Publications by authors named "Arun J Sanyal"

451 Publications

Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD.

Hepatology 2022 May 13. Epub 2022 May 13.

Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

Background And Aims: Bile acids are hepatic metabolites and have many properties considered to be relevant to the pathophysiology of nonalcoholic fatty liver disease (NAFLD). Circulating levels of the intestinal microbiome-modified bile acid deoxycholate are increased in cirrhosis.

Methods: To further elucidate the role of bile acids and intestinal microbiota linked to bile acids in progressively severe NAFLD, a multi-omic study of feces including 16s rRNA sequencing, microbial transcriptomics and metabolomics was performed in a cohort with varying phenotypes of NAFLD.

Results: Several bile acids of microbial origin derived from deoxycholic acid (DCA) (glycodeoxycholate, 7-ketodeoxycholic acid, dehydrocholic acid) increased with disease activity and fibrosis stage. These were linked to increased expression of microbial bile salt hydrolase, bile acid operon (BaiCD) and hydroxysteroid dehydrogenases (hdhA) required for DCA and downstream metabolite synthesis providing a mechanistic basis for altered bile acid profiles with disease progression. Bacteroidetes and several genera of Lachnospiraceae family containing DCA generating genes increased with increasing disease severity, while several potentially beneficial microbes sensitive to antibacterial effects of DCA e.g. Ruminococcaceae were decreased. The clinical relevance of these data was confirmed in an independent cohort enrolled in a clinical trial for non-alcoholic steatohepatitis (NASH) where at entry DCA and its conjugates were associated with advanced fibrosis. In placebo treated patients, DCA declined in those with fibrosis regression and increased in those with fibrosis progression. DCA rose further in those with compensated cirrhosis when they experienced decompensation.

Conclusions: These novel findings demonstrate a role for bile acids and the bile acid dependent microbiome in the development and progression of NAFLD and set the stage to leverage these findings for NASH biomarker development and for therapeutics.
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http://dx.doi.org/10.1002/hep.32568DOI Listing
May 2022

Comprehensive Review and Updates on Holistic Approach Towards Non-Alcoholic Fatty Liver Disease Management with Cardiovascular Disease.

Curr Atheroscler Rep 2022 May 4. Epub 2022 May 4.

Division of Gastroenterology and Hepatology, Virginia Commonwealth University, Richmond, VA, 23298-0341, USA.

Purpose Of Review: The global prevalence of non-alcoholic fatty liver disease (NAFLD) presents an unmet need in treating these, often asymptomatic, individuals. In this review, we summarised NAFLD management and described recent developments in non-alcoholic steatohepatitis (NASH) therapeutics that can shape the future of NAFLD.

Recent Findings: A multi-disciplinary effort in promoting sustainable lifestyle measures is paramount, with the goal of either limiting energy surplus alone or in combination with targeting downstream pathways of inflammation and fibrosis. Several antidiabetic medications like PPAR-γ agonist and glucagon-like peptide receptor agonists have beneficial effects on the metabolic profile as well as NASH histology. Vitamin E has shown promise in specific groups of patients with the haptoglobin2 allele protein. Newer drugs have demonstrated promising results in NASH resolution and fibrosis improvement such as obeticholic acid, resmetirom, aramchol, efruxifermin, aldafermin and lanifibranor. Apart from discussing the results of late stage clinical trials and the possible challenges in managing these patients with limited approved therapies, we also discussed the specific management of comorbidities (diabetes, hypertension, hyperlipidaemia, cardiovascular diseases) in NAFLD patients. Treatment strategy needs to target improvements in liver-related outcomes and cardiometabolic profile.
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http://dx.doi.org/10.1007/s11883-022-01027-5DOI Listing
May 2022

Validation of the accuracy of the FAST™ score for detecting patients with at-risk nonalcoholic steatohepatitis (NASH) in a North American cohort and comparison to other non-invasive algorithms.

PLoS One 2022 15;17(4):e0266859. Epub 2022 Apr 15.

Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266859PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012361PMC
April 2022

Non-alcoholic fatty liver disease-associated DNA methylation and gene expression alterations in the livers of Collaborative Cross mice fed an obesogenic high-fat and high-sucrose diet.

Epigenetics 2022 Mar 24:1-15. Epub 2022 Mar 24.

Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease, and patient susceptibility to its onset and progression is influenced by several factors. In this study, we investigated whether altered hepatic DNA methylation in liver tissue correlates with the degree of severity of NAFLD-like liver injury induced by a high-fat and high-sucrose (HF/HS) diet in Collaborative Cross (CC) mice. Using genome-wide targeted bisulphite DNA methylation next-generation sequencing, we found that mice with different non-alcoholic fatty liver (NAFL) phenotypes could be distinguished by changes in hepatic DNA methylation profiles. Specifically, NAFL-prone male CC042 mice exhibited more prominent DNA methylation changes compared with male CC011 mice and female CC011 and CC042 mice that developed only a mild NAFL phenotype. Moreover, these mouse strains demonstrated different patterns of DNA methylation. While the HF/HS diet induced both DNA hypomethylation and DNA hypermethylation changes in all the mouse strains, the NAFL-prone male CC042 mice demonstrated a global predominance of DNA hypermethylation, whereas a more pronounced DNA hypomethylation pattern developed in the mild-NAFL phenotypic mice. In a targeted analysis of selected genes that contain differentially methylated regions (DMRs), we identified NAFL phenotype-associated differences in DNA methylation and gene expression of the , and genes in severe NAFL-prone mice but not in mice with mild NAFL phenotypes. These changes in the expression of and coincided with similar findings in a human in vitro cell model of diet-induced steatosis and in patients with NAFL. These results suggest that changes in the expression and DNA methylation status of these three genes may serve as a set of predictive markers for the development of NAFLD.
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http://dx.doi.org/10.1080/15592294.2022.2043590DOI Listing
March 2022

Comparison of clinical prediction rules for ruling out cirrhosis in nonalcoholic fatty liver disease (NAFLD).

Aliment Pharmacol Ther 2022 Jun 17;55(11):1441-1451. Epub 2022 Mar 17.

NAFLD Research Center, Department of Medicine, University of California San Diego, San Diego, California, USA.

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 <65, unlikely to have cirrhosis so higher-risk patients maintain access to specialty care.
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http://dx.doi.org/10.1111/apt.16874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098681PMC
June 2022

Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis.

Aliment Pharmacol Ther 2022 May 14;55(9):1076-1087. Epub 2022 Mar 14.

Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Centre, Los Angeles, California, USA.

Background And Aims: Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta-analysis evaluating drug classes through comparing histological outcomes and targets of drugs.

Approach And Results: Medline, EMBASE and CENTRAL were searched for randomised controlled trials evaluating NASH drugs in biopsy-proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, at least 2-point reduction in Non-alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and at least 1-point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. Among 49 included trials, treatments modulating energy (Risk ratio (RR): 1.92, Credible intervals (Crl): 1.59-2.34) were most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.66, Crl: 0.65-4.50), bile acids (RR: 1.37, Crl: 0.99-1.92) and inflammation (RR: 1.00, Crl: 0.75-1.33). Energy and bile acids modulation were effective in at least 2-point NAS reduction without worsening of fibrosis (RR: 1.52, Crl 1.30-1.77; RR: 1.69, Crl 1.41-2.03) and at least 1-point reduction in fibrosis (RR: 1.26, Crl:1.05-1.49; RR: 1.54, Crl: 1.20-1.97).

Conclusions: This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies.
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http://dx.doi.org/10.1111/apt.16808DOI Listing
May 2022

Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis.

Lancet Oncol 2022 Apr 4;23(4):521-530. Epub 2022 Mar 4.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA. Electronic address:

Background: The clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma.

Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios.

Findings: Of 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9-18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p<0·0001), had higher BMI (p<0·0001), and were more likely to present with metabolic comorbidities (diabetes [p<0·0001], hypertension [p<0·0001], and hyperlipidaemia [p<0·0001]) or cardiovascular disease at presentation (p=0·0055) than patients with hepatocellular carcinoma due to other causes. They were also more likely to be non-cirrhotic (38·5%, 27·9-50·2 vs 14·6%, 8·7-23·4 for hepatocellular carcinoma due to other causes; p<0·0001). Patients with NAFLD-related hepatocellular carcinoma had larger tumour diameters (p=0·0087), were more likely to have uninodular lesions (p=0·0003), and had similar odds of Barcelona Clinic Liver Cancer stages, TNM stages, alpha fetoprotein concentration, and Eastern Cooperative Oncology Group (ECOG) performance status to patients with non-NAFLD-related hepatocellular carcinoma. A lower proportion of patients with NAFLD-related hepatocellular carcinoma underwent surveillance (32·8%, 12·0-63·7) than did patients with hepatocellular carcinoma due to other causes (55·7%, 24·0-83·3; p<0·0001). There were no significant differences in treatment allocation (curative therapy, palliative therapy, and best supportive care) between patients with NAFLD-related hepatocellular carcinoma and those with hepatocellular carcinoma due to other causes. Overall survival did not differ between the two groups (hazard ratio 1·05, 95% CI 0·92-1·20, p=0·43), but disease-free survival was longer for patients with NAFLD-related hepatocellular carcinoma (0·79, 0·63-0·99; p=0·044). There was substantial heterogeneity in most analyses (I>75%), and all articles had low-to-moderate risk of bias.

Interpretation: NAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(22)00078-XDOI Listing
April 2022

Distinct hepatic immunological patterns are associated with the progression or inhibition of hepatocellular carcinoma.

Cell Rep 2022 03;38(9):110454

Department of Microbiology & Immunology, VCU School of Medicine, Richmond, VA 23298, USA; VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA. Electronic address:

To discover distinct immune responses promoting or inhibiting hepatocellular carcinoma (HCC), we perform a three-dimensional analysis of the immune cells, correlating immune cell types, interactions, and changes over time in an animal model displaying gender disparity in nonalcoholic fatty liver disease (NAFLD)-associated HCC. In response to a Western diet (WD), animals mount acute and chronic patterns of inflammatory cytokines, respectively. Tumor progression in males and females is associated with a predominant CD8 CD4, Th1 > Th17 > Th2, NKT > NK, M1 > M2 pattern in the liver. A complete rescue of females from HCC is associated with an equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern, while a partial rescue of males from HCC is associated with an equilibrium CD8 = CD4, NKT = NK and a semi-equilibrium Th1 = Th17 > Th2 but a sustained M1 > M2 pattern in the liver. Our data suggest that immunological pattern-recognition can explain immunobiology of HCC and guide immune modulatory interventions for the treatment of HCC in a gender-specific manner.
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http://dx.doi.org/10.1016/j.celrep.2022.110454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028248PMC
March 2022

NAFLD increases Risk of Carotid Atherosclerosis and Ischemic Stroke. An Updated Meta-Analysis with 135,602 Individuals.

Clin Mol Hepatol 2022 Mar 2. Epub 2022 Mar 2.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Background & Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) is associated with the development of cardiovascular disease. While existing studies have examined cardiac remodeling in NAFLD, there has been less emphasis on the development of carotid atherosclerosis and stroke. We sought to conduct a meta-analysis to quantify the prevalence, risk factors and degree of risk increment of carotid atherosclerosis and stroke in NAFLD.

Methods: Embase and Medline were searched for articles relating to NAFLD, carotid atherosclerosis, and stroke. Proportional data was analysed using a generalized linear mixed model. Pairwise meta-analysis was conducted to obtain odds ratio or weighted mean difference for comparison between patients with and without NAFLD.

Results: From pooled analysis of 30 studies involving 7,951 patients with NAFLD, 35.02% (95%CI: 27.36% to 43.53%) had carotid atherosclerosis with an odds ratio of 3.20 (95%CI: 2.37 to 4.32; p<0.0001). Pooled analysis of 25,839 patients with NAFLD found the prevalence of stroke to be 5.04% (95%CI: 2.74% to 9.09%) with an odds ratio of 1.88 (95%CI: 1.23 to 2.88; p=0.02) compared to non-NAFLD. The degree of steatosis assessed by ultrasonography in NAFLD was closely associated with increment in odds of carotid atherosclerosis and stroke. Older age significantly increased the odds of developing carotid atherosclerosis but not stroke in NAFLD.

Conclusions: This meta-analysis shows that a stepwise increment of steatosis of NAFLD can significantly increase the odds of carotid atherosclerosis and stroke development in NAFLD. More than a third suffer from carotid atherosclerosis and routine assessment of carotid atherosclerosis is quintessential in NAFLD.
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http://dx.doi.org/10.3350/cmh.2021.0406DOI Listing
March 2022

Generation of a Diet-Induced Mouse Model of Nonalcoholic Fatty Liver Disease.

Methods Mol Biol 2022 ;2455:19-30

Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.

The obesity epidemic is driving the increased prevalence of nonalcoholic fatty liver disease (NAFLD) globally. The more aggressive subtype of NAFLD, nonalcoholic steatohepatitis (NASH), can lead to progressive disease and ultimately lead to cirrhosis, liver cancer, and death. There are many unmet needs in the field of NAFLD including understanding of molecular mechanisms driving disease, natural history, risk for liver cancer, and most importantly FDA approved therapeutics. Animal models serve as a tool to aid in answering some of these questions. Here, we describe the diet-induced animal model of NAFLD (DIAMOND), a mouse model with many characteristics that mimic human NASH.
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http://dx.doi.org/10.1007/978-1-0716-2128-8_2DOI Listing
March 2022

Protein and miRNA profile of circulating extracellular vesicles in patients with primary sclerosing cholangitis.

Sci Rep 2022 02 22;12(1):3027. Epub 2022 Feb 22.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego, 3020 Children's Way, MC 5030, San Diego, CA, 92103-8450, USA.

Primary sclerosing cholangitis (PSC) is an idiopathic and heterogenous cholestatic liver disease characterized by chronic inflammation and fibrosis of the biliary tree. Currently, no effective therapies are available for this condition, whose incidence is rising. At present, specificity and sensitivity of current serum markers used to diagnose PSC are limited and often unreliable. In this study, we characterize circulating extracellular vesicles and provide supporting data on their potential use as novel surrogate biomarkers for PSC. EVs are membrane surrounded structures, 100-1000 nm in size, released by cells under various conditions and which carry a variety of bioactive molecules, including small non-coding RNAs, lipids and proteins. In recent years, a large body of evidence has pointed to diagnostic implications of EVs and relative cargo in various human diseases. We isolated EVs from serum of well-characterized patients with PSC or control subjects by differential centrifugation and size-exclusion chromatography. A complete characterization identified elevated levels of circulating EVs in PSC patients compared to healthy control subjects (2000 vs. 500 Calcein-FITC + EVs/μL). Tissue and cell specificity of circulating EVs was assessed by identification of liver-specific markers and cholangiocyte marker CK-19. Further molecular characterization identified 282 proteins that were differentially regulated in PSC-derived compared to healthy control-EVs. Among those, IL-13Ra1 was the most significantly and differentially expressed protein in PSC-derived EVs and correlated with the degree of liver fibrosis. In addition to protein profiling, we performed a miRNA-sequencing analysis which identified 11 among established, liver-specific (e.g., miR-122 and miR-192) and novel miRNAs. One of the newly identified miRNAs, miR-4645-3p, was significantly up-regulated fourfold in PSC-derived EVs compared to circulating EVs isolated from healthy controls. This study provides supporting evidence of the potential role of circulating EVs and associated protein and miRNA cargo as surrogate noninvasive and reliable biomarker for PSC.
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http://dx.doi.org/10.1038/s41598-022-06809-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8863778PMC
February 2022

Differential fuel utilization in liver transplant recipients and its relationship with non-alcoholic fatty liver disease.

Liver Int 2022 Feb 7. Epub 2022 Feb 7.

Division of Transplant Surgery, Virginia Commonwealth University, Richmond, Virginia, USA.

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT).

Methods: Patients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation).

Results: The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue.

Conclusion: Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT.
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http://dx.doi.org/10.1111/liv.15178DOI Listing
February 2022

Reply.

Hepatology 2022 Jan 31. Epub 2022 Jan 31.

Hospital Clinic-IDIBAPS and Ciberhed, University of Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1002/hep.32373DOI Listing
January 2022

Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD.

J Hepatol 2022 May 25;76(5):1030-1041. Epub 2022 Jan 25.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Electronic address:

Background & Aims: Histologically assessed hepatocyte ballooning is a key feature discriminating non-alcoholic steatohepatitis (NASH) from steatosis (NAFL). Reliable identification underpins patient inclusion in clinical trials and serves as a key regulatory-approved surrogate endpoint for drug efficacy. High inter/intra-observer variation in ballooning measured using the NASH CRN semi-quantitative score has been reported yet no actionable solutions have been proposed.

Methods: A focused evaluation of hepatocyte ballooning recognition was conducted. Digitized slides were evaluated by 9 internationally recognized expert liver pathologists on 2 separate occasions: each pathologist independently marked every ballooned hepatocyte and later provided an overall non-NASH NAFL/NASH assessment. Interobserver variation was assessed and a 'concordance atlas' of ballooned hepatocytes generated to train second harmonic generation/two-photon excitation fluorescence imaging-based artificial intelligence (AI).

Results: The Fleiss kappa statistic for overall interobserver agreement for presence/absence of ballooning was 0.197 (95% CI 0.094-0.300), rising to 0.362 (0.258-0.465) with a ≥5-cell threshold. However, the intraclass correlation coefficient for consistency was higher (0.718 [0.511-0.900]), indicating 'moderate' agreement on ballooning burden. 133 ballooned cells were identified using a ≥5/9 majority to train AI ballooning detection (AI-pathologist pairwise concordance 19-42%, comparable to inter-pathologist pairwise concordance of between 8-75%). AI quantified change in ballooned cell burden in response to therapy in a separate slide set.

Conclusions: The substantial divergence in hepatocyte ballooning identified amongst expert hepatopathologists suggests that ballooning is a spectrum, too subjective for its presence or complete absence to be unequivocally determined as a trial endpoint. A concordance atlas may be used to train AI assistive technologies to reproducibly quantify ballooned hepatocytes that standardize assessment of therapeutic efficacy. This atlas serves as a reference standard for ongoing work to refine how ballooning is classified by both pathologists and AI.

Lay Summary: For the first time, we show that, even amongst expert hepatopathologists, there is poor agreement regarding the number of ballooned hepatocytes seen on the same digitized histology images. This has important implications as the presence of ballooning is needed to establish the diagnosis of non-alcoholic steatohepatitis (NASH), and its unequivocal absence is one of the key requirements to show 'NASH resolution' to support drug efficacy in clinical trials. Artificial intelligence-based approaches may provide a more reliable way to assess the range of injury recorded as "hepatocyte ballooning".
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http://dx.doi.org/10.1016/j.jhep.2022.01.011DOI Listing
May 2022

Clinicopathological Profile and Outcome of a Large Cohort of Patients with Nonalcoholic Fatty Liver Disease from South Asia: Interim Results of the Indian Consortium on Nonalcoholic Fatty Liver Disease.

Metab Syndr Relat Disord 2022 Apr 25;20(3):166-173. Epub 2022 Jan 25.

Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.

Previous data from South Asia and India had shown that patients with nonalcoholic fatty liver disease (NAFLD) have mild liver disease severity. There are no data regarding long-term clinical outcomes in patients with NAFLD from South Asia. The aim of the study was to evaluate the clinicopathological profile, severity of NAFLD, and clinical outcomes in a large cohort of patients with NAFLD from South Asia. In an ongoing real-life study [Indian Consortium on nonalcoholic fatty liver disease (ICON-D)], interim data captured across 23 centers in India over 18 months was analyzed for clinicopathological profile, severity of NAFLD, and hepatic/extrahepatic events on follow-up. Of 4313 patients (mean age 45 ± 12.2 years, males 52%), data on metabolic risk factors in 3553 (82.3%) patients revealed that 378 (10.6%) were lean, 575 (16.2%) overweight, 2584 (72.7%) obese; metabolic syndrome in 1518 (42.7%) and at least one metabolic risk factor in 3292 (92.6%) patients. Evidence of significant or advanced fibrosis assessed with [aspartate transaminase to platelet ratio index (APRI),  = 3196 (74%)], [fibrosis-4 (FIB-4),  = 3554 (82.4%)], [NAFLD fibrosis score (NFS),  = 1924 (44.6%)], [Fibroscan,  = 2475, (57.3%)], and histology [ = 267 (6.2%)] was present in 682 (21.3%), 676 (19%), 397 (20.6%), 715 (29%), and 41 (15.4%) patients, respectively; 246 (10%) patients on Fibroscan and 22 (8.2%) on histology had evidence of cirrhosis. On a mean follow-up 43.5 months, hepatic and extrahepatic events recorded in 1353 (31.3%) patients showed that patients with compensated cirrhosis [71 (5.2%)] had more hepatic [26 (36.7%)] and extrahepatic events [8 (11.3%)] in comparison with those without cirrhosis ( < 0.0001). Around one fifth of patients with NAFLD in South Asia have significant liver disease. Both hepatic and extrahepatic events on follow-up are observed more commonly in patients with nonalcoholic steatohepatitis-related compensated cirrhosis.
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http://dx.doi.org/10.1089/met.2021.0104DOI Listing
April 2022

Nonalcoholic Fatty Liver Disease. Reply.

N Engl J Med 2022 01;386(3):296

Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1056/NEJMc2118255DOI Listing
January 2022

Derivation and Validation of a Model to Predict Clinically Significant Portal Hypertension Using Transient Elastography and FIB-4.

J Clin Gastroenterol 2022 Jan 10. Epub 2022 Jan 10.

Division of Gastroenterology, Hepatology, and Nutrition Department of Biostatistics Division of Interventional Radiology, Virginia Commonwealth University Division of Gastroenterology and Hepatology, Hunter-Holmes McGuire Veterans Affairs Medical Center, Richmond, VA Section of Digestive Diseases, Yale University, New Haven, CT.

Background: Liver biopsy and hepatic venous pressure gradient (HVPG), the gold standard for assessing advanced fibrosis (AF) and clinically significant portal hypertension (CSPH), are invasive, costly, and time-consuming.

Goal: We investigated if the combination of fibrosis index based on 4 factors (FIB-4) and liver stiffness measure (LSM) can identify AF and more importantly, CSPH.

Patients And Methods: Patients with chronic liver disease referred for transjugular liver biopsy were analyzed retrospectively. FIB-4 and LSM were compared with liver histology for diagnosing AF. FIB-4, LSM, and platelet count were compared with HVPG for diagnosing CSPH. Optimal cutoffs for predicting CSPH were determined by grid search. A composite log-odds to predict CSPH was derived from logistic regression using LSM, FIB-4, and gender. Internal bootstrap validation and external validation were performed.

Results: A total of 142 patients were included in the derivation; 42.3% had AF, and 11.3% had CSPH using the current gold standards. The area under the receiver operating characteristic curve (AUROC) for LSM, FIB-4, and their combination to predict AF were 0.7550, 0.7049, and 0.7768, respectively. LSM, FIB-4, and platelet count predicted CSPH with AUROC 0.6818, 0.7532, and 0.7240, respectively. LSM plus FIB-4 showed the best performance in predicting CSPH with AUROC 0.8155. Based on LSM, FIB-4, and gender, a novel model-the Portal Hypertension Assessment Tool (PHAT)-was developed to predict CSPH. PHAT score ≥-2.76 predicted CSPH with sensitivity 94%, specificity 67%, positive predictive value 27%, negative predictive value 99%, and accuracy 70%. In internal and external validation, AUROCs for the model were 0.8293 and 0.7899, respectively.

Conclusion: A model consisting of FIB-4, LSM, and gender can identify CSPH among patients with chronic liver disease.
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http://dx.doi.org/10.1097/MCG.0000000000001664DOI Listing
January 2022

Placebo effect on progression and regression in NASH: Evidence from a meta-analysis.

Hepatology 2022 Jun 24;75(6):1647-1661. Epub 2022 Jan 24.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Background And Aims: The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH.

Methods: A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences.

Results: This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients.

Conclusions: Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.
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http://dx.doi.org/10.1002/hep.32315DOI Listing
June 2022

Development of Alcohol-Associated Hepatitis Is Associated With Specific Changes in Gut-Modified Bile Acids.

Hepatol Commun 2022 May 4;6(5):1073-1089. Epub 2022 Jan 4.

Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.

The perturbations in bile acids (BAs) in alcohol-associated hepatitis (AH) and its relationship to disease severity is not well defined. The aims of this study were to define (1) the effects of heavy alcohol consumption on BAs and related microbiome, (2) the additional changes with AH, and (3) the relationship of these changes to disease severity. In this multicenter study, plasma and fecal BAs and related microbiome were interrogated in healthy individuals, heavy drinking controls (HDCs) without overt liver disease, and AH. Compared to healthy controls, HDCs had increased glycine-conjugated 7α and 27α primary BAs and increased secondary BA glycocholenic sulfate (multiple-comparison adjusted P < 0.05 for all). Plasma-conjugated cholic and chenodeoxycholic acid increased in AH along with the secondary BAs ursodeoxycholic and lithocholic acid (P < 0.001 for all), whereas deoxycholic acid decreased; however fecal concentrations of both deoxycholic acid and lithocholic acid were decreased. Glycocholenic acid further increased significantly from HDCs to AH. HDCs and AH had distinct plasma and fecal BA profiles (area under the curve, 0.99 and 0.93, respectively). Plasma taurochenodeoxycholic acid and tauroursodeoxycholic acid were directly related to disease severity, whereas fecal ursodeoxycholic acid was inversely related. The fecal abundance of multiple taxa involved in formation of secondary BAs, especially deoxycholic acid (Clostridium cluster XIVa) was decreased in AH. Multiple genera containing taxa expressing 3α, 3β, 7α, and 7β epimerases were decreased with concordant changes in fecal BAs that required these functions for formation. Conclusion: There are distinct changes in BA-transforming microbiota and corresponding BAs in AH that are related to disease severity.
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http://dx.doi.org/10.1002/hep4.1885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035568PMC
May 2022

Pegbelfermin selectively reduces secondary bile acid concentrations in patients with non-alcoholic steatohepatitis.

JHEP Rep 2022 Jan 12;4(1):100392. Epub 2021 Nov 12.

Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.

Background & Aims: Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms.

Methods: Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses.

Results: Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed.

Conclusions: PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation.

Lay Summary: Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver.
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http://dx.doi.org/10.1016/j.jhepr.2021.100392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689226PMC
January 2022

An Observational Data Meta-analysis on the Differences in Prevalence and Risk Factors Between MAFLD vs NAFLD.

Clin Gastroenterol Hepatol 2021 Dec 4. Epub 2021 Dec 4.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore. Electronic address:

Background & Aims: The shift to redefine nonalcoholic fatty liver disease (NAFLD) as metabolic associated fatty liver disease (MAFLD) can profoundly affect patient care, health care professionals, and progress within the field. To date, there remains no consensus on the characterization of NAFLD vs MAFLD. Thus, this study sought to compare the differences between the natural history of NAFLD and MAFLD.

Methods: Medline and Embase databases were searched to include articles on prevalence, risk factors, or outcomes of patients with MAFLD or NAFLD. Meta-analysis of proportions was conducted using the generalized linear mix model. Risk factors and outcomes were evaluated in conventional pairwise meta-analysis.

Results: Twenty-two articles involving 379,801 patients were included. Pooled prevalence of MAFLD was 39.22% (95% confidence interval [CI], 30.96%-48.15%) with the highest prevalence in Europe and Asia, followed by North America. The current MAFLD Definition only accounted for 81.59% (95% CI, 66.51%-90.82%) of NAFLD diagnoses. Patients had increased odds of being diagnosed with MAFLD compared with NAFLD (odds ratio, 1.37; 95% CI, 1.16-1.63; P < .001). Imaging modality resulted in a significantly higher odds of being diagnosed with MAFLD compared with NAFLD, but not biopsy. MAFLD was significantly associated with males, higher body mass index, hypertension, diabetes, lipids, transaminitis, and greater fibrosis scores compared with NAFLD.

Conclusions: There were stark differences in the prevalence and risk factors between MAFLD and NAFLD. However, in the use of the MAFLD Definition, a greater emphasis on the management of concomitant metabolic diseases and a collaborative effort is required to explore the complex pathophysiologic mechanisms underlying the disease.
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http://dx.doi.org/10.1016/j.cgh.2021.11.038DOI Listing
December 2021

Outcomes of Nonalcoholic Steatohepatitis After Liver Transplantation: An Updated Meta-Analysis and Systematic Review.

Clin Gastroenterol Hepatol 2021 Nov 18. Epub 2021 Nov 18.

Yong Loo Lin School of Medicine; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore. Electronic address:

Background & Aims: Nonalcoholic steatohepatitis (NASH) is the fastest growing indication of liver transplantation (LT) and is projected to be the leading cause of LT in the near future. The systemic pathogenesis of NASH increases risks of adverse clinical outcomes in patients with NASH receiving LT. Thus, this study aimed to conduct a time-dependent survival analysis between LT recipients with and without NASH using hazard ratios.

Methods: A search was conducted on Medline and Embase databases for articles relating to LT outcomes for NASH recipients. A survival analysis was conducted of hazard ratios using the DerSimonian and Laird random-effects model with meta-regression. To account for censoring, survival data were reconstructed from published Kaplan-Meier curves and pooled to derive more accurate hazard estimates and all-cause mortality in NASH patients after LT. Pairwise meta-analysis was conducted to analyze secondary outcomes.

Results: Fifteen studies involving 119,327 LT recipients were included in our analysis with a prevalence of NASH of 20.2% (95% CI, 12.9-30.2). The pooled 1-year, 5-year, and 10-year all-cause mortality in NASH patients after LT were 12.5%, 24.4%, and 37.9%, respectively. Overall survival was comparable between LT recipients for NASH vs non-NASH (hazard ratio, 0.910; 95% CI, 0.760 to 1.10; P = .34). Meta-regression showed that a higher model for end-stage liver disease score was associated with significantly worse overall survival in NASH compared with non-NASH after LT (95% CI, -0.0856 to -0.0181; P = .0026).

Conclusions: This study shows that patients undergoing LT for NASH cirrhosis have comparable complication rates, overall survival, and graft survival compared with non-NASH patients, although close monitoring may be indicated for those with higher model for end-stage liver disease scores.
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http://dx.doi.org/10.1016/j.cgh.2021.11.014DOI Listing
November 2021

Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study.

J Hepatol 2022 03 15;76(3):536-548. Epub 2021 Nov 15.

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié - Salpêtrière, Institute for Cardiometabolism and Nutrition, INSERM UMRS 1138 CRC, Paris, France. Electronic address:

Background & Aims: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study.

Methods: Patients with NASH and fibrosis stage F2 or F3 (n = 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study.

Results: Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable.

Conclusions: Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS.

Gov Number: NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy.
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http://dx.doi.org/10.1016/j.jhep.2021.10.029DOI Listing
March 2022

Circulating high density lipoprotein distinguishes alcoholic hepatitis from heavy drinkers and predicts 90-day outcome: lipoproteins in alcoholic hepatitis.

J Clin Lipidol 2021 Nov-Dec;15(6):805-813. Epub 2021 Oct 20.

Divison of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Alcohol-associated liver disease (ALD) and alcoholic hepatitis (AH) significantly impact the liver, an organ central to the lipid and lipoprotein metabolism.

Objective: To define changes in the lipid and lipoprotein profiles in subjects with alcoholic hepatitis (AH) versus heavy drinkers with normal liver function and to determine the association of the AH-mediated lipoprotein phenotype with AH severity and outcomes.

Methods: AH cases (n=196) and a heavy drinker control group (n=169) were identified in a multicenter, prospective cohort. The relationships between lipid panels and lipoprotein profiles among AH and heavy drinkers were interrogated using three common measurements: the conventional lipid panel, extended lipid panel by NMR, and NMR-based direct lipoprotein profiling. Predictive values for AH severity and mortality were determined using Harrell's C-Index.

Results: Lipid and lipoprotein profiles were significantly different in AH compared to heavy drinkers. Among them, high density lipoprotein (HDL) particle concentration exhibited the most significant reduction in AH compared to heavy drinkers (5.3 ± 3.4 vs 22.3 ± 5.4 μmol/L, p < 0.001). Within AH patients, HDL particle concentration was inversely associated with Maddrey's Discriminant Function (DF) (p < 0.001), and independently associated with mortality at both 90 and 365 days even after adjustment for DF (p = 0.02, p = 0.05 respectively). HDL particle concentration less than 3.5 μmol/L and total cholesterol ≤ 96 mg/dL identified AH patients with higher 90-day mortality.

Conclusion: Lipid and lipoprotein profiles are profoundly altered in AH and can help in prognosticating disease severity and mortality.
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http://dx.doi.org/10.1016/j.jacl.2021.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688310PMC
March 2022

Dissecting the Balance Between Metabolic and Oncogenic Functions of Astrocyte-Elevated Gene-1/Metadherin.

Hepatol Commun 2022 03 5;6(3):561-575. Epub 2021 Nov 5.

Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.

Obesity is an enormous global health problem, and obesity-induced nonalcoholic steatohepatitis (NASH) is contributing to a rising incidence and mortality for hepatocellular carcinoma (HCC). Increase in de novo lipogenesis and decrease in fatty acid β-oxidation (FAO) underlie hepatic lipid accumulation in NASH. Astrocyte-elevated gene-1/metadherin (AEG-1) overexpression contributes to both NASH and HCC. AEG-1 harbors an LXXLL motif through which it blocks activation of peroxisome proliferator activated receptor α (PPARα), a key regulator of FAO. To better understand the role of LXXLL motif in mediating AEG-1 function, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, we generated a mouse model (AEG-1-L24K/L25H) in which the LXXLL motif in AEG-1 was mutated to LXXKH. We observed increased activation of PPARα in AEG-1-L24K/L25H livers providing partial protection from high-fat diet-induced steatosis. Interestingly, even with equal gene dosage levels, compared with AEG-1-wild-type livers, AEG-1-L24K/L25H livers exhibited increase in levels of lipogenic enzymes, mitogenic activity and inflammation, which are attributes observed when AEG-1 is overexpressed. These findings indicate that while LXXLL motif favors steatotic activity of AEG-1, it keeps in check inflammatory and oncogenic functions, thus maintaining a homeostasis in AEG-1 function. AEG-1 is being increasingly appreciated as a viable target for ameliorating NASH and NASH-HCC, and as such, in-depth understanding of the functions and molecular attributes of this molecule is essential. Conclusion: The present study unravels the unique role of the LXXLL motif in mediating the balance between the metabolic and oncogenic functions of AEG-1.
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http://dx.doi.org/10.1002/hep4.1834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870024PMC
March 2022

Adverse muscle composition predicts all-cause mortality in the UK Biobank imaging study.

J Cachexia Sarcopenia Muscle 2021 12 29;12(6):1513-1526. Epub 2021 Oct 29.

AMRA Medical, Linköping, Sweden.

Background: Adverse muscle composition (MC) as measured by magnetic resonance imaging has previously been linked to poor function, comorbidity, and increased hospitalization. The aim of this study was to investigate if adverse MC predicts all-cause mortality using data from UK Biobank.

Methods: There were 40 178 participants scanned using a 6 min magnetic resonance imaging protocol. Images were analysed for thigh fat-tissue free muscle volume and muscle fat infiltration (MFI) using AMRA® Researcher (AMRA Medical, Linköping, Sweden). For each participant, a sex, weight, and height invariant muscle volume z-score was calculated. Participants were partitioned into four MC groups: (i) normal MC, (ii) only low muscle volume [<25th percentile for muscle volume z-score (population wide)], (iii) only high MFI [>75th percentile (population wide, sex-specific)], and (iv) adverse MC (low muscle volume z-score and high MFI). Association of MC groups with mortality was investigated using Cox proportional-hazard modelling with normal MC as referent (unadjusted and adjusted for low hand grip strength, sex, age, body mass index, previous diagnosis of disease (cancer, type 2 diabetes and coronary heart disease), lifestyle, and socioeconomic factors (smoking, alcohol consumption, physical activity, and Townsend deprivation index).

Results: Muscle composition measurements were complete for 39 804 participants [52% female, mean (SD) age 64.2 (7.6) years and body mass index 26.4 (4.4) kg/m ]. Three hundred twenty-eight deaths were recorded during a follow-up period of 2.9 (1.4) years after imaging. At imaging, adverse MC was detected in 10.5% of participants. The risk of death from any cause in adverse MC compared with normal MC was 3.71 (95% confidence interval 2.81-4.91, P < 0.001). Only low muscle volume and only high MFI were independently associated with all-cause mortality [1.58 (1.13-2.21), P = 0.007, and 2.02 (1.51-2.71), P < 0.001, respectively]. Adjustment of low hand grip strength [1.77 (1.28-2.44), P < 0.001] did not attenuate the associations with any of the MC groups. In the fully adjusted model, adverse MC and only high MFI remained significant (P < 0.001 and P = 0.020) while the association with only low muscle volume was attenuated to non-significance (P = 0.560). The predictive performance of adverse MC [1.96 (1.42-2.71), P < 0.001] was comparable with that of previous cancer diagnosis [1.93 (1.47-2.53), P < 0.001] and smoking [1.71 (1.02-2.84), P = 0.040]. Low hand grip strength was borderline non-significant [1.34 (0.96-1.88), P = 0.090].

Conclusions: Adverse MC was a strong and independent predictor of all-cause mortality. Sarcopenia guidelines can be strengthened by including cut-offs for myosteatosis enabling detection of adverse MC.
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http://dx.doi.org/10.1002/jcsm.12834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718078PMC
December 2021

Evolution of Fatty Liver Disease and Relationship With Lipoproteins and Clinical Outcomes in Hepatitis B/Human Immunodeficiency Virus Coinfection.

Clin Infect Dis 2021 Oct 25. Epub 2021 Oct 25.

Virginia Commonwealth University, Richmond, Virginia, USA.

Background: Fatty liver disease (FLD) and hepatitis B virus (HBV) infection occur commonly in human immunodeficiency virus (HIV). FLD resolution is associated with improvement in lipoproteins in HIV-uninfected patients. We evaluated changes in FLD in an HBV/HIV-coinfected cohort.

Methods: One hundred eight HBV/HIV-coinfected adults with baseline liver biopsies were followed every 24 weeks (median, 166 weeks) and 60 had follow-up biopsies. Baseline FLD categories (none, ≥5% steatosis, steatohepatitis), their change, and relationships with clinical and lipid/lipoprotein parameters were explored using multivariable modeling.

Results: Median age was 50 years, and 93% were male. At baseline 30% had FLD. With control for lipid-lowering medications and body mass index, low-density lipoprotein (LDL) cholesterol (LDL-C), LDL particle concentration (LDL-P), and apolipoprotein B (apoB) decreased and adiponectin increased over time (all P < .05); On follow-up (vs baseline), there was no significant difference in FLD category (P = .85); 60% remained without FLD, 17% had unchanged, 12% worsening, and 12% improved FLD. Baseline low-density lipoproteins (LDL-C, LDL-P, small LDL-P) and apoB appeared highest in those with unchanged FLD status (all P < .05). No associations between changes in FLD across follow-up (worsening/improvement vs unchanged) and lipid/lipoproteins changes were identified.

Conclusions: In this cohort, there was no significant change in FLD prevalence over a relatively short timeframe. Baseline atherogenic lipids appeared highest in those with persistent steatosis or steatohepatitis, suggesting potentially increased cardiovascular risk in this group, but an independent relationship between individual-level change in FLD status and lipid/lipoprotein levels across follow-up was not observed.
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http://dx.doi.org/10.1093/cid/ciab764DOI Listing
October 2021

Liver biopsy in the real world-reporting, expert concordance and correlation with a pragmatic clinical diagnosis.

Aliment Pharmacol Ther 2021 12 25;54(11-12):1472-1480. Epub 2021 Oct 25.

University of North Carolina, Chapel Hill, NC, USA.

Background: Patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage ≥2 comprise a target population for pharmacotherapy. Liver biopsy, the reference standard for identifying this population, requires complete and accurate assessment of steatohepatitis and fibrosis. Aims To investigate the completeness of real-world NASH-related pathology reports, assess concordance between site pathologists and central expert interpretation of the histologic elements of NASH, and determine concordance between biopsy-diagnosed NASH and a pragmatic clinical definition of NASH.

Methods: Liver pathology reports from 222 patients across 38 TARGET-NASH sites were analysed for documentation of the histologic features of NASH. Biopsy slides were over-read by a blinded central expert pathologist. Concordance of histologic scores and interpretation was assessed. Histologic concordance with a clinical definition of NASH was determined. TARGET-NASH clinically defined NASH: elevated ALT, hepatic steatosis on biopsy or imaging and ≥1 of the following: BMI ≥30 kg/m , type 2 diabetes mellitus and dyslipidaemia.

Results: Documentation of steatosis, lobular inflammation, portal inflammation and ballooning were missing from 21%, 35%, 46% and 40% of reports, respectively. There was slight-to-fair concordance (weighted kappa 0.01-0.35) between site and central pathologists for inflammatory features, and moderate concordance (weighted kappa 0.56-0.57) for fibrosis staging. Clinical definition of NASH was 75%-91% concordant (94%-95% sensitive) with biopsy-diagnosed NASH.

Conclusions: There is substantial variability in reporting and grading NASH and fibrosis staging in clinical practice. This heterogeneity may adversely impact patient assessment and translation of practice guidelines into reality. The TARGET-NASH pragmatic clinical definition may serve as a valuable tool to accurately identify NASH patients in clinical practice.
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http://dx.doi.org/10.1111/apt.16674DOI Listing
December 2021

Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease.

N Engl J Med 2021 10;385(17):1559-1569

From the Virginia Commonwealth University School of Medicine, Richmond (A.J.S.); the Bloomberg School of Public Health, Johns Hopkins University, Baltimore (M.L.V.N., J.C., L.A.W., K.P.Y., P.B., M.L., J.T.), and the Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda (D.E.K.) - both in Maryland; Saint Louis University, St. Louis (B.A.N.-T.); Duke University, Durham, NC (A.M.D.); Cleveland Clinic, Cleveland (S.D.); the University of California, San Diego, School of Medicine, La Jolla (R.L., C.B.), and the University of California, San Francisco, School of Medicine, San Francisco (B.H.); Indiana University School of Medicine, Indianapolis (N.C.); and the Liver Institute Northwest, Seattle (K.K.).

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.).
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http://dx.doi.org/10.1056/NEJMoa2029349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8881985PMC
October 2021
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