (-2.2 vs. -0.6; P=0.001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Hp 2-1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1-1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2-2 or 2-1 versus 1-1 for all liver enzyme. Conclusions Hp 2 allele is associated with greater histologic and biological improvement in NASH with VitE treatment compared with the Hp 1 allele.

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

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth. METHODS: We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8–17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis. RESULTS: At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH or in fibrosis occurred in 36% of the children, and both occurred in 11% of the children. Any improvement in NASH or fibrosis occurred in 52%, and both occurred in 20% of children. Type 2 diabetes developed in 5% of the cohort. Any progression to NASH and/or fibrosis was associated with adolescent age, higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein-cholesterol at baseline, increasing level of alanine aminotransferase, and hemoglobin A1C (P < .05). Progression to NASH and/or fibrosis were also associated with increasing level of gamma-glutamyl transferase and development of type 2 diabetes (P < .01). Increasing level of gamma-glutamyl transferase also associated with reduced odds of any improvement (P = .003). CONCLUSIONS: One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.

The liver R2* value is widely used as a measure of liver iron but may be confounded by the presence of hepatic steatosis and other covariates.To identify the most influential covariates for liver R2* values in patients with nonalcoholic fatty liver disease (NAFLD).Retrospective analysis of prospectively acquired data.Baseline data from 204 subjects enrolled in NAFLD/NASH (nonalcoholic steatohepatitis) treatment trials.1.5T and 3T; chemical-shift encoded multiecho gradient echo.Correlation between liver proton density fat fraction and R2*; assessment for demographic, metabolic, laboratory, MRI-derived, and histological covariates of liver R2*.Pearson's and Spearman's correlations; univariate analysis; gradient boosting machines (GBM) multivariable machine-learning method.Hepatic proton density fat fraction (PDFF) was the most strongly correlated covariate for R2* at both 1.5T (r = 0.652, P 0.0001) and at 3T (r = 0.586, P 0.0001). In the GBM analysis, hepatic PDFF was the most influential covariate for hepatic R2*, with relative influences (RIs) of 61.3% at 1.5T and 47.5% at 3T; less influential covariates had RIs of up to 11.5% at 1.5T and 16.7% at 3T. Nonhepatocellular iron was weakly associated with R2* at 3T only (RI 6.7%), and hepatocellular iron was not associated with R2* at either field strength.Hepatic PDFF is the most influential covariate for R2* at both 1.5T and 3T; nonhepatocellular iron deposition is weakly associated with liver R2* at 3T only.4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1456-1466.

Markers are needed to predict progression of nonalcoholic fatty liver disease (NAFLD). The proton density fat fraction, measured by magnetic resonance imaging (MRI-PDFF), provides an accurate, validated marker of hepatic steatosis. However, it is not clear whether the proton density fat fraction identifies patients at risk for NAFLD progression. We performed a follow-up study of 95 well-characterized patients with biopsy-proven NAFLD and examined the association between liver fat content and fibrosis progression. MRI-PDFF measurements were made at study entry (baseline). Biopsies were collected from patients at baseline and after a mean time period of 1.75 years. Among patients with no fibrosis at baseline, a higher proportion of patients in the higher liver fat group (MRI-PDFF ≥ 15.7%) had fibrosis progression (38.1%) than in the lower liver fat group (11.8%) (P=.067). In multivariable-adjusted logistic regression models (adjusted for age, sex, ethnicity, and body mass index), patients in the higher liver fat group had a significantly higher risk of fibrosis progression (multivariable adjusted odds ratio, 6.7; 95% CI, 1.01–44.1) (P=.049). Our findings associate higher liver fat content, measured by MRI-PDFF, with fibrosis progression.

Diagnostic whole-exome sequencing has proven highly successful in a range of rare diseases, particularly early-onset genetic conditions. In more common conditions, however, exome sequencing for diagnostic purposes remains the exception. Here we describe a patient initially diagnosed with a common, complex liver disease, nonalcoholic fatty liver disease (NAFLD), who was determined to have Wilson disease (WD) upon research-related exome sequencing. The patient presented as a 14.5-yr-old adolescent with chronically elevated aminotransferases, normal ceruloplasmin, and histologic examination consistent with NAFLD with advanced fibrosis. He was enrolled in a large longitudinal study of patients with NAFLD and was found to have WD by exome sequencing performed 4 yr later. This new diagnosis, confirmed clinically by 24 h urine copper quantification, led to a change in the therapy from lifestyle counseling to directed treatment with d-penicillamine, a copper chelating agent. In this case, the likelihood of making the correct diagnosis and thereby choosing the appropriate treatment was increased by exome sequencing and careful interpretation. This example illustrates the utility of exome sequencing diagnostically in more common conditions not currently considered as targets for genome-wide evaluation and adds to a growing body of evidence that patients diagnosed with more common conditions often in fact have rarer genetically determined syndromes that have escaped clinical detection.

Author(s): Schwimmer, Jeffrey B; Middleton, Michael S; Behling, Cynthia; Newton, Kimberly P; Awai, Hannah I; Paiz, Melissa N; Lam, Jessica; Hooker, Jonathan C; Hamilton, Gavin; Fontanesi, John; Sirlin, Claude B | Abstract: UnlabelledNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. In order to advance the field of NAFLD, noninvasive imaging methods for measuring liver fat are needed. Advanced magnetic resonance imaging (MRI) has shown great promise for the quantitative assessment of hepatic steatosis but has not been validated in children. Therefore, this study was designed to evaluate the correlation and diagnostic accuracy of MRI-estimated liver proton density fat fraction (PDFF), a biomarker for hepatic steatosis, compared to histologic steatosis grade in children. The study included 174 children with a mean age of 14.0 years. Liver PDFF estimated by MRI was significantly (P l 0.01) correlated (0.725) with steatosis grade. The correlation of MRI-estimated liver PDFF and steatosis grade was influenced by both sex and fibrosis stage. The correlation was significantly (P l 0.01) stronger in girls (0.86) than in boys (0.70). The correlation was significantly (P l 0.01) weaker in children with stage 2-4 fibrosis (0.61) than children with no fibrosis (0.76) or stage 1 fibrosis (0.78). The diagnostic accuracy of commonly used threshold values to distinguish between no steatosis and mild steatosis ranged from 0.69 to 0.82. The overall accuracy of predicting the histologic steatosis grade from MRI-estimated liver PDFF was 56%. No single threshold had sufficient sensitivity and specificity to be considered diagnostic for an individual child.ConclusionsAdvanced magnitude-based MRI can be used to estimate liver PDFF in children, and those PDFF values correlate well with steatosis grade by liver histology. Thus, magnitude-based MRI has the potential for clinical utility in the evaluation of NAFLD, but at this time no single threshold value has sufficient accuracy to be considered diagnostic for an individual child.

Objective Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. Design Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. Results Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. Conclusions Although ‘substantial’ to ‘almost perfect’ ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two-dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross-validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P

To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD.A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category.Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62).Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.

Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines interleukin (IL) 6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin, and IL6 and IL1β, and other risk factors in patients with nonalcoholic fatty liver disease (NAFLD) with iron deficiency.We collected data on 675 adult subjects (18 years old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, and serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency.One-third of patients (231 of 675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P.01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61 ± 45 vs 81 ± 51 ng/mL; P.0001). Iron deficiency was significantly associated with female gender, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, black or American Indian/Alaska Native race (P ≤ .018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal, P ≤ .0001; and 0.45 vs 0.32 for iron normal, P ≤ .005).Iron deficiency is prevalent in patients with NAFLD and associated with female gender, increased body mass index, and nonwhite race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiologic response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

BACKGROUND Ulcerative colitis (UC) is an idiopathic inflammatory disorder. Currently, the main goals of treatment are to induce and maintain clinical and/or endoscopic remission. However, evidence indicates that persistent disease activity on colonic biopsies in the setting of clinical or endoscopic remission is an independent predictor of poor outcomes. A number of previous studies have proposed histologic indices for use in specific trials of UC. The aim of this study was to systematically review the existing histological indices for UC and assess their potential use in both patient management and clinical trials. METHODS We performed a systematic review of histological indices evaluating disease activity in UC. MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and Digestive Diseases Week (DDW) abstracts of randomized and/or controlled trials clinical trials were searched from inception to February 2013 for applicable studies. Data from these studies were reviewed and analyzed. RESULTS After systematically applying inclusion criteria, we identified 108 scientific articles including 88 clinical studies and 21 related clinical reviews. Eighteen indices of histological activity in UC were identified and reviewed. CONCLUSIONS Although multiple histological scoring indices for assessment of UC disease activity currently exist, none of these instruments were developed using a formal validation process and their operating properties remain poorly understood. Future studies are needed to address this deficiency.

BACKGROUND & AIMS: Noninvasive methods are needed to determine disease stage in patients with nonalcoholic fatty liver disease (NAFLD). We evaluated the diagnostic performance of several widely available fibrosis models for the assessment of hepatic fibrosis in patients with NAFLD. METHODS: We performed a retrospective analysis of data from individuals enrolled in the NIDDK NASH Clinical Research Network, from 2004 through 2018. Using biopsy as the reference standard, we determined the diagnostic performance of the aspartate aminotransferase (AST):platelet ratio (APRI), FIB-4, ratio of AST:alanine aminotransferase (ALT) and the NAFLD fibrosis score (NFS) in a cross-sectional study of 1904 subjects. The ability of these models to detect changes in fibrosis stage was assessed in a longitudinal data set of 292 subjects with 2 biopsies and accompanying laboratory data. Outcomes were detection of fibrosis of any stage (stages 0 to 4), detection of moderate fibrosis (stages 0–1 vs 2–4), and detection of advanced fibrosis (stages 0–2 vs 3–4). Diagnostic performance was evaluated using the C-statistic, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) analyses. RESULTS: In the cross-sectional study, FIB-4 and NFS outperformed other non-invasive models for detecting advanced fibrosis; the C-statistics were 0.80 for FIB-4 and 0.78 for NFS. In the longitudinal study, 216 patients had non-advanced fibrosis at baseline and 35 patients progressed to advanced fibrosis after median follow up of 2.6 years. After we adjusted for fibrosis stage and model score at initial biopsy, change in APRI, FIB-4, and NFS were significantly associated with change in fibrosis. A unit change in APRI, FIB-4, or NFS was associated with changes in fibrosis stage of 0.33 (95% CI, 0.20-0.45; P

To determine potential associations between histologic features of pediatric nonalcoholic fatty liver disease (NAFLD) and estimated quantitative magnetic resonance diffusion-weighted imaging (DWI) parameters.This prospective, cross-sectional study was performed as part of the Magnetic Resonance Assessment Guiding NAFLD Evaluation and Treatment (MAGNET) ancillary study to the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Sixty-four children underwent a 3T DWI scan (b-values: 0, 100, and 500 s/mmEstimated means ± standard deviations were: ADC: 1.3 (0.94-1.8) × 10In children with NAFLD, steatosis and fibrosis have independent effects on DWI-estimated parameters ADC, D, and F. Further research is needed to determine the underlying mechanisms and clinical implications of these effects.1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1149-1158.

BACKGROUND & AIMS: Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. METHODS: We performed a cross-sectional study of baseline data from 813 children (age less than 18 years; mean age, 12.8±2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the NASH Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. RESULTS: Zone 1 steatosis was present in 18% of children with NAFLD (n=146) and zone 3 steatosis was present in 32% (n=244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P

Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease in children in the United States and is associated with insulin resistance. In adults, NAFLD is also associated with type 2 diabetes. To our knowledge, the prevalence of type 2 diabetes in children with NAFLD is unknown.To determine the prevalence of type 2 diabetes and prediabetes in children with NAFLD and assess type 2 diabetes and prediabetes as risk factors for nonalcoholic steatohepatitis (NASH).This was a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network. Children younger than 18 years with biopsy-confirmed NAFLD enrolled in the NASH Clinical Research Network.The presence of type 2 diabetes and prediabetes as determined by American Diabetes Association screening criteria using clinical history and fasting laboratory values.There were 675 children with NAFLD included in the study with a mean age of 12.6 years and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 32.5. Most of the children were boys (480 of 675) and Hispanic (445 of 675).The estimated prevalence of prediabetes was 23.4% (95% CI, 20.2%-26.6%), and the estimated prevalence of type 2 diabetes was 6.5% (95% CI, 4.6%-8.4%). Girls with NAFLD had 1.6 (95% CI, 1.04-2.40) times greater odds of having prediabetes and 5.0 (95% CI, 2.49-9.98) times greater odds of having type 2 diabetes than boys with NAFLD. The prevalence of NASH was higher in those with type 2 diabetes (43.2%) compared with prediabetes (34.2%) or normal glucose (22%) (P .001). The odds of having NASH were significantly higher in those with prediabetes (OR, 1.9; 95% CI, 1.21-2.9) or type 2 diabetes (OR, 3.1; 95% CI, 1.5-6.2) compared with those with normal glucose.In this study, nearly 30% of children with NAFLD also had type 2 diabetes or prediabetes. These children had greater odds of having NASH and thus were at greater long-term risk for adverse hepatic outcomes.

Objectives The aim of this study was to test the ability of hepatocyte-specific functional imaging to stage fibrosis in experimental rat models of liver fibrosis and progressive NASH. Using ROC analysis we tested the ability of a functional imaging metric to discriminate early ( F1 ) from moderate ( F2 ) fibrosis in the absence and presence of non-alcoholic steatohepatitis, which has not been achieved by any modality other than biopsy. Methods Galactosyl Human Serum Albumin (GSA) was radiolabeled with the positron-emitter, 68 Ga, and injected (i.v., 45–95μCi, 1.5pmol/g TBW) into 44 healthy, 19 DEN-, and 22 CDAA-treated male rats. Quantification of liver function was achieved by calculating T90 , defined as the time for the liver to accumulate 90 percent of the [ 68 Ga]GSA plateau value. All livers were excised immediately after imaging and prepared for a "blinded" histologic examination, which included fibrosis and fat content scores. Two sets of fibrosis scores were recorded for all of animals. The dominant fibrosis stage was recorded as the "Dominant Pattern" score and the "Maximum Pattern" score was assigned if a smaller distinct region with a higher fibrosis score was observed. Results Animals with Dominant Pattern F0 – F1 liver fibrosis ( D − =39) demonstrated significantly ( P 68 Ga]GSA (2.40±0.52min) than those with moderate to advanced Dominant Pattern fibrosis F2 and F4 ( D + =26) (3.48±1.01min). ROC analysis ( F0 – F1 vs F2 – F4 ) produced an area under the binormal curve ( AUC ) of 0.867±0.045. Twenty-seven of the 65 rats had small regions with higher fibrosis scores. Six of these Maximum Pattern scores reclassified the animals from D − to D + . ROC analysis of F0 – F1 versus F2 – F4 rats without liver fat produced AUCs of 0.881±0.053 for the Dominant Pattern Score and 0.944±0.035 for the Maximum Pattern Score. Conclusions PET Functional Imaging of [ 68 Ga]GSA accurately discriminates early from moderate experimental fibrosis independent of steatosis grade. If validated in human studies, molecular imaging may emerge as a potential alternative to invasive liver biopsy.

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.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.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.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.

OBJECTIVE. Fatty liver disease is diagnosed increasingly in children, but the prevalence remains unknown. We sought to determine the prevalence of pediatric fatty liver as diagnosed by histology in a population-based sample. METHODS. We conducted a retrospective review of 742 children between the ages of 2 and 19 years who had an autopsy performed by a county medical examiner from 1993 to 2003. Fatty liver was defined as ≥5% of hepatocytes containing macrovesicular fat. RESULTS. Fatty liver was present in 13% of subjects. For children and adolescents age 2 to 19 years, the prevalence of fatty liver adjusted for age, gender, race, and ethnicity is estimated to be 9.6%. Fatty liver prevalence increases with age, ranging from 0.7% for ages 2 to 4 up to 17.3% for ages 15 to 19 years. Fatty liver prevalence differs significantly by race and ethnicity (Asian: 10.2%; black: 1.5%; Hispanic: 11.8%; white: 8.6%). The highest rate of fatty liver was seen in obese children (38%). CONCLUSIONS. Fatty liver is the most common liver abnormality in children age 2 to 19 years. The presence of macrovesicular hepatic steatosis in ∼1 of every 10 children has important ramifications for the long-term health of children and young adults. The influence of the risk factors identified should be taken into consideration in the development of protocols designed to screen at-risk children and adolescents.

Although population prevalence is very difficult to establish, nonalcoholic fatty liver disease (NAFLD) is probably the most common cause of liver disease in the preadolescent and adolescent age groups. There seems to be an increase in the prevalence of NAFLD, likely related to the dramatic rise in the incidence of obesity during the past 3 decades. Despite an increase in public awareness, overweight/obesity and related conditions, such as NAFLD, remain underdiagnosed by health care providers. Accurate diagnosis and staging of nonalcoholic steatohepatitis (NASH) requires liver biopsy. The development of noninvasive surrogate markers and the advancements in imaging technology will aid in the screening of large populations at risk for NAFLD. Two distinct histological patterns of NASH have been identified in the pediatric population, and discrete clinical and demographic features are observed in children with these 2 patterns. The propensity for NASH to develop in obese, insulin-resistant pubertal boys of Hispanic ethnicity or a non-Hispanic white race may provide clues to the pathogenesis of NAFLD in children. The natural history of pediatric NASH has yet to be defined, but most biopsies in this age group demonstrate some degree of fibrosis. In addition, cirrhosis can be observed in children as young as 10 years. While the optimal treatment of pediatric NAFLD has yet to be determined, lifestyle modification through diet and exercise should be attempted in children diagnosed with NAFLD. A large, multicenter trial of vitamin E and metformin is underway as part of the NASH clinical research network.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, ballooning degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD.

The distinction among inflammatory, benign, and malignant lesions of the biliary tract can at times be difficult. Several methods have been used, including immunohistochemistry (IHC), with variable success. We evaluated a panel of IHC stains to determine their utility in discriminating between bile duct lesions. Formalin-fixed, paraffin-embedded 4-microm sections from 12 inflammatory lesions, 10 bile duct adenomas, and 13 bile duct carcinomas were immunostained using a modified avidin-biotin-complex technique after epitope enhancement using antibodies for p53, Ki-67, and bcl-2. For p53 and bcl-2, greater than 1% of cells staining positive was interpreted as positive. The proliferation index was calculated by determining the number of Ki-67-positive cells in a 1000 cell count. In the inflammatory group, 0 of 12 reacted with anti-p53, 2 of 12 were positive with anti-bcl-2, and the proliferation index with was 22.9% +/- 3.9%. Two of 10 bile duct adenomas showed reactivity with anti-bcl-2, and none were decorated with anti-p53 or Ki-67. In the carcinoma group, 6 of 13 were positive with anti-p53, 9 of 12 were positive with anti-bcl-2, and the proliferation index was 35.3% +/- 5.5%. The proliferation rates differed significantly between groups (P < 0.05). The presence of bcl-2 and p53 immunoreactivity coupled with a high proliferative rate in a biliary tract lesion suggests a malignant process. A panel using these antibodies may be useful in difficult cases.

To describe the clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in children, including insulin resistance, and to test for correlation with liver pathology.A retrospective review of children with biopsy-proven NAFLD at Children's Hospital San Diego from 1999 to 2002. Liver biopsy specimens were independently reviewed by two pathologists.Children with NAFLD (n=43) were mostly male (70%), Hispanic American (53%) and obese (88%). The criteria for insulin resistance were met by 95% of subjects. Steatosis was predicted by the combination of quantitative insulin sensitivity check index, age, and ethnicity (P.0001). Portal inflammation was predicted by the combination of ALT and fasting insulin (P=.0009). Perisinusoidal fibrosis was predicted by the combination of AST, fasting insulin, and BMI Z score (P.0001). Portal fibrosis was predicted by the combination of right upper quadrant pain and homeostasis model assessment of insulin resistance (P=.0028).We identified significant predictors of liver pathology in children with NAFLD. Children being evaluated for NAFLD should be screened for insulin resistance, which is nearly universal and correlates with liver histology.

Background and Aim: Hyaluronic acid (HA) is a glycosaminoglycan synthesized by hepatic stellate cells that has been shown to correlate with liver fibrosis in chronic hepatitis C (HCV) patients. However, its use in monitoring fibrosis over time has not been established. The aim of the present study was to assess the serial relationships between HA and liver fibrosis before and after treatment. Methods: Seventy-six previously untreated chronic HCV patients received interferon-based therapy over 48 weeks. Serum HA levels were measured and liver biopsies were obtained at baseline, and 24 weeks post-treatment. Histological fibrosis was assessed by using the Knodell and METAVIR scoring systems. Results: Knodell fibrosis was evaluated in 76 patients; METAVIR fibrosis in 72 patients. Following treatment, patients were grouped into those with increased fibrosis (Knodell = 17; METAVIR = 16), no change (Knodell = 50; METAVIR = 45), or decreased fibrosis (Knodell = 9; METAVIR = 11), relative to baseline. Moderate correlations between HA and fibrosis scores were found before treatment (Knodell R = 0.45; METAVIR R = 0.40) and post-treatment (Knodell R = 0.45; METAVIR R = 0.61). However, changes in HA correlated poorly with changes in fibrosis scores over the study period (Knodell R = 0.11; METAVIR R = 0.06). There was poor qualitative agreement between the direction of HA change and the direction of change in fibrosis scores (Knodell kappa = 0.04; METAVIR kappa = 0.08). The sus-tained virological response group (n = 18) had a significantly decreased mean HA compared with non-responders (−27.9 vs 21.7 µg/L; P = 0.009), but pretreatment HA did not predict a response. Conclusions: Serum HA showed a modest association with hepatic fibrosis, and remains a useful non-invasive marker. However, serum HA alone has limited value in predicting histological changes over a treatment period.

Balloon angioplasty and stent placement for pulmonary arterial stenoses in children are well-established therapies. In contrast, management of isolated peripheral pulmonary arterial stenoses in adults remains relatively unexplored. Four women (ages 18-63 years) with multiple discrete intralobar pulmonary arterial stenoses were treated with balloon angioplasty. Initially, 4-5 stenoses were dilated in each patient. The mean minimum diameter of the stenoses increased from 1.3 to 3.1 mm (P < 0.001), and the mean ratio of right ventricular to aortic systolic pressure decreased from 0.92 to 0.62 (P < 0.05). Each patient had marked symptomatic improvement. However, three patients developed recurrence of symptoms 4-24 months after angioplasty, and two had angiographic evidence of restenosis at previously dilated sites. These restenoses were treated with repeat angioplasty or stent implantation (three stents in each patient). One of these two patients developed near-occlusive restenosis of the stents and had successful bilateral lung transplantation. The other patient had a third catheterization with successful implantation of three additional stents. The third patient with recurrent symptoms died 2 years later, without further intervention. Transcutaneous catheter therapy for multiple intralobar pulmonary arterial stenoses in adults is highly successful acutely, but restenosis is common within several months. For some patients, balloon angioplasty and stent implantation may provide definitive management, while for others these procedures may serve as a bridge to lung transplantation.

PURPOSE To document the safety of main portal vein (PV) access to create transjugular portosystemic intrahepatic shunts (TIPS), provided that three-dimensional ultrasonography (3D US) can document the puncture to have entered a surface of the PV suitable for tamponade. MATERIALS AND METHODS In 11 patients who underwent conventional TIPS creation ( n = 10) or a transjugular portacaval shunt procedure ( n = 1), the puncture was found angiographically to enter the main PV. In seven cases, this occurred at the PV bifurcation and, in four, it occurred in the superior third of the PV. 3D US was used to determine whether the point of PV entry was functionally intrahepatic or extrahepatic. The puncture site was deemed to be intrahepatic if liver covered the puncture site on all three orthogonal imaging planes (sagittal, coronal, and transverse). If the puncture site was surrounded by liver, the access was used to deploy a metallic stent (uncovered, n = 10; covered, n = 1). Medical records and follow-up cross-sectional imaging studies were reviewed for evidence of hemorrhage complications. Pathologic correlation was performed in one explanted liver and autopsy specimens in five other patients. RESULTS In nine of 11 patients, 3D US was diagnostic and confidently verified that liver completely covered the portal vein access site. In two patients with diagnostically uncertain 3D US results, transcatheter injection of contrast medium documented no extravasation. All TIPS and direct portacaval shunt procedures were technically successful. No hemorrhagic complications occurred. Examination of pathologic specimens documented this portion of the portal vein to be extraperitoneal, but attached to the superior surface of the caudate lobe with fibrous tissue and small portal vein branches. CONCLUSIONS The bifurcation and posterior aspect of the superior third of the main PV can be safely used for TIPS procedures, provided access is proven to be surrounded by liver. 3D US can usually confidently determine if the PV entry site is functionally intrahepatic.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the presence of hepatic steatosis in individuals who consume little or no alcohol and who have no other identifiable secondary cause of steatosis.1–5. NAFLD is associated with features of metabolic syndrome, including obesity, insulin resistance, hypertension, diabetes, and dyslipidemia.1,4,6,7 It is the most common cause of chronic liver disease (CLD) in the United States.2–5 It affects 80-100 million Americans, of whom 10%-22% may have nonalcoholic steatohepatitis (NASH),8–13 a progressive form that may lead to cirrhosis11,14 and hepatocellular carcinoma.11,15–19 Patients with NASH and especially those with advanced fibrosis are at particularly high risk for these outcomes and require more-intense monitoring and therapy. The current diagnostic gold standard to diagnose advanced fibrosis is liver biopsy.20 However, biopsy is invasive and costly and may be complicated by morbidity and even death.21 Accurate noninvasive objective methods to detect advanced fibrosis in patients with NAFLD are needed, but are not yet commercially available. There are no approved noninvasive tests to diagnose advanced fibrosis. Cytokeratin-18,22 NAFLD fibrosis score,23 and Enhanced Liver Fibrosis (ELF™) Test24 are promising, but may not be sufficiently accurate for routine clinical use.1,25 Ultrasound elastography methods have high (21%-50%) failure rates in NAFLD.26–29 Recent retrospective studies demonstrate that two-dimensional magnetic resonance (MR) elastography (2D-MRE) may be useful in noninvasive diagnosis of advanced fibrosis in NAFLD.30 However, prospective studies of 2D-MRE with paired liver biopsies in well-characterized patients with biopsy-proven NAFLD with a clinical indication for a liver biopsy are needed. Utilizing a prospective cohort study design, we aimed to determine the accuracy of 2D-MRE for noninvasive diagnosis of advanced fibrosis in well-characterized patients with biopsy-proven NAFLD. We also aimed to determine the accuracy of 2D-MRE for noninvasive diagnosis of the presence of NASH, as well as dichotomized stages of fibrosis.

© 2015 AGA Institute. Background & Aims: The association between quantity of liver fat and the presence of metabolic syndrome needs to be assessed systematically. We aimed to determine the association between the quantity of liver fat and the presence of the metabolic syndrome in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), independent of nonalcoholic steatohepatitis (NASH). Methods: We recruited 146 patients with well-characterized biopsy-proven NAFLD and 50 individuals without NAFLD (controls) to participate in a case-control study at the NAFLD Translational Research Unit at the University of California San Diego. Liver fat was quantified in patients with NAFLD and controls using an advanced magnetic resonance imaging-based biomarker, the proton-density-fat-fraction (MRI-PDFF). Patients with NAFLD were divided into groups based on whether they were above or below the median MRI-PDFF value (15.4% in patients with NAFLD); the MRI-PDFF value for controls was less than 5%. The primary outcome was the presence of the metabolic syndrome using Adult Treatment Panel III criteria without and with adjustment for the presence of NASH. Results: Compared with NAFLD patients with MRI-PDFF values below the median, and compared with controls, NAFLD patients with MRI-PDFF values above the median were more likely to have abdominal obesity (. P < .0001), lower levels of high-density cholesterol (. P < .0001), higher levels of triglycerides (. P < .0001), and higher fasting glucose levels (. P < .001). Compared with NAFLD patients with MRI-PDFF values below the median, NAFLD patients with MRI-PDFF above the median were more likely to have the metabolic syndrome (60.3% vs 44.4%; P < .04), independent of biopsy-detected NASH. Conclusions: Increased liver fat content in patients with NAFLD is associated with increased rates of the metabolic syndrome, independent of NASH. There appears to be an association between the quantity of liver fat and the risk for cardiovascular disease in patients with NAFLD.

Background & Aims: Fatty liver is a common problem in children and increases their risk for cirrhosis, diabetes, and cardiovascular disease. Liver biopsy is the clinical standard for diagnosing and grading fatty liver. However, noninvasive imaging modalities are needed to assess liver fat in children. We performed a systematic review of studies that evaluated imaging liver fat in children. Methods: We searched PubMed for original research articles in peer-reviewed journals from January 1, 1982, through December 31, 2012, using the key words "imaging liver fat." Studies included those in English, and those performed in children from birth to 18 years of age. To be eligible for inclusion, studies were required to measure hepatic steatosis via an imaging modality and a quantitative comparator as the reference standard. Results: We analyzed 9 studies comprising 610 children; 4 studies assessed ultrasonography and 5studies assessed magnetic resonance imaging (MRI). Ultrasonography was used in the diagnosis of fatty liver with positive predictive values of 47% to 62%. There was not a consistent relationship between ultrasound steatosis score and the reference measurement of hepatic steatosis. Liver fat as measurements by MRI or by spectroscopy varied with the methodologies used. Liver fat measurements by MRI correlated with results from histologic analyses, but sample size did not allow for an assessment of diagnostic accuracy. Conclusions: Available evidence does not support the use of ultrasonography for the diagnosis or grading of fatty liver in children. Although MRI is a promising approach, the data are insufficient to make evidence-based recommendations regarding its use in children for the assessment of hepatic steatosis. © 2014 AGA Institute.

In patients with chronic hepatitis C virus (HCV) infection, liver fibrosis stage is a prognostic factor for therapy outcome. So far, a liver biopsy is necessary to determine disease stage accurately. We sought to develop a simple, noninvasive method of accurately predicting the degree of liver fibrosis in chronic HCV infection.We retrospectively studied 211 consecutive patients with chronic HCV, who received a liver biopsy at the Liver Center of the University of California, San Diego. A total of 58 of these patients had a positive history of alcohol abuse, and we analyzed them separately in a sensitivity analysis. AST/ALT ratio and platelet counts were determined in all patients. Fibrosis was staged using the METAVIR score.Both AST/ALT ratio and platelet counts correlated significantly with the disease stage (r = 0.190, p = 0.006, and r = -0.543, p0.00, respectively). In a sensitivity analysis, there was no correlation between AST/ALT ratio and disease stage for patients with a history of alcohol abuse. For patients without history of alcohol abuse, the correlation between disease stage, AST/ALT ratio, and platelet counts was r = 0.297, p0.00, and r = 0.560, p0.00, respectively. In these patients, AST/ALT ratioor =1 in combination with a platelet count of150,000/mm3 can identify patients with severe fibrosis or cirrhosis (stages 3 and 4) with a positive predictive value of 93.1%. Sensitivity, specificity, and negative predictive value were 41.2%, 99.1%, and 85.0%, respectively. In patients with ALT/AST ratio of1 or platelet counts of150,000/mm3, these laboratory parameters cannot predict liver fibrosis stage.AST/ALT ratio in combination with platelet counts may obviate a liver biopsy for fibrosis staging in some patients with chronic HCV infection.