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Introduction: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis., Methods: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis., Results: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration., Discussion: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH) are at high risk of morbidity and mortality. We previously found that a combination of the farnesoid X receptor agonist cilofexor (CILO) and the acetyl-CoA carboxylase inhibitor firsocostat (FIR) improved liver histology and biomarkers in NASH with advanced fibrosis but was associated with hypertriglyceridemia. We evaluated the safety and efficacy of icosapent ethyl (Vascepa) and fenofibrate to mitigate triglyceride elevations in patients with NASH treated with CILO and FIR., Methods: Patients with NASH with elevated triglycerides (≥150 and <500 mg/dL) were randomized to Vascepa 2 g twice daily (n = 33) or fenofibrate 145 mg daily (n = 33) for 2 weeks, followed by the addition of CILO 30 mg and FIR 20 mg daily for 6 weeks. Safety, lipids, and liver biochemistry were monitored., Results: All treatments were well-tolerated; most treatment-emergent adverse events were Grade 1 to 2 severity, and there were no discontinuations due to adverse events. At baseline, median (interquartile range [IQR]) triglycerides were similar in the Vascepa and fenofibrate groups (median, 177 [IQR, 154-205] vs 190 [IQR, 144-258] mg/dL, respectively). Median changes from baseline in triglycerides for Vascepa vs fenofibrate after 2 weeks of pretreatment were -12 mg/dL (IQR, -33 to 7 mg/dL; P = .09) vs -32 mg/dL (IQR, -76 to 6 mg/dL; P = .012) and at 6 weeks were +41 mg/dL (IQR, 16-103 mg/dL; P < .001) vs -2 mg/dL (IQR, -42 to 54 mg/dL; P = .92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (+6 vs +39 mg/dL); similar trends were observed in patients with baseline triglycerides ≥250 mg/d (-61 vs +99 mg/dL)., Conclusions: In patients with NASH with hypertriglyceridemia treated with CILO and FIR, fenofibrate was safe and effectively mitigated increases in triglycerides associated with acetyl-CoA carboxylase inhibition., Clinicaltrials: gov, Number: NCT02781584., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis., Approach and Results: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events., Conclusions: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm., Approach and Results: Patients with NASH with compensated cirrhosis from a phase 2b trial were included. HVPG and biopsies from baseline and weeks 48 and 96 were reviewed centrally, and biopsies evaluated with a convolutional neural network (PathAI, Boston, MA). Using trichrome-stained biopsies in the training set (n = 130), an ML model was developed to recognize fibrosis patterns associated with HVPG, and the resultant ML HVPG score was validated in a held-out test set (n = 88). Associations between the ML HVPG score with measured HVPG and liver-related events, and performance of the ML HVPG score for clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mm Hg), were determined. The ML-HVPG score was more strongly correlated with HVPG than hepatic collagen by morphometry (ρ = 0.47 vs. ρ = 0.28; P < 0.001). The ML HVPG score differentiated patients with normal (0-5 mm Hg) and elevated (5.5-9.5 mm Hg) HVPG and CSPH (median: 1.51 vs. 1.93 vs. 2.60; all P < 0.05). The areas under receiver operating characteristic curve (AUROCs) (95% CI) of the ML-HVPG score for CSPH were 0.85 (0.80, 0.90) and 0.76 (0.68, 0.85) in the training and test sets, respectively. Discrimination of the ML-HVPG score for CSPH improved with the addition of a ML parameter for nodularity, Enhanced Liver Fibrosis, platelets, aspartate aminotransferase (AST), and bilirubin (AUROC in test set: 0.85; 95% CI: 0.78, 0.92). Although baseline ML-HVPG score was not prognostic, changes were predictive of clinical events (HR: 2.13; 95% CI: 1.26, 3.59) and associated with hemodynamic response and fibrosis improvement., Conclusions: An ML model based on trichrome-stained liver biopsy slides can predict CSPH in patients with NASH with cirrhosis., (© 2021 by the American Association for the Study of Liver Diseases.)

Background and Aims: Manual histological assessment is currently the accepted standard for diagnosing and monitoring disease progression in NASH, but is limited by variability in interpretation and insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response., Approach and Results: Here, we describe a machine learning (ML)-based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We use samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histological features in NASH, including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML-based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver-related clinical events. We developed a heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment Liver Fibrosis score, which measured antifibrotic treatment effects that went undetected by manual pathological staging and was concordant with histological disease progression., Conclusions: Our ML method has shown reproducibility and sensitivity and was prognostic for disease progression, demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of therapies., (© 2021 PathAI. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background & Aim: Fibrosis is an independent predictor of death in nonalcoholic steatohepatitis (NASH). We assessed the associations between histologic and noninvasive tests (NITs) for fibrosis with clinical and patient-reported outcomes (PROs) in advanced NASH., Methods: Patients with advanced NASH (NASH Clinical Research Network stage F3 or F4) were enrolled in 4 multinational clinical trials of simtuzumab and selonsertib. Liver biopsy samples, NIT results, and PROs (Short Form-36, Chronic Liver Disease Questionnaire-NASH, EuroQol-5D, and Work Productivity and Activity Impairment) were prospectively collected., Results: A total of 2154 patients with advanced NASH were included: 52.5% with F4 NASH, 40% male, 72% with type 2 diabetes, baseline liver stiffness of 24.1 ± 14.2 kPa in F4 disease and 14.6 ± 8.0 kPa in F3 disease, baseline mean Enhanced Liver Fibrosis score of 11.4 ± 1.2 in F4 disease and 10.3 ± 1.0 in F3 disease, and a median follow-up of 16 months. Of those with baseline F3 disease, 16.7% experienced disease progression to cirrhosis, whereas for those with F4 disease, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NIT scores (all P < .0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both the F3 and F4 groups (P < .01 for all NITs in F3 and for ELF, NAFLD Fibrosis Score, Fibrosis-4 (FIB-4), and liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF, ≥10.43; Nonalcoholic Fatty Liver Disease Fibrosis Score, ≥1.80; Fibrotest score, ≥0.54; liver stiffness, ≥23.4 kPa. During treatment, patients with decreases in NIT scores experienced improvement of their PRO scores, whereas those with increase in NIT scores had their PRO scores worsen (P < .05)., Conclusions: Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH. (ClinicalTrials.gov, Numbers NCT01672866, NCT01672879, NCT03053050, and NCT03053063)., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (n = 74) enrolled in a 96-week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events., Approach and Results: The effect of fibrosis was subtracted from gene expression using a computational approach. The fibrosis-adjusted gene expression patterns were associated with time to first PSC-related clinical event (e.g., cholangitis, hepatic decompensation), and differential expression based on risk groups and Ingenuity Pathway Analysis were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA-sequencing data accounted for 18% of variance and correlated with fibrosis stage (ρ = -0.80; P < 0.001). After removing the effect of fibrosis-related genes, the first principle component was not associated with fibrosis (ρ = -0.19; P = 0.11), and a semisupervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC-related event (P < 0.0001). The two groups had similar fibrosis stage, hepatic collagen content, and α-smooth muscle actin expression by morphometry, Enhanced Liver Fibrosis score, and serum liver biochemistry, bile acids, and IL-8 (all P > 0.05). The top pathways identified by Ingenuity Pathway Analysis were eukaryotic translation inhibition factor 2 (eIF2) signaling and regulation of eIF4/p70S6K signaling. Genes involved in the unfolded protein response, activating transcription factor 6 (ATF6) and eIF2, were differentially expressed between the PSC clusters (down-regulated in the high-risk group by log-fold changes of -0.18 [P = 0.02] and -0.16 [P = 0.02], respectively). Clinical events were enriched in the high-risk versus low-risk group (38% [12/32] vs. 2.4% [1/42], P < 0.0001)., Conclusions: Removing the contribution of fibrosis-related pathways uncovered alterations in the unfolded protein response, which were associated with liver-related complications in PSC., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease., Approach and Results: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients., Conclusions: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH., (© 2020 by the American Association for the Study of Liver Diseases.)

Background & Aims: Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH., Methods: We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events., Results: Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups., Conclusions: Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH., Lay Summary: Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients., Trial Registration Details: Clinicaltrials.gov numbers NCT03053050 and NCT03053063., Competing Interests: Conflict of interest Dr. Harrison consults for, advises, and has received grants from, and owns stock in Galectin, GENFIT, and Madrigal. He consults for, advises, and has received grants from Axcella, Cirius, CymaBay, Galmed, Gilead, HighTide, Intercept, NGM, Novartis, Novo Nordisk, and Pfizer. He consults for, advises, and owns stock in Akero and Metacrine. He consults for and advises 3V Bio, Albireo, Blade, Bristol-Myers Squibb, CLDF, ContraVir, Consynance, Corcept, Echosens, Gelesis, HistoIndex, Innovate, IQVIA, Perspectum, Poxel, Prometheus, Prometic, Terns, and Lipocine. He is on the speakers' bureau for Alexion. He received grants from Conatus, Immuron, Second Genome, and Tobira/Allergan. Dr. Wong has received honoraria from Echosens and Gilead Sciences; consults for and advises AbbVie, Merck, Gilead Sciences, NovaMedica, Janssen Pharmaceuticals; and has received research funding from Gilead Sciences, Roche; and compensation for travel, accommodations, and other expenses from Gilead Sciences, Otsuka Pharmaceutical. Dr. Okanoue: None. Dr. Bzowej has received grants from Gilead, Bristol-Myers Squibb, Allergan, and Cirius. Dr. Vuppalanchi: None. Dr. Younes advises, is on the speakers' bureau for, and has received grants from Gilead. He is on the speakers' bureau for and received grants from AbbVie. He received grants from Intercept, Bristol-Myers Squibb, NGM, Madrigal, CymaBay, Allergan, Novartis, Axcella, Zydus, Cato, Novo Nordisk, and Cirius. Dr. Kohli received grants from Gilead. Dr. Sarin: None. Dr. Caldwell has received grants from Gilead, Genfit, Galmed, NGM, Conatus, Immuron, VitalTherapy, and Intercept. Dr. Alkhouri advises, is on the speakers' bureau for, and has received grants from Gilead and Intercept. He advises and has received grants from Allergan. He has received grants from GENFIT, Madrigal, and Galmed. Dr. Shiffman advises, is on the speakers' bureau for, and has received grants from Bristol-Myers Squibb, Dova, Gilead, Intercept, and Valeant. He advises and is on the speakers' bureau for AbbVie, Bayer, and Shionogi. He advises and has received grants from HepQuant. He advises Mallinckrodt. He is on the speakers' bureau for Eisai and Daiichi Sankyo. He has received grants from Afimmune, Conatus, CymaBay, Enanta, Exalenz, GENFIT, and Genkyotex. Drs. Camargo, Li, Kersey, Jia, Zhu, Djedjos, Subramanian, Myers are employed by and own stock in Gilead. Drs. Li and Djedjos were employed by Gilead at the time the study was conducted. Dr. Gunn has received research grant support from Conatus, CymaBay, Galectin, Gilead, and Immuron and has received speaker fees from Abbvie, Gilead, and Salix. Dr. Sheikh has served on the advisory board for BMS, Gilead, Intercept, and AbbVie, has performed research for BMS, Gilead, Merck, Intercept, Pfizer, Genentech, Actelion, Theravance, and Cubist, has served as a speaker for BMS, Gilead, and AbbVie, and owns stock in Gilead. Dr. Anstee consults for, is on the speakers' bureau for, and has received grants from Allergan/Tobira. He consults for and is on the speakers' bureau for GENFIT SA and Gilead. He consults for and has received grants from Novartis and Pfizer. He consults for Acuitas, BBN Cardio, Blade, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly, Galmed, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept, Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGM, North Sea, Novo Nordisk, Poxel, ProSciento, Raptor, Servier, and Viking. He is on the speakers' bureau for Bristol-Myers Squibb, Clinical Care Options, Falk, Fishawack, Integritas, and Medscape. He has received grants from AstraZeneca, GlaxoSmithKline, Glympse Bio, and Vertex. He has received royalties from Elsevier. Dr. Romero-Gomez consults for, advises, and is on the speakers' bureau for Gilead. He has received restricted and unrestricted research grants from Gilead and Intercept. Dr. Trauner consults for, is on the speakers' bureau for, and has received grants from Falk, Gilead, and MSD. He consults for and has received grants from Intercept and Albireo. He is on the speakers' bureau for and has received grants from Roche. He consults for Phenex, Novartis, Bristol-Myers Squibb, and Regulus. He has received grants from Takeda. Dr. Goodman has received grants from Gilead, Intercept, Novartis, Bristol-Myers Squibb, and Allergan. Dr. Lawitz is on the speakers' bureau for and has received grants from Gilead and AbbVie. Dr. Alkhouri advises, is on the speakers' bureau for, and has received grants from Gilead and Intercept. He advises and has received grants from Allergan. He has received grants from GENFIT, Madrigal, and Galmed. Dr. Younossi consults for Gilead, Intercept, BMS, NovoNordisk, Shinogi, and Novartis. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described., Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials., Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120., Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001., Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

Progression of nonalcoholic steatohepatitis (NASH) is incompletely characterized. We analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo-controlled trials of simtuzumab. The trials were terminated after 96 weeks because of lack of efficacy, so data from treatment groups were combined. Liver biopsies and HVPG measurements (only for patients with F4 fibrosis) were collected at screening and at weeks 48 and 96. Patients were assessed for Ishak fibrosis stage, hepatic collagen content and alpha-smooth muscle actin (by morphometry), NAFLD Activity Score (NAS), and serum markers of fibrosis. Associations with progression to cirrhosis (in patients with F3 fibrosis) and liver-related clinical events (in patients with F4 fibrosis) were determined. Progression to cirrhosis occurred in 22% (48/217) of F3 patients, and liver-related clinical events occurred in 19% (50/258) of patients with cirrhosis. Factors significantly associated with progression to cirrhosis included higher baseline values of and greater increases in hepatic collagen content, level of alpha-smooth muscle actin, and Enhanced Liver Fibrosis score. Similar factors, plus lack of fibrosis stage improvement (hazard ratio, 9.30; 95% confidence interval, 1.28-67.37), higher HVPG at baseline, and greater increase in HVPG over time, were associated with an increased risk of liver-related clinical events in patients with cirrhosis. Disease progression was not associated with the NAS at baseline or changes in NAS during treatment after adjustment for fibrosis stage. Conclusion: In patients with advanced fibrosis due to NASH, the primary determinant of clinical disease progression is fibrosis and its change over time., (© 2019 by the American Association for the Study of Liver Diseases.)

Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration-controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5-fold cross-validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0-F2 fibrosis and 2,262 with F3-F4 fibrosis. Significant differences between median values of NITs for patients with F0-F2 versus F3-F4 fibrosis were observed: -0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB-4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P < 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB-4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB-4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real-world population., (© 2019 by the American Association for the Study of Liver Diseases.)

Background: Patient-reported outcomes (PROs) are used to measure patients' experience with their disease. However, there are few PRO data from patients with NASH. We collected data from the STELLAR clinical trials to assess PROs for NASH and advanced fibrosis., Methods: We analyzed data from 1667 patients (58 ± 9 years, 40% male, 52% with cirrhosis, 74% with diabetes) with NASH and bridging fibrosis or compensated cirrhosis (metavir scores, F3 or F4) enrolled in the phase 3 STELLAR trials of selonsertib (NCT03053050 and NCT03053063) who completed PRO questionnaires (SF-36, CLDQ-NASH, EQ-5D, or WPAI:SHP) before treatment initiation., Results: Compared with patients with F3 fibrosis, higher proportions of patients with F4 fibrosis were female, were white, had more hematologic and gastrointestinal comorbidities, and had type 2 diabetes (P ≤ .01). Mean physical health-related PRO scores were significantly lower than those of the general population: patients with F4 fibrosis had score reductions of 4.4% to 12.9% in 6/8 SF-36 domains and patients with F3 fibrosis had score reductions of 3.9% to 11.7% in 4/8 domains (P < .01). Compared to patients with F3 fibrosis, those with F4 fibrosis had lower scores in all but 1 domains of CLDQ-NASH, Role Physical, Bodily Pain, and Social Functioning domains of the SF-36, and EQ-5D (P ≤ 01). In multivariate regression analysis, factors independently associated with lower PRO scores included having cirrhosis, female sex, higher body mass index, history of smoking, and diabetes or other comorbidities (P < .01)., Conclusions: PROs are significantly lower in patients with NASH with advanced fibrosis who participated in the STELLAR clinical trials. Treatment of patients with NASH should focus on improving not only clinical outcomes but also quantifiable symptom burden and health-related quality of life., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Although there is substantial evidence suggesting poor health-related quality of life (HRQL) in patients with chronic hepatitis C (CHC), similar data in nonalcoholic steatohepatitis (NASH) have not been fully assessed. The aim is to compare HRQL scores in patients with CHC to those with NASH., Methods: Matched patients with advanced fibrosis (bridging fibrosis and compensated cirrhosis) due to CHC and NASH completed Short Form-36 (SF-36) questionnaire, Chronic Liver Disease Questionnaire (CLDQ), and Work Productivity and Activity Instrument questionnaire., Results: We included 1,338 patients with NASH with advanced fibrosis (mean age 57.2 years, 47% men, 55% cirrhosis) and 1,338 matched patients with CHC. Patients with CHC and NASH had similar rates of employment and psychiatric disorders (P > 0.05). As expected, patients with NASH had higher body mass index (mean 33.7 vs 27.6) and more type 2 diabetes (74% vs 16%) (all P < 0.01). Patients with NASH had significantly lower HRQL scores related to physical health: Physical Functioning, Bodily Pain, General Health, Vitality, Physical Summary of SF-36, and Fatigue of CLDQ (P < 0.02). By contrast, patients with CHC had a lower Mental Health score of SF-36 and Emotional score of CLDQ and reported greater impairment in daily activities as measured by the Work Productivity and Activity Instrument questionnaire (P < 0.002). In multivariate analysis, after adjustment for demographic parameters, cirrhosis, and history of psychiatric disorders, having NASH was associated with lower physical HRQL scores and higher mental health-related scores (P < 0.05)., Discussion: Patients with NASH and advanced fibrosis have more impairment of their physical health-related scores than patients with CHC with advanced fibrosis. These data should dispel the misconception that NASH is an asymptomatic disease with little negative impact on patients' well-being.

Background & Aims: Although patients with cryptogenic cirrhosis have historically been considered as having "burnt-out" non-alcoholic steatohepatitis (NASH), some controversy remains. The aim of this study was to compare outcomes of patients with cryptogenic cirrhosis and NASH-related cirrhosis from a cohort with longitudinal follow-up data., Methods: Patients with cryptogenic cirrhosis or NASH cirrhosis were screened for a clinical trial. Patients with <5% hepatic steatosis regardless of other histologic features were considered to have cryptogenic cirrhosis. Clinico-laboratory data and adjudicated liver-related events (e.g. decompensation, qualification for transplantation, death) were available., Results: A total of 247 patients with cirrhosis (55.3 ± 7.4 years, 37% male) were included; 144 had NASH cirrhosis and 103 had cryptogenic cirrhosis. During a median follow-up of 29 (IQR 21-33) months (max 45 months), 20.6% of patients had liver-related clinical events. Patients with NASH cirrhosis and cryptogenic cirrhosis were of a similar age and gender, as well as having a similar body mass index, PNPLA3 rs738409 genotype, and prevalence of diabetes (p >0.05). However, patients with cryptogenic cirrhosis had higher serum fibrosis markers and greater collagen content and α-smooth muscle actin expression on liver biopsy. Compared to cirrhotic patients with NASH, patients with cryptogenic cirrhosis experienced significantly shorter mean time to liver-related clinical events (12.0 vs. 19.4 months; p = 0.001) with a hazard ratio of 1.76 (95% CI 1.02-3.06)., Conclusions: Populations with NASH and cryptogenic cirrhosis have similar demographics, but patients with cryptogenic cirrhosis have evidence of more active fibrosis and a higher risk of liver-related clinical events. Thus, we believe these patients belong to the same spectrum of disease, with cryptogenic cirrhosis representing a more advanced stage of fibrosis., Lay Summary: Significant liver damage and cirrhosis of the liver may develop without a known cause - a liver disease referred to as cryptogenic cirrhosis. In this work we found that, in the presence of metabolic abnormalities, cryptogenic cirrhosis may actually be a part of the non-alcoholic fatty liver disease spectrum. Yet, it appears to be more progressive than typical non-alcoholic fatty liver disease, leading to advanced liver disease at a faster rate., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH., Methods: We analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy., Results: A relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976., Conclusions: In a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patient-reported outcomes (PROs) represent patients' perspective about their well-being., Aim: To assess PRO changes in patients with non-alcoholic steatohepatitis (NASH) after treatment with selonsertib (SEL) and to associate them with different biomarkers., Methods: Patients with NASH and stage 2-3 fibrosis received SEL 6 mg or 18 mg orally QD alone or in combination with simtuzumab (SIM, 125 mg SC weekly) or SIM alone for 24 weeks. Biopsies were obtained at baseline and at treatment week 24. PROs were assessed using SF-36, CLDQ and WPAI:SHP., Results: Seventy-two patients with NASH were included (54 ± 10 years, 31% male, 65% stage 3, 71% diabetes). Baseline physical health-related PRO scores were significantly lower than population norms (P < .05). During treatment, there were no consistent differences in treatment-emergent PRO changes between different regimens (P > .05). However, NASH subjects who experienced ≥2 decrease in NAFLD Activity Score or ≥1-stage reduction in fibrosis showed significant improvements in their PROs (up to +15.5% of a PRO range size, P < .05). Additionally, improvements in PROs (up to +21.5%, P < .05) were noted in patients with at least 50% relative reduction in collagen, while NASH subjects with >17% increase in their collagen experienced PRO worsening (up to -13.9%, P < .05). Baseline serum CK-18, IL-6 and CRP significantly correlated with PROs (rho from -0.24 to -0.38, P < .05)., Conclusions: A decrease in hepatic collagen is the most prominently associated with improvement of PROs in NASH patients with F2-F3 treated with SEL. Furthermore, serum cytokines are associated with baseline PROs and with treatment-emergent changes in PROs in patients with NASH., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis., Methods: We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96., Results: The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis-including those given placebo-had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (-0.2%, 95% confidence interval [CI] -1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (-0.4%, 95% CI -1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI -1.2 to 1.5, P = .84 for 200 mg; 95% CI -1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups., Conclusion: In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.govNCT01672866 and NCT01672879., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Risk adjustment is essential for valid comparison of patients' health outcomes or performances of health care providers. Several risk adjustment methods for liver diseases are commonly used but the optimal approach is unknown. This study aimed to compare the common risk adjustment methods for predicting in-hospital mortality in cirrhosis patients using electronic medical record (EMR) data., Methods: The sample was derived from Beijing YouAn hospital between 2010 and 2014. Previously validated EMR extraction methods were applied to define liver disease conditions, Charlson comorbidity index (CCI), Elixhauser comorbidity index (ECI), Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD), MELD sodium (MELDNa), and five-variable MELD (5vMELD). The performance of the common risk adjustment models as well as models combining disease severity and comorbidity indexes for predicting in-hospital mortality was compared using c-statistic., Results: Of 11,121 cirrhotic patients, 69.9% were males and 15.8% age 65 or older. The c-statistics across compared models ranged from 0.785 to 0.887. All models significantly outperformed the baseline model with age, sex, and admission status (c-statistic: 0.628). The c-statistics for the CCI, ECI, MELDNa, and CTP were 0.808, 0.825, 0.849, and 0.851, respectively. The c-statistic was 0.887 for combination of CTP and ECI, and 0.882 for combination of MELDNa score and ECI., Conclusions: The liver disease severity indexes (i.e., CTP and MELDNa score) outperformed the CCI and ECI for predicting in-hospital mortality among cirrhosis patients using Chinese EMRs. Combining liver disease severity and comorbidities indexes could improve the discrimination power of predicting in-hospital mortality.

Background. Portal hypertension, an elevation in the hepatic venous pressure gradient (HVPG), can be used to monitor disease progression and response to therapy in cirrhosis. Since obtaining HVPG measurements is invasive, reliable noninvasive methods of assessing portal hypertension are needed. Methods. Noninvasive markers of fibrosis, including magnetic resonance elastography (MRE) shear wave velocity, were correlated with histologic fibrosis and HVPG measurements in hepatitis C (HCV) and/or HIV-infected patients with advanced liver disease enrolled in a clinical trial of treatment with simtuzumab, an anti-LOXL2 antibody. Results. This exploratory analysis includes 23 subjects: 9 with HCV monoinfection, 9 with HIV and HCV, and 5 with HIV and nonalcoholic steatohepatitis. Median Ishak fibrosis score was 4 (range 1-6); 11 subjects (48%) had cirrhosis. Median HVPG was 6 mmHg (range 3-16). Liver stiffness measured by MRE correlated with HVPG ( r = 0.64, p = 0.01), histologic fibrosis score ( r = 0.71, p = 0.004), noninvasive fibrosis indices, including APRI ( r = 0.81, p < 0.001), and soluble LOXL2 ( r = 0.82, p = 0.001). On stepwise multivariate regression analysis, MRE was the only variable independently associated with HVPG ( R 2 = 0.377, p = 0.02). Conclusions. MRE of the liver correlated independently with HVPG. MRE is a valid noninvasive measure of liver disease severity and may prove to be a useful tool for noninvasive portal hypertension assessment. Trial Registration Number . This trial is registered with NCT01707472.

Background: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed., Aim: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease., Methods: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis., Results: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-β3 and IL-10 pathways with treatment., Conclusion: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-β3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials., Competing Interests: Dr. Meissner receives grant support from Gilead Sciences, Inc. Drs. Kanwar, Myers and Subramanian are employed by and own stock in Gilead Sciences Inc. Dr. Goodman reports grant support from Gilead Sciences, Inc., Tobira, Intercept, Galectin, Conatus, and Alexion. All other co-authors report no conflicts of interest., (© 2016 This article is a U.S. Government work and is in the public domain in the USA.)

The Society of Radiologists in Ultrasound convened a panel of specialists from radiology, hepatology, pathology, and basic science and physics to arrive at a consensus regarding the use of elastography in the assessment of liver fibrosis in chronic liver disease. The panel met in Denver, Colo, on October 21-22, 2014, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies and are thought to represent a reasonable approach to the noninvasive assessment of diffuse liver fibrosis.

Background & Aims: Chronic liver diseases are highly prevalent and require an accurate evaluation of liver fibrosis to determine patient management. Over the last decade, great effort has been made to develop non-invasive liver fibrosis tests. The ensuing increase of literature is, however, impaired by extensive heterogeneity in the quality of published reports. The Standards for Reporting of Diagnostic Accuracy Studies (STARD), first published in 2003, were developed to improve the quality of research reports on diagnostic studies. We aimed to evaluate STARD statements in the setting of diagnostic studies on non-invasive liver fibrosis tests, and to propose an extended version developed specifically for those studies., Methods: Eight French experts evaluated STARD statement adequacy in 10 studies on non-invasive liver fibrosis tests and then developed an extended version with a glossary. The new checklist and glossary were independently evaluated by seven international experts., Results: Fourteen of the 25 STARD items were considered only partially adequate for the evaluation of diagnostic studies on non-invasive liver fibrosis tests. Inter-expert agreement was at least very good for 8 STARD items (32%), moderate for 9 (36%), and poor or very poor for 8 (32%). The experts' proposals were developed into the new Liver-FibroSTARD standards including a checklist with 62 items/sub-items and a corresponding comprehensive glossary. New proposals were inserted in the 25 STARD items as a complementary module. Independent evaluation of the Liver-FibroSTARD checklist showed at least very good inter-expert agreement for 39 items/sub-items (63%), moderate agreement for 11 (18%), and poor or very poor agreement for only 12 (19%)., Conclusions: As a supplement of the STARD statements, the Liver-FibroSTARD checklist and its glossary are new tools specifically designed for the evaluation of diagnostic studies about non-invasive liver fibrosis tests., (Copyright © 2015. Published by Elsevier B.V.)

Background and Aim: The data on the prevalence and predictors of significant fibrosis (≥F2, METAVIR) in chronic hepatitis B virus (HBV) patients with low viremia are limited. We aimed to assess both the prevalence predictors of ≥F2 fibrosis in hepatitis B envelope antigen-negative patients with HBV DNA <20,000 IU/mL., Methods: Hepatitis B envelope antigen-negative patients (n=213) with mean HBV DNA <2000 IU/mL (n=97) and HBV DNA 2000 to 20,000 IU/mL (n=116) were included and all had liver biopsy. Variables significantly associated with ≥F2 fibrosis on an univariate analysis were included in a multivariate logistic regression model., Results: Overall, 40 (18.8%) patients had ≥F2 fibrosis, with no difference between those with mean HBV DNA <2000 IU/mL (19.6%) compared with patients with HBV DNA of 2000 to 20,000 IU/mL (18.1%; P=0.782). Fibrosis ≥F2 was similar in patients with HBV DNA <2000 versus 2000 to 20,000 IU/mL in relation to varying alanine aminotransferase thresholds (P>0.05), and was less frequent in persistently normal alanine aminotransferase patients (13.6%) when compared with those with elevated or fluctuating levels (25.3%, P=0.030). Fewer patients under 40 years of age had ≥F2 fibrosis (12.5%) as compared with older ones (28.2%; P=0.004). Logistic regression analysis identified higher aspartate aminotransferase [odds ratio (OR), 6.21; 95% confidence interval (CI), 2.48-15.54; P<0.0001], lower albumin (OR, 0.86; 95% CI, 0.78-0.95; P=0.002), platelet count (OR, 0.99; 95% CI, 0.98-0.99; P=0.013), and age (OR, 1.05; 95% CI, 1.01-1.09; P=0.024) as independent predictors of significant fibrosis., Conclusions: A small but significant minority of HBV patients with low viremia harbor significant fibrosis, although its rate is not different in those with viremia above or below 2000 IU/mL. Our findings may guide in decisions regarding liver biopsy and treatment in this category of patients.

Background: Liver stiffness measurement (LSM) using transient elastography is widely used in the management of patients with chronic liver disease., Objectives: To examine the feasibility and reliability of LSM, and to identify patient and operator characteristics predictive of poorly reliable results., Methods: The present retrospective study investigated the frequency and determinants of poorly reliable LSM (interquartile range [IQR]⁄median LSM [IQR⁄M] >30% with median liver stiffness ≥7.1 kPa) using the FibroScan (Echosens, France) over a three-year period. Two experienced operators performed all LSMs. Multiple logistic regression analyses examined potential predictors of poorly reliable LSMs including age, sex, liver disease, the operator, operator experience (<500 versus ≥500 scans), FibroScan probe (M versus XL), comorbidities and liver stiffness. In a subset of patients, medical records were reviewed to identify obesity (body mass index ≥30 kg⁄m2)., Results: Between July 2008 and June 2011, 2335 patients with liver disease underwent LSM (86% using the M probe). LSM failure (no valid measurements) occurred in 1.6% (n=37) and was more common using the XL than the M probe (3.4% versus 1.3%; P=0.01). Excluding LSM failures, poorly reliable LSMs were observed in 4.9% (n=113) of patients. Independent predictors of poorly reliable LSM included older age (OR 1.03 [95% CI 1.01 to 1.05]), chronic pulmonary disease (OR 1.58 [95% CI 1.05 to 2.37), coagulopathy (OR 2.22 [95% CI 1.31 to 3.76) and higher liver stiffness (OR per kPa 1.03 [95% CI 1.02 to 1.05]), including presumed cirrhosis (stiffness ≥12.5 kPa; OR 5.24 [95% CI 3.49 to 7.89]). Sex, diabetes, the underlying liver disease and FibroScan probe were not significant. Although reliability varied according to operator (P<0.0005), operator experience was not significant. In a subanalysis including 434 patients with body mass index data, obesity influenced the rate of poorly reliable results (OR 2.93 [95% CI 0.95 to 9.05]; P=0.06)., Conclusions: FibroScan failure and poorly reliable LSM are uncommon. The most important determinants of poorly reliable results are older age, obesity, higher liver stiffness and the operator, the latter emphasizing the need for adequate training.

Objective: To determine practices among physicians in Canada for the assessment of liver fibrosis in patients with chronic liver diseases., Methods: Hepatologists, gastroenterologists, infectious diseases specialists, members of the Canadian Gastroenterology Association and⁄or the Canadian HIV Trials Network who manage patients with liver diseases were invited to participate in a web-based, national survey., Results: Of the 237 physicians invited, 104 (43.9%) completed the survey. Routine assessment of liver fibrosis was requested by the surveyed physicians mostly for chronic hepatitis C (76.5%), followed by autoimmune⁄cholestatic liver disease (59.6%) and chronic hepatitis B (52.9%). Liver biopsy was the main diagnostic tool for 46.2% of the respondents, Fibroscan (Echosens, France) for 39.4% and Fibrotest (LabCorp, USA) for 7.7%. Etiology-specific differences were observed: noninvasive methods were mostly used for hepatitis C (63% versus 37% liver biopsy) and hepatitis B (62.9% versus 37.1% liver biopsy). For 42.7% of respondents, the use of noninvasive methods reduced the need for liver biopsy by >50%. Physicians' characteristics associated with higher use of noninvasive methods were older age and being based at a university hospital or in private practice versus community hospital. Physicians' main concerns regarding noninvasive fibrosis assessment methods were access⁄availability (42.3%), lack of guidelines for clinical use (26.9%) and cost⁄lack of reimbursement (14.4%)., Conclusions: Physicians who manage patients with chronic liver diseases in Canada require routine assessment of liver fibrosis stage. Although biopsy remains the primary diagnostic tool for almost one-half of respondents, noninvasive methods, particularly Fibroscan, have significantly reduced the need for liver biopsy in Canada. Limitations in access to and availability of the noninvasive methods represent a significant barrier. Finally, there is a need for clinical guidelines and a better reimbursement policy to implement noninvasive tools to assess liver fibrosis.

Background & Aims: Differing threshold levels of hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) are recommended by international guidelines for commencement of antiviral therapy. These guidelines advocate therapy for patients with significant fibrosis (METAVIR score ≥F2); we assessed the accuracy of these guideline-defined thresholds in identifying patients with ≥F2 fibrosis., Methods: We applied the European (European Association for the Study of the Liver [EASL] 2012), Asian-Pacific (Asian-Pacific Association for the Study of the Liver [APASL] 2012), American (American Association for the Study of Liver Diseases [AASLD] 2009), and United States Panel Algorithm (USPA 2008) criteria to 366 consecutive hepatitis B e antigen-negative patients with liver biopsy samples: EASL, ALT >laboratory-defined upper limit of normal (ULN) and HBV DNA ≥2000 IU/mL (n = 171); APASL, ALT >2-fold laboratory-defined ULN and HBV DNA ≥2000 IU/mL (n = 87); AASLD, ALT >2-fold the updated ULN (0.5-fold ULN [corresponding to ≤19 U/L] for women and 0.75-fold the ULN [corresponding to ≤30 U/L] for men) and HBV DNA ≥20,000 IU/mL (n = 53); and USPA, ALT >updated ULN (>0.5-fold ULN for women and >0.75-fold ULN for men) and HBV DNA ≥2000 IU/mL (n = 173)., Results: Overall, 113 patients (30.9%) had ≥F2 fibrosis, which was more frequent among patients who fulfilled any guideline criteria (45.7% vs 17.9% for those who did not fulfill any criteria, P < .0001). In applying the EASL, AASLD, APASL, and USPA criteria, sensitivity and specificity values for detection of ≥F2 fibrosis were 45.6%, 58.5%, 56.3%, and 45.7% (P = .145) and 82.1%, 73.8%, 77.1%, and 82.4% (P = .366), respectively. The EASL criteria (area under the receiver operating characteristic [AUROC] curve, 0.66; 95% confidence interval [CI], 0.61-0.71) and USPA criteria (AUROC, 0.66; 95% CI, 0.58-0.73) performed better than APASL (AUROC, 0.64; 95% CI, 0.59-0.69; P = .421) and significantly better than the AASLD criteria (AUROC, 0.59; 95% CI, 0.54-0.64; P = .013)., Conclusions: In hepatitis B e antigen-negative patients with chronic hepatitis, the EASL, AASLD, APASL, and USPA criteria identify patients with ≥F2 fibrosis with low levels of accuracy. However, the EASL and USPA criteria are the most accurate for identification of these patients., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: An estimated one in 10 Canadians have some form of liver disease. The reference standard for staging and monitoring liver fibrosis is percutaneous liver biopsy--an invasive procedure associated with risks and complications. Transient elastography (TE) represents a noninvasive, ultrasound-based alternative., Objective: To assess the efficacy of TE compared with liver biopsy for fibrosis staging in adults with five common types of liver disease: hepatitis B, hepatitis C, nonalcoholic fatty liver disease, cholestatic liver disease and complications post-liver transplantation., Methods: A systematic review of published and grey literature from 2001 to June 2011 was conducted. Included were observational studies evaluating the accuracy of TE using liver biopsy as the comparator. An economic model was developed to estimate the cost per correct diagnosis gained with liver biopsy compared with TE. Identification of moderate fibrosis (stages 2 to 4) and cirrhosis (stage 4) were considered., Results: Fifty-seven studies were included in the review. The diagnostic accuracy of TE for the five clinical subgroups had sensitivities ranging from 0.67 to 0.92 and specificities ranging from 0.72 to 0.95. Liver biopsy was associated with an additional $1,427 to $7,030 per correct diagnosis gained compared with TE. The model was sensitive to the sensitivity and specificity of TE and the prevalence of fibrosis., Conclusions: TE is an accurate diagnostic method in patients with moderate fibrosis or cirrhosis. TE is less effective but less expensive than liver biopsy. Systemic implementation of TE should be considered for the noninvasive assessment of liver fibrosis.

Background: The success of liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is influenced by anthropometric factors. In smaller adults, the M probe may fail due to narrow intercostals spaces and rib interference. We aimed to compare LSM using the FibroScan S2 (pediatric) probe with the M probe in small adults with chronic liver disease., Material and Methods: In this prospective study, 41 liver disease patients and 18 controls with a thoracic perimeter ≤ 75 cm underwent LSM using the FibroScan M and S2 probes. TE failure was defined as no valid LSMs and unreliable examinations as < 10 valid LSMs, an interquartile range (IQR)/LSM > 30%, or success rate < 60%., Results: TE failure was not observed and reliability did not differ between the M and S2 probes (86% vs. 95%; P = 0.20). Liver stiffness measured using the M and S2 probes was highly correlated (ρ = 0.81; P < 0.0005) and median liver stiffness did not differ between probes (4.5 vs. 4.4 kPa; P = 0.10). However, in participants with a skin-capsular distance ≥ 15 mm, median liver stiffness was higher using the S2 probe (5.5 vs. 4.9 kPa; P = 0.008). When compared with validated liver stiffness cut-offs, the S2 probe would have overestimated the stage of fibrosis compared with the M probe in 10% of patients., Conclusions: The FibroScan S2 probe does not improve the feasibility of LSM in adults of smaller stature and may overestimate liver stiffness compared with the M probe. The FibroScan M probe should remain the preferred tool for LSM in small adults with chronic liver disease.

As detected by cross-sectional imaging, severe muscle depletion, which is termed sarcopenia, holds promise for prognostication in patients with cirrhosis. Our aims were to describe the prevalence and predictors of sarcopenia in patients with cirrhosis listed for liver transplantation (LT) and to determine its independent prognostic significance for the prediction of waiting-list mortality. Adults listed for LT who underwent abdominal computed tomography/magnetic resonance imaging within 6 weeks of activation were retrospectively identified. The exclusions were hepatocellular carcinoma, acute liver failure, prior LT, and listing for multivisceral transplantation or living related LT. Sixty percent of the 142 eligible patients were male, the median age was 53 years, and the median Model for End-Stage Liver Disease (MELD) score at listing was 15. Forty-one percent were sarcopenic; sarcopenia was more prevalent in males versus females (54% versus 21%, P < 0.001) and increased with the Child-Pugh class (10% for class A, 34% for class B, and 54% for class C, P = 0.007). Male sex, the dry-weight body mass index (BMI), and Child-Pugh class C cirrhosis (but not the MELD score) were independent predictors of sarcopenia. Sarcopenia was an independent predictor of mortality (hazard ratio = 2.36, 95% confidence interval = 1.23-4.53) after adjustments for age and MELD scores. In conclusion, sarcopenia is associated with increased waiting-list mortality and is poorly predicted by subjective nutritional assessment tools such as BMI and subjective global assessment. If this is validated in larger studies, the objective assessment of sarcopenia holds promise for prognostication in this patient population., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Hospital outcome report cards are used to judge provider performance, including for liver transplantation. We aimed to determine the impact of the choice of risk adjustment method on hospital rankings based on mortality rates in cirrhotic patients., Material and Methods: We identified 68,426 cirrhotic patients hospitalized in the Nationwide Inpatient Sample database. Four risk adjustment methods (the Charlson/Deyo and Elixhauser algorithms, Disease Staging, and All Patient Refined Diagnosis Related Groups) were used in logistic regression models for mortality. Observed to expected (O/E) death rates were calculated for each method and hospital. Statistical outliers with higher or lower than expected mortality were identified and rankings compared across methods., Results: Unadjusted mortality rates for the 553 hospitals ranged from 1.4 to 30% (overall, 10.6%). For 163 hospitals (29.5%), observed mortality differed significantly from expected when judged by one or more, but not all four, risk adjustment methods (25.9% higher than expected mortality and 3.6% lower than expected mortality). Only 28% of poor performers and 10% of superior performers were consistently ranked as such by all methods. Agreement between methods as to whether hospitals were flagged as outliers was moderate (kappa 0.51-0.59), except the Charlson/Deyo and Elixhauser algorithms which demonstrated excellent agreement (kappa 0.75)., Conclusions: Hospital performance reports for patients with cirrhosis require sensitivity to the method of risk adjustment. Depending upon the method, up to 30% of hospitals may be flagged as outliers by one, but not all methods. These discrepancies could have important implications for centers erroneously labeled as high mortality outliers.

Background: Accurate tools for the noninvasive detection of hepatic steatosis are needed. The Controlled Attenuation Parameter (CAP) specifically targets liver steatosis using a process based on transient elastography., Methods: Patients with chronic liver disease and body mass index (BMI) ≥28 kg/m(2) underwent biopsy and liver stiffness measurement (LSM) with simultaneous CAP determination using the FibroScan(®) M probe. The performance of the CAP for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROC)., Results: A total of 153 patients were included: 69% were male, median BMI was 32 kg/m(2); 47% had nonalcoholic fatty liver disease (NAFLD); and 65% had significant (≥10%) steatosis. The CAP was significantly correlated with the percentage of steatosis (ρ = 0.47) and steatosis grade (ρ = 0.51; both P < 0.00005). The median CAP was higher among patients with significant steatosis (317 [IQR 284-339] vs. 250 [227-279] dB/m with <10% steatosis; P < 0.0005) and the AUROC for this outcome was 0.81 (95% CI 0.74-0.88). At a cut-off of 283 dB/m, the CAP was 76% sensitive, 79% specific, and had positive and negative predictive values of 87% and 64%, respectively. CAP performance was not influenced by measurement variability, but was higher in patients with mild (F0-F1) fibrosis (AUROC 0.89 vs. 0.72 with F2-F4; P = 0.03). The AUROCs of the CAP for ≥5%, >33% and >66% steatosis were 0.79, 0.76 and 0.70, respectively., Conclusions: The CAP is a promising tool for the noninvasive detection of hepatic steatosis. Advantages of CAP include its ease of measurement, operator-independence and simultaneous availability with LSM for fibrosis assessment., (© 2012 John Wiley & Sons A/S.)

Background & Aims: The FibroScan XL probe facilitates liver stiffness measurement (LSM) by transient elastography (TE) in obese patients, yet factors affecting its accuracy have not been described. Our objectives were to examine the prevalence, risk factors, and causes of discordance between fibrosis estimated by the FibroScan XL probe and biopsy., Methods: Two hundred and ten patients with chronic liver disease (45% viral hepatitis, 55% nonalcoholic fatty liver disease (NAFLD) and a body mass index (BMI) ≥ 28 kg/m(2)) underwent liver biopsy and TE with the FibroScan XL probe. Predictors of discordance ≥ 2 fibrosis stages between measures, which occurred in 11% of patients (n=24), were identified by comparing patient, TE, and biopsy characteristics of discordant and non-discordant cases., Results: Fibrosis estimated by the FibroScan XL probe was greater than biopsy in 75% (18/24) of discordant cases. Although biopsy quality was not associated with discordance, discordant cases were less likely to have ≥ 10 valid shots (75% vs. 97%; p=0.001), a success rate ≥ 60% (67% vs. 95%; p <0.0005), and an interquartile range over median liver stiffness (IQR/M) <21% (37% vs. 57%; p=0.07) than non-discordant cases. However, only increased BMI (odds ratio [OR] 1.09 per kg/m(2); 95% confidence interval [CI] 1.01-1.18; p=0.04) was independently associated with discordance; liver stiffness was of borderline significance (OR 1.73 per log(10)-transformed value; 95% CI 0.95-3.18; p=0.08). Discordance was 4- to 5-fold more frequent among patients with severe obesity (BMI ≥ 40 kg/m(2): 32% vs. 8%) and liver stiffness above the median of 7.0 kPa (20% vs. 4%; both p <0.0005)., Conclusions: Discordance between liver fibrosis estimated by biopsy and TE using the FibroScan XL probe was infrequent in this obese population. Patients with severe obesity and elevated liver stiffness have the greatest risk of discordance., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Noninvasive biomarkers of liver fibrosis represent an intense area of research with the goals of improving patient care, disease stratification, and aiding the development of future antifibrotic therapies. Despite the rapid progress in recent years, there remain questions about how diagnostic studies are designed, statistical methods to account for spectrum bias, clinically relevant thresholds of fibrosis that should be delineated, how diagnostics can be improved, and strengthening the reference test to judge emerging biomarkers. This review discusses the current methods to address these issues and where further progress is needed., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background: Liver stiffness measurement (LSM) using transient elastography (TE) is a promising tool for the noninvasive assessment of hepatic fibrosis., Objectives: To determine the feasibility and performance of TE in a North American cohort of patients with chronic liver disease., Methods: LSMs were obtained using TE in 260 patients with chronic hepatitis B or C, or nonalcoholic fatty liver disease from four Canadian hepatology centres. The accuracy of TE compared with liver biopsy for the prediction of significant fibrosis (Metavir fibrosis score of F2 or greater), bridging fibrosis (Metavir fibrosis score of F3 or greater) and cirrhosis (Metavir fibrosis score of F4 ) was assessed using area under ROC curves (AUROCs), and compared with the aspartate aminotransferase-to-platelet ratio index. The influence of alanine aminotransferase (ALT) levels and other factors on liver stiffness was determined using linear regression analyses., Results: failure of TE occurred in 2.7% of patients, while liver biopsies were inadequate for staging in 0.8%. Among the remaining 251 patients, the AUROCs of TE for Metavir fibrosis scores of F2 and F3 or greater, and F4 were 0.74 (95% CI 0.68 to 0.80), 0.89 (95% CI 0.84 to 0.94), and 0.94 (95% CI 0.90 to 0.97), respectively. LSM was more accurate than the aminotransferase-to-platelet ratio index for bridging fibrosis (AUROC 0.78) and cirrhosis (AUROC 0.88), but not significant fibrosis (AUROC 0.76). At a cut-off of 11.1 kPa, the sensitivity, specificity, and positive and negative predictive values for cirrhosis (prevalence 11%) were 96%, 81%, 39% and 99%, respectively. For significant fibrosis (prevalence 53%), a cut-off of 7.7 kPa was 68% sensitive and 69% specific, and had a positive predictive value of 70% and a negative predictive value of 65%. Liver stiffness was independently associated with ALT, body mass index and steatosis. The optimal LSM cut-offs for cirrhosis were 11.1 kPa and 11.5 kPa in patients with ALT levels lower than 100 U⁄L and 100 U⁄L or greater, respectively. For fibrosis scores of F2 or greater, these figures were 7.0 kPa and 8.6 kPa, respectively., Conclusions: the major role of TE is the exclusion of bridging fibrosis and cirrhosis. However, TE cannot replace biopsy for the diagnosis of significant fibrosis. Because liver stiffness may be influenced by significant ALT elevation, body mass index and⁄or steatosis, tailored liver stiffness cut-offs may be necessary to account for these factors.

Background and Aims: Liver stiffness measurement (LSM) by transient elastography (TE) is widely used for the noninvasive assessment of fibrosis. Our objectives were to examine the prevalence, risk factors and causes of discordance between fibrosis estimated by TE and liver biopsy., Methods: Two hundred and fifty-one patients with hepatitis B, C and nonalcoholic fatty liver disease underwent LSM by TE and liver biopsy. Predictors of discordance (≥2 fibrosis stages) between measures, which occurred in 14% of patients (n=35), were identified by comparing patient, TE and biopsy characteristics of discordant and nondiscordant cases., Results: According to predefined criteria, 40% of discordances were attributed to TE error and 23% to biopsy error; 37% were indeterminate. In multivariate analysis, mild fibrosis (F0-2 vs. F3-4), and higher body mass index (BMI), ALT and LSM variability [assessed by the ratio of the interquartile range to median LSM (IQR/M)] were independently associated with discordance. Discordance was three-fold more common in patients with obesity (28 vs. 9%), ALT ≥60 U/L (20 vs. 7%) and IQR/M ≥0.17 (22 vs. 7%; all P<0.005). Based on these variables, a discordance risk score assigning 1 point to each factor was developed. The prevalence of discordance in patients with 0, 1, 2 and 3 factors were 2, 7, 20, and 55% respectively (P<0.0005)., Conclusions: Discordance between liver fibrosis estimated by TE and biopsy occurs in one in seven patients. In assessing the validity of TE results, clinicians must recognize risk factors for discordance and in at-risk patients, consider alternative measures including biomarkers and possibly biopsy., (© 2010 John Wiley & Sons A/S.)

Background: The outcomes of pregnancy in patients with cirrhosis are poorly described. Our objective was to assess obstetric outcomes in cirrhotic women and their infants from a population-based perspective., Methods: We analysed the 1993-2005 US Nationwide Inpatient Sample database to identify obstetric hospitalizations among patients with cirrhosis (n=339) and controls matched on age, hospital and year (n=6625). The effect of cirrhosis on maternal and fetal outcomes was evaluated using regression models with adjustment for patient and hospital factors., Results: Between 1993 and 2005, 114 antepartum and 225 delivery admissions in cirrhotic patients were identified. The estimated mean number of deliveries nationwide increased from 68 to 106 annually between 1993 and 1999 and 2000 and 2005 (P=0.0004). Patients with cirrhosis were more likely to deliver by caesarean [42 vs. 28%; adjusted odds ratio (OR) 1.41; 95% confidence interval (CI) 1.06-1.88]. Maternal (1.8 vs. 0%; P<0.0001) and fetal mortality (5.2 vs. 2.1%; P<0.0001), antepartum admission (OR 2.97; 95% CI 2.24-3.96), and maternal (OR 2.03; 95% CI 1.60-2.57) and fetal complications (OR 3.66; 95% CI 2.74-4.88) were greater among cirrhotic patients than controls. Gestational hypertension, placental abruption and uterovaginal haemorrhage were more common in patients with cirrhosis; their infants had higher rates of prematurity and growth restriction. Hepatic decompensation occurred in 15%, including ascites in 11% and variceal haemorrhage in 5%. In women with decompensation, maternal and fetal mortality were 6 and 12% respectively., Conclusions: Although rare, pregnancies among women with cirrhosis are increasing. Cirrhotic patients and their infants have an increased risk of obstetric complications, emphasizing the importance of close maternal-fetal monitoring during pregnancy.

Background: The risk of cardiac surgery in patients with cirrhosis is poorly defined. Our objective was to describe outcomes of coronary artery bypass graft (CABG) surgery in cirrhotic patients from a population-based perspective., Methods: We analysed the 1998-2004 Nationwide In-patient Sample to identify patients hospitalized for CABG surgery. The effect of cirrhosis on mortality, complications, length of stay (LOS) and charges was evaluated using logistic regression models., Results: Between 1998 and 2004, there were 403 094 CABG admissions; 711 patients (0.2%) had cirrhosis. The average annual number of surgeries increased 4.2% [95% confidence interval (CI) 0.7-7.8] in cirrhotic patients, but decreased 5.5% (3.4-7.5) in non-cirrhotic patients. Patients with cirrhosis had an increased risk of mortality [17 vs. 3%; adjusted odds ratio (OR) 6.67; 95% CI 5.31-8.31], complications [43 vs. 28%; OR 1.99 (95% CI 1.72-2.30)] and greater LOS and charges (P<0.0001). Predictors of mortality included age over 60 (OR 2.21; 95% CI 1.31-3.73), female gender (OR 1.92; 95% CI 1.08-3.41), ascites (OR 3.80; 95% CI 1.95-7.39) and congestive heart failure (OR 1.75; 95% CI 1.08-2.84). Hospital volume and off-pump CABG did not affect mortality., Conclusions: Patients with cirrhosis have an increased risk of morbidity and mortality following CABG surgery. Additional studies are necessary to refine risk stratification in this high-risk patient population.

Background & Aims: Patients discharged from hospital against medical advice are at risk of adverse health outcomes. The frequency and predictors of self-discharge in cirrhotic patients have not been examined., Methods: By using the 1993-2005 US Nationwide Inpatient Sample, we identified 581,380 cirrhotic patients who had been admitted to hospitals. The proportion discharged against medical advice and predictors of self-discharge were analyzed by using regression models with adjustments for clinical factors, including illness severity., Results: Of the patients with cirrhosis identified, 2.8% left their hospital against medical advice. Self-discharge was most common in patients with alcoholic cirrhosis (4.2%) and hepatitis B or C ( approximately 3%) and least common among those with chronic cholestasis (0.4%). Independent predictors of self-discharge included male sex, younger age, non-private insurance, and admission to urban, nonteaching hospitals. Patients undergoing surgery and those with more comorbidities were less likely to leave against medical advice, whereas those with human immunodeficiency virus, drug and alcohol abuse, or psychosis were more likely to leave against medical advice. Self-discharge was less common among patients with hepatic decompensation (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.76-0.82), primary liver cancer (OR, 0.49; 95% CI, 0.41-0.59), or prior transplantation (OR, 0.37; 95% CI, 0.25-0.55). Length of stay and hospital charges were lower in patients discharged against medical advice (P < .0001)., Conclusions: Approximately 1 in 36 hospitalized cirrhotic patients leave hospital against medical advice. Self-discharge is most common among patients with alcoholic cirrhosis, lower socioeconomic status, psychiatric disorders, substance abuse, and less severe liver disease. These findings might assist in the prevention of self-discharge and, ultimately, improve health outcomes in patients with cirrhosis.

Unlabelled: Risk-adjusted health outcomes are often used to measure the quality of hospital care, yet the optimal approach in patients with liver disease is unclear. We sought to determine whether assessments of illness severity, defined as risk for in-hospital mortality, vary across methods in patients with cirrhosis. We identified 258,731 patients with cirrhosis hospitalized in the Nationwide Inpatient Sample between 2002 and 2005. The performance of four common risk adjustment methods (the Charlson/Deyo and Elixhauser comorbidity algorithms, Disease Staging, and All Patient Refined Diagnosis Related Groups [APR-DRGs]) for predicting in-hospital mortality was determined using the c-statistic. Subgroup analyses were conducted according to a primary versus secondary diagnosis of cirrhosis and in homogeneous patient subgroups (hepatic encephalopathy, hepatocellular carcinoma, congestive heart failure, pneumonia, hip fracture, and cholelithiasis). Patients were also ranked according to the probability of death as predicted by each method, and rankings were compared across methods. Predicted mortality according to the risk adjustment methods agreed for only 55%-67% of patients. Similarly, performance of the methods for predicting in-hospital mortality varied significantly. Overall, the c-statistics (95% confidence interval) for the Charlson/Deyo and Elixhauser algorithms, Disease Staging, and APR-DRGs were 0.683 (0.680-0.687), 0.749 (0.746-0.752), 0.832 (0.829-0.834), and 0.875 (0.873-0.878), respectively. Results were robust across diagnostic subgroups, but performance was lower in patients with a primary versus secondary diagnosis of cirrhosis., Conclusion: Mortality analyses in patients with cirrhosis require sensitivity to the method of risk adjustment. Because different methods often produce divergent severity rankings, analyses of provider-specific outcomes may be biased depending on the method used.

Background: Accurately staging hepatitis C virus (HCV)-related fibrosis is crucial for treatment decisions and prognostication. Our objective was to systematically review studies describing the accuracy of serum marker panels for predicting fibrosis in HIV/HCV-coinfected patients., Method: Studies comparing serum marker panels with biopsy in HIV/HCV-coinfected patients were identified. Random effects meta-analyses and areas under summary receiver operating characteristics curves (AUC) examined test accuracy for detecting significant fibrosis (F2-4) and cirrhosis. Heterogeneity was explored using meta-regression., Results: Five studies (n = 574) including four fibrosis measures (APRI [n = 4 studies], Forns' [n = 2], FibroTest [n = 1], SHASTA [n = 1]) met the inclusion criteria. The prevalence of significant fibrosis and cirrhosis were 51% and 16%, respectively. For the prediction of significant fibrosis, the summary AUC was 0.82 (95% CI 0.78-86) and diagnostic odds ratio was 7.8 (5.1-11.9). For cirrhosis, these figures were 0.83 (0.69-0.97) and 11.0 (4.6-26.2), respectively. Meta-regression including study factors (methodological quality and biopsy adequacy), patient characteristics (age, gender, CD4 count), and fibrosis measure failed to identify important predictors of accuracy., Conclusion: Available fibrosis marker panels have acceptable performance for identifying significant fibrosis and cirrhosis in HIV/HCV-coinfected patients but are not yet adequate to replace liver biopsy. Additional studies are necessary to identify the optimal measure.

Background: The accurate diagnosis of hepatitis C virus (HCV)-related fibrosis is crucial for prognostication and treatment decisions. Due to the limitations of biopsy, noninvasive alternatives including FibroTest and FibroScan have been developed. Our objective was to systematically review studies describing the accuracy of these tests for predicting HCV-related fibrosis., Methods: Studies comparing FibroTest or FibroScan versus biopsy in HCV patients were identified via an electronic search. Random effects meta-analyses and areas under summary receiver operating characteristics curves (AUC) were examined to characterize test accuracy for significant fibrosis (F2-4) and cirrhosis. Heterogeneity was explored using meta-regression., Results: Twelve studies were identified, 9 for FibroTest (N = 1,679) and 4 for FibroScan (N = 546). In heterogeneous analyses for significant fibrosis, the AUCs for FibroTest and FibroScan were 0.81 (95% CI 0.78-84) and 0.83 (0.03-1.00), respectively. At a threshold of approximately 0.60, the sensitivity and specificity of the FibroTest were 47% (35-59%) and 90% (87-92%). For FibroScan (threshold approximately 8 kPa), corresponding values were 64% (50-76%) and 87% (80-91%), respectively. Methodological quality, the length of liver biopsy specimens, and inclusion of special populations did not explain the observed heterogeneity. However, the diagnostic accuracy of both measures was associated with the prevalence of significant fibrosis and cirrhosis in the study populations. For cirrhosis, the summary AUCs for FibroTest and FibroScan were 0.90 (95% CI not calculable) and 0.95 (0.87-0.99), respectively., Conclusions: FibroTest and FibroScan have excellent utility for the identification of HCV-related cirrhosis, but lesser accuracy for earlier stages. Refinements are necessary before these tests can replace liver biopsy.

Unlabelled: The development of noninvasive markers of liver fibrosis is a clinical and research priority. The aspartate aminotransferase-to-platelet ratio index (APRI) is a promising tool with limited expense and widespread availability. Our objective was to systematically review the performance of the APRI in hepatitis C virus (HCV)-infected patients. Random effects meta-analyses and areas under summary receiver operating characteristic curves (AUC) were examined to characterize APRI accuracy for significant fibrosis (stages 2-4) and cirrhosis. In 22 studies (n = 4,266), the summary AUCs of the APRI for significant fibrosis and cirrhosis were 0.76 [95% confidence interval (CI), 0.74-0.79] and 0.82 (95%CI, 0.79-0.86), respectively. For significant fibrosis, an APRI threshold of 0.5 was 81% sensitive and 50% specific. At a 40% prevalence of significant fibrosis, this threshold had a negative predictive value (NPV) of 80%, but could reduce the necessity of liver biopsy by only 35%. For cirrhosis, a threshold of 1.0 was 76% sensitive and 71% specific. At a 15% cirrhosis prevalence, the NPV of this threshold was 91%. Higher APRI thresholds had suboptimal positive predictive values except in settings with a high prevalence of cirrhosis. APRI accuracy was not affected by the prevalence of advanced fibrosis, or study and biopsy quality. However, the accuracy for cirrhosis was greater in studies including human immunodeficiency virus (HIV)/HCV-co-infected patients., Conclusion: The major strength of the APRI is the exclusion of significant HCV-related fibrosis. Future studies of novel markers should demonstrate improved accuracy and cost-effectiveness compared with this economical and widely available index.

Female sex is a protective factor for the progression of fibrosis in patients with chronic hepatitis C virus (HCV) infection. Experimental data suggest that estrogens may have an antifibrotic effect. The objective of this study was to evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV-infected women. Four hundred seventy-two HCV-infected women received a survey regarding prior pregnancies, menopause, and the use of oral contraceptives and HRT. The impact of these variables on liver fibrosis and its progression were evaluated using multivariate analyses considering all putative confounding factors. Two hundred one women completed the survey (43% response rate), 157 of whom had an estimated date of HCV infection (96 postmenopausal women, 96 women with previous pregnancies, and 105 women with past use of oral contraceptives). Through multivariate analyses, the estimated rate of fibrosis progression was higher in postmenopausal (P < .05) and nulliparous (P = .02) women and was associated with greater histological activity (P < .001). Prior use of oral contraceptives had no significant influence. Among postmenopausal women, the estimated rate of fibrosis progression (+/-SE) was lower in women who received HRT compared with untreated patients (0.099 +/- 0.016 vs. 0.133 +/- 0.006 METAVIR units/yr; P = .02) and was similar to that of premenopausal women (0.093 +/- 0.012 METAVIR units/yr; P value not significant). In conclusion, menopause appears to be associated with accelerated liver fibrosis progression in HCV-infected women, an effect that may be prevented by HRT. Pregnancies may have a beneficial impact on the long-term progression of liver fibrosis.