Publications by authors named "Kathleen E Corey"

117 Publications

ADAMTSL2 protein and a soluble biomarker signature identify significant and advanced fibrosis in adults with NAFLD.

J Hepatol 2021 Sep 30. Epub 2021 Sep 30.

Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

Aims And Background: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and inform treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD.

Methods: We used aptamer-based proteomics to measure 4783 proteins in two cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modelling-logistic regression assessed the candidate proteins to classify fibrosis.

Results: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n=62) and B (n=98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n=71) and D (n=84). The protein A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) accurately distinguished NAFL/NASH with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4 with an AUROC of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3) with an AUROC of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROC 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROC 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and Fibrosis-4 score.

Conclusion: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis with superior performance to standard of care fibrosis scores.

Lay Summary: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in blood which may identify fibrosis without the need for a liver biopsy.
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http://dx.doi.org/10.1016/j.jhep.2021.09.026DOI Listing
September 2021

Risk of Cardiovascular Disease in Individuals With Nonobese Nonalcoholic Fatty Liver Disease.

Hepatol Commun 2021 Sep 2. Epub 2021 Sep 2.

Harvard Medical School, Boston, MA, USA.

Nonalcoholic fatty liver disease (NAFLD) is independently associated with obesity and cardiovascular disease (CVD). CVD is the primary cause of mortality in the predominantly obese population of adults with NAFLD. NAFLD is increasingly seen in individuals who are lean and overweight (i.e., nonobese), but it is unclear whether their risk of CVD is comparable to those with NAFLD and obesity. Using a prospective cohort of patients with NAFLD, we compared the prevalence and incidence of CVD in individuals with and without obesity. NAFLD was diagnosed by biopsy or imaging after excluding other chronic liver disease etiologies. Logistic regression was used to compare the odds of baseline CVD by obesity status. Cox proportional hazards regression was used to evaluate obesity as a predictor of incident CVD and to identify predictors of CVD in subjects with and without obesity. At baseline, adults with obesity had a higher prevalence of CVD compared to those without obesity (12.0% vs. 5.0%, P = 0.02). During follow-up, however, obesity did not predict incident CVD (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.69-2.22) or other metabolic diseases. Findings were consistent when considering body mass index as a continuous variable and after excluding subjects who were overweight. Age (adjusted HR [aHR], 1.05; 95% CI, 1.03-1.08), smoking (aHR, 4.61; 95% CI, 1.89-11.22), and decreased low-density lipoprotein levels (aHR, 0.98; 95% CI, 0.96-1.00) independently predicted incident CVD in the entire cohort, in subjects with obesity, and in those without obesity, respectively. Conclusion: Individuals with overweight or lean NAFLD are not protected from incident CVD compared to those with NAFLD and obesity, although CVD predictors appear to vary between these groups. Patients without obesity also should undergo rigorous risk stratification and treatment.
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http://dx.doi.org/10.1002/hep4.1818DOI Listing
September 2021

Distinct Hepatic Gene-Expression Patterns of NAFLD in Patients With Obesity.

Hepatol Commun 2021 Aug 11. Epub 2021 Aug 11.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene-expression patterns associated with different patterns of liver injury in a high-risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1-4 (NASH F1-F4). One hundred twenty-five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma-interferon-inducible lysosomal thiol reductase (IFI30) and chemokine (C-X-C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1-F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high-risk individuals.
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http://dx.doi.org/10.1002/hep4.1789DOI Listing
August 2021

Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.

Lancet Gastroenterol Hepatol 2021 Nov 21;6(11):903-913. Epub 2021 Sep 21.

Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy. Electronic address:

Background: Studies have reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased incidence of cardiovascular disease (CVD). However, the magnitude of the risk and whether this risk changes with the severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CVD events.

Methods: We systematically searched PubMed, Scopus, and Web of Science from database inception to July 1, 2021, to identify eligible observational studies examining the risk of incident CVD events amongst adult (age ≥18 years) individuals with and without NAFLD and in which NAFLD was diagnosed by imaging, International Classification of Diseases codes, or liver biopsy. The primary outcomes were CVD death, non-fatal CVD events, or both. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95% CIs. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on Open Science Framework, number osf.io/5z7gf.

Findings: We identified 36 longitudinal studies with aggregate data on 5 802 226 middle-aged individuals (mean age 53 years [SD 7]) and 99 668 incident cases of fatal and non-fatal CVD events over a median follow-up of 6·5 years (IQR 5·0-10·2). NAFLD was associated with a moderately increased risk of fatal or non-fatal CVD events (pooled random-effects HR 1·45, 95% CI 1·31-1·61; I=86·18%). This risk markedly increased across the severity of NAFLD, especially the stage of fibrosis (pooled random-effects HR 2·50, 95% CI 1·68-3·72; I=73·84%). All risks were independent of age, sex, adiposity measures, diabetes, and other common cardiometabolic risk factors. Sensitivity analyses did not modify these results.

Interpretation: NAFLD is associated with an increased long-term risk of fatal or non-fatal CVD events. CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage. These results provide evidence that NAFLD might be an independent risk factor for CVD morbidity and mortality.

Funding: None.
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http://dx.doi.org/10.1016/S2468-1253(21)00308-3DOI Listing
November 2021

Molecular characterization and cell type composition deconvolution of fibrosis in NAFLD.

Sci Rep 2021 Sep 10;11(1):18045. Epub 2021 Sep 10.

Liver Center, Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. In adults with NAFLD, fibrosis can develop and progress to liver cirrhosis and liver failure. However, the underlying molecular mechanisms of fibrosis progression are not fully understood. Using total RNA-Seq, we investigated the molecular mechanisms of NAFLD and fibrosis. We sequenced liver tissue from 143 adults across the full spectrum of fibrosis stage including those with stage 4 fibrosis (cirrhosis). We identified gene expression clusters that strongly correlate with fibrosis stage including four genes that have been found consistently across previously published transcriptomic studies on NASH i.e. COL1A2, EFEMP2, FBLN5 and THBS2. Using cell type deconvolution, we estimated the loss of hepatocytes versus gain of hepatic stellate cells, macrophages and cholangiocytes with advancing fibrosis stage. Hepatocyte-specific functional analysis indicated increase of pro-apoptotic pathways and markers of bipotent hepatocyte/cholangiocyte precursors. Regression modelling was used to derive predictors of fibrosis stage. This study elucidated molecular and cell composition changes associated with increasing fibrosis stage in NAFLD and defined informative gene signatures for the disease.
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http://dx.doi.org/10.1038/s41598-021-96966-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433177PMC
September 2021

Fatty Acids Activate the Transcriptional Coactivator YAP1 to Promote Liver Fibrosis via p38 Mitogen-Activated Protein Kinase.

Cell Mol Gastroenterol Hepatol 2021 Jun 9;12(4):1297-1310. Epub 2021 Jun 9.

Liver Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background & Aims: Patients with simple steatosis (SS) and nonalcoholic steatohepatitis can develop progressive liver fibrosis, which is associated with liver-related mortality. The mechanisms contributing to liver fibrosis development in SS, however, are poorly understood. SS is characterized by hepatocellular free fatty acid (FFA) accumulation without lobular inflammation seen in nonalcoholic steatohepatitis. Because the Hippo signaling transcriptional coactivator YAP1 (YAP) has previously been linked with nonalcoholic fatty liver disease (NAFLD)-related fibrosis, we sought to explore how hepatocyte FFAs activate a YAP-mediated profibrogenic program.

Methods: We analyzed RNA sequencing data from a GEO DataSet (accession: GSE162694) consisting of 143 patients with NAFLD. We also performed immunohistochemical, immunofluorescence, immunoblot, and quantitative reverse-transcription polymerase chain reaction analyses (qRT-PCR) in liver specimens from NAFLD subjects, from a murine dietary NAFLD model, and in FFA-treated hepatic spheroids and hepatocytes.

Results: YAP-target gene expression correlated with increasing fibrosis stage in NAFLD patients and was associated with fibrosis in mice fed a NAFLD-inducing diet. Hepatocyte-specific YAP deletion in the murine NAFLD model attenuated diet-induced fibrosis, suggesting a causative role of YAP in NAFLD-related fibrosis. Likewise, in hepatic spheroids composed of Huh7 hepatoma cells and primary human hepatic stellate cells, Huh7 YAP silencing reduced FFA-induced fibrogenic gene expression. Notably, inhibition of p38 mitogen-activated protein kinase could block YAP activation in FFA-treated Huh7 cells.

Conclusions: These studies provide further evidence for the pathological role of YAP in NAFLD-associated fibrosis and that YAP activation in NAFLD may be driven by FFA-induced p38 MAPK activation.
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http://dx.doi.org/10.1016/j.jcmgh.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463869PMC
June 2021

Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach.

Sci Rep 2021 05 18;11(1):10485. Epub 2021 May 18.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street 5LON207, Boston, MA, 02114, USA.

NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log-fold change - 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, - 0.35 ± 0.56 vs. - 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, - 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831.
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http://dx.doi.org/10.1038/s41598-021-89966-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131688PMC
May 2021

The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments.

Nat Rev Gastroenterol Hepatol 2021 09 10;18(9):599-612. Epub 2021 May 10.

Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical outcomes. T2DM is also one of the strongest risk factors for the faster progression of NAFLD to nonalcoholic steatohepatitis, advanced fibrosis or cirrhosis. However, the link between NAFLD and T2DM is more complex than previously believed. Strong evidence indicates that NAFLD is associated with an approximate twofold higher risk of developing T2DM, irrespective of obesity and other common metabolic risk factors. This risk parallels the severity of NAFLD, such that patients with more advanced stages of liver fibrosis are at increased risk of incident T2DM. In addition, the improvement or resolution of NAFLD (on ultrasonography) is associated with a reduction of T2DM risk, adding weight to causality and suggesting that liver-focused treatments might reduce the risk of developing T2DM. This Review describes the evidence of an association and causal link between NAFLD and T2DM, discusses the putative pathophysiological mechanisms linking NAFLD to T2DM and summarizes the current pharmacological treatments for NAFLD or T2DM that might benefit or adversely affect the risk of T2DM or NAFLD progression.
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http://dx.doi.org/10.1038/s41575-021-00448-yDOI Listing
September 2021

Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis.

Metabolism 2021 07 21;120:154780. Epub 2021 Apr 21.

Harvard Medical School, Boston, MA, United States of America; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, United States of America; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States of America. Electronic address:

Background & Aims: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk.

Methods: We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI).

Results: Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86-0.97, I = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83-0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87-1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02-1.14, I = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02-1.11, I = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89-1.60, I = 72%).

Conclusions: Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.
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http://dx.doi.org/10.1016/j.metabol.2021.154780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217281PMC
July 2021

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.

Clin Infect Dis 2021 08;73(4):621-630

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD).

Methods: 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways.

Results: Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways.

Conclusions: Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation. Clinical Trials Registration. NCT02196831.
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http://dx.doi.org/10.1093/cid/ciab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366828PMC
August 2021

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease.

Clin Liver Dis (Hoboken) 2021 Jan 1;17(1):19-22. Epub 2021 Feb 1.

Liver Center Division of Gastroenterology Department of Medicine Massachusetts General Hospital Boston MA.

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http://dx.doi.org/10.1002/cld.1017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849297PMC
January 2021

Association Between Liver Fat and Bone Density is Confounded by General and Visceral Adiposity in a Community-Based Cohort.

Obesity (Silver Spring) 2021 03 2;29(3):595-600. Epub 2021 Feb 2.

Section of Gastroenterology, Boston Medical Center, School of Medicine, Boston University, Boston, Massachusetts, USA.

Objective: Nonalcoholic fatty liver disease (NAFLD) is associated with low bone mineral density (BMD); however, it is not known whether early-stage NAFLD may be associated with BMD after accounting for BMI or visceral adipose tissue (VAT).

Methods: This was a cross-sectional study of 3,462 Framingham Heart Study participants who underwent computed tomographic measurement of liver fat, VAT volume, volumetric spine BMD, vertebral cross-sectional area (CSA), and vertebral compressive strength. This study excluded heavy alcohol consumers. Multivariable linear regression models were used to assess the association between NAFLD and volumetric BMD, CSA, and vertebral compressive strength after accounting for covariates, including BMI or VAT.

Results: A total of 2,253 participants (mean age, 51.2  [SD 10.7] years; 51.1% women) were included. In multivariable-adjusted models, positive associations between NAFLD and integral BMD, trabecular BMD, and vertebral compressive strength were observed. However, results were attenuated and no longer significant after additionally adjusting for BMI or VAT. NAFLD was observed to be weakly associated with a lower vertebral CSA in adjusted models.

Conclusions: In a community-based cohort, the associations between NAFLD and BMD and vertebral strength were confounded by BMI and VAT. However, NAFLD was associated with a reduced vertebral CSA in adjusted models.
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http://dx.doi.org/10.1002/oby.23100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904629PMC
March 2021

Aspirin Use Is Associated with a Reduced Incidence of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Hepatol Commun 2021 01 13;5(1):133-143. Epub 2020 Nov 13.

Harvard Medical School Boston MA USA.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death worldwide, with a growing incidence and poor prognosis. While some recent studies suggest an inverse association between aspirin use and reduced HCC incidence, other data are conflicting. To date, the precise magnitude of risk reduction-and whether there are dose-dependent and duration-dependent associations-remains unclear. To provide an updated and comprehensive assessment of the association between aspirin use and incident HCC risk, we conducted a systematic review and meta-analysis of all observational studies published through September 2020. Using random-effects meta-analysis, we calculated the pooled relative risks (RRs) and 95% confidence intervals (CIs) for the association between aspirin use and incident HCC risk. Where data were available, we evaluated HCC risk according to the defined daily dose of aspirin use. Among 2,389,019 participants, and 20,479 cases of incident HCC, aspirin use was associated with significantly lower HCC risk (adjusted RR, 0.61; 95% CI, 0.51-0.73; ≤ 0.001; I = 90.4%). In subgroup analyses, the magnitude of benefit associated with aspirin was significantly stronger in studies that adjusted for concurrent statin and/or metformin use (RR, 0.45; 95% CI, 0.28-0.64) versus those that did not (  = 0.02), studies that accounted for cirrhosis (RR, 0.49; 95% CI, 0.45-0.52) versus those that did not (  = 0.02), and studies that confirmed HCC through imaging/biopsy (RR, 0.30; 95% CI, 0.15-0.58) compared with billing codes (  < 0.001). In four studies, each defined daily dose was associated with significantly lower HCC risk (RR, 0.98; 95% CI, 0.97-0.98), corresponding to an 8.4% risk reduction per year of aspirin use. In this comprehensive systematic review and meta-analysis, aspirin use was associated with a significant reduction in HCC risk. These benefits appeared to increase with increasing dose and duration of aspirin use.
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http://dx.doi.org/10.1002/hep4.1640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789838PMC
January 2021

Pro-Inflammatory Interleukin-18 is Associated with Hepatic Steatosis and Elevated Liver Enzymes in People with HIV Monoinfection.

AIDS Res Hum Retroviruses 2021 05 25;37(5):385-390. Epub 2021 Jan 25.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

People with HIV (PWH) are at an increased risk of developing nonalcoholic fatty liver disease (NAFLD). Interleukin (IL)-18 is regulated by inflammasomes in response to pathogens and danger signals and has been implicated in both the pathogenesis of NAFLD and HIV disease progression. We hypothesized that increased IL-18 may be associated with NAFLD and liver injury in PWH. This was an observational study of 125 PWH and 59 individuals without HIV in the Boston area. Participants with known hepatitis B, hepatitis C, and excessive alcohol use were excluded. IL-18 was measured in serum by enzyme-linked immunosorbent assay. Liver lipid content was assessed by liver-to-spleen computed tomography (CT) attenuation ratio. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and IL-18 levels were higher in PWH than in controls. In PWH, log IL-18 was associated with logAST ( = 0.34,  = .0001), logALT ( = 0.33,  = .0002), logHIV RNA ( = 0.29,  = .002), and inversely associated with liver-to-spleen ratio ( = -0.24,  = .02). In addition, log IL-18 was associated with log triglycerides ( = 0.26,  = .003), log MCP-1 (monocyte chemoattractant protein-1;  = 0.33,  = .0004), logcaspase-1 ( = 0.35,  < .0001), logLPS ( = 0.28,  = .004), and inversely associated with high-density lipoprotein ( = -0.28,  = .002), and CD4/CD8 T cell ratio ( = -0.24,  = .007). In controls without HIV, log IL-18 was also associated with logALT ( = 0.44,  = .0005). After adjusting for potential confounders, the relationships between IL-18 and AST ( = .004) and ALT ( = .003) remained significant, and the relationship between IL-18 and liver-to-spleen ratio ( = .02). Increased inflammasome activation and subsequent monocyte recruitment in PWH may contribute to the development and progression of NAFLD. Clinical Trials Registration. NCT00455793.
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http://dx.doi.org/10.1089/AID.2020.0177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112718PMC
May 2021

AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review.

Gastroenterology 2021 02 9;160(3):912-918. Epub 2020 Dec 9.

Yale Liver Center and Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease, with global public health impact affecting more than 25% of the global population. NAFLD is associated with significant morbidity and mortality from cirrhosis, hepatocellular carcinoma, solid organ malignancies, diabetes mellitus, cardiovascular disease, and obstructive sleep apnea, resulting in significant health care resource use and decreased health-related quality of life. NAFLD cirrhosis is a leading indication for liver transplantation in the United States. Lifestyle modification to achieve weight loss remains a first-line intervention in patients with NAFLD. We summarize evidence-based interventions for lifestyle modification in the treatment of NAFLD and provided best practice advice statements to address key issues in clinical management.
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http://dx.doi.org/10.1053/j.gastro.2020.11.051DOI Listing
February 2021

NAFLD, and cardiovascular and cardiac diseases: Factors influencing risk, prediction and treatment.

Diabetes Metab 2021 03 6;47(2):101215. Epub 2020 Dec 6.

Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK; National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton, UK.

Background And Aim: Non-alcoholic fatty liver disease (NAFLD), affecting up to around 30% of the world's adult population, causes considerable liver-related and extrahepatic morbidity and mortality. Strong evidence indicates that NAFLD (especially its more severe forms) is associated with a greater risk of all-cause mortality, and the predominant cause of mortality in this patient population is cardiovascular disease (CVD). This narrative review aims to discuss the strong association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications. Also discussed are the putative mechanisms linking NAFLD to CVD and other cardiac/arrhythmic complications, with a brief summary of CVD risk prediction/stratification and management of the increased CVD risk observed in patients with NAFLD.

Results: NAFLD is associated with an increased risk of CVD events and other cardiac complications (left ventricular hypertrophy, valvular calcification, certain arrhythmias) independently of traditional CVD risk factors. The magnitude of risk of CVD and other cardiac/arrhythmic complications parallels the severity of NAFLD (especially liver fibrosis severity). There are most likely multiple underlying mechanisms through which NAFLD may increase risk of CVD and cardiac/arrhythmic complications. Indeed, NAFLD exacerbates hepatic and systemic insulin resistance, promotes atherogenic dyslipidaemia, induces hypertension, and triggers synthesis of proatherogenic, procoagulant and proinflammatory mediators that may contribute to the development of CVD and other cardiac/arrhythmic complications.

Conclusion: Careful assessment of CVD risk is mandatory in patients with NAFLD for primary prevention of CVD, together with pharmacological treatment for coexisting CVD risk factors.
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http://dx.doi.org/10.1016/j.diabet.2020.101215DOI Listing
March 2021

Hepatic Fibrosis Associates With Multiple Cardiometabolic Disease Risk Factors: The Framingham Heart Study.

Hepatology 2021 02 6;73(2):548-559. Epub 2021 Feb 6.

Evans Department of Medicine, Whitaker Cardiovascular Institute and Cardiology Section, Boston University School of Medicine, Boston, MA.

Background And Aims: NAFLD is increasing in prevalence and will soon be the most common chronic liver disease. Liver stiffness, as assessed by vibration-controlled transient elastography (VCTE), correlates with hepatic fibrosis, an important predictor of liver-related and all-cause mortality. Although liver fat is associated with cardiovascular risk factors, the association between hepatic fibrosis and cardiovascular risk factors is less clear.

Approach And Results: We performed VCTE, assessing controlled attenuation parameter (CAP; measure of steatosis) and liver stiffness measurement (LSM) in 3,276 Framingham Heart Study adult participants (53.9% women, mean age 54.3 ± 9.1 years) presenting for a routine study visit. We performed multivariable-adjusted logistic regression models to determine the association between LSM and obesity-related, vascular-related, glucose-related, and cholesterol-related cardiovascular risk factors. The prevalence of hepatic steatosis (CAP ≥ 290 dB/m) was 28.8%, and 8.8% had hepatic fibrosis (LSM ≥ 8.2 kPa). Hepatic fibrosis was associated with multiple cardiovascular risk factors, including increased odds of obesity (OR, 1.82; 95% CI, 1.35-2.47), metabolic syndrome (OR, 1.49; 95% CI 1.10-2.01), diabetes (OR, 2.67; 95% CI, 1.21-3.75), hypertension (OR, 1.52; 95% CI, 1.15-1.99), and low high-density lipoprotein cholesterol (OR, 1.47; 95% CI, 1.09-1.98), after adjustment for age, sex, smoking status, alcohol drinks/week, physical activity index, aminotransferases, and CAP.

Conclusions: In our community-based cohort, VCTE-defined hepatic fibrosis was associated with multiple cardiovascular risk factors, including obesity, metabolic syndrome, diabetes, hypertension, and high-density lipoprotein cholesterol, even after accounting for covariates and CAP. Additional longitudinal studies are needed to determine if hepatic fibrosis contributes to incident cardiovascular disease risk factors or events.
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http://dx.doi.org/10.1002/hep.31608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515503PMC
February 2021

Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.

J Clin Endocrinol Metab 2021 01;106(2):e520-e533

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Context: Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD).

Objective: To assess relationships between hepatic expression of IGF1 and IGF-binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH-releasing hormone (GHRH) on circulating IGFBPs.

Design: Analysis of data from a randomized clinical trial of GHRH.

Setting: Two US academic medical centers.

Participants: Participants were 61 men and women 18 to 70 years of age with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy.

Main Outcome Measures: Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis.

Results: Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBPs, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) were higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA levels were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6.

Conclusions: These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.
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http://dx.doi.org/10.1210/clinem/dgaa792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823253PMC
January 2021

Expert Panel Review on Nonalcoholic Fatty Liver Disease in Persons With Human Immunodeficiency Virus.

Clin Gastroenterol Hepatol 2020 Oct 16. Epub 2020 Oct 16.

Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Nonalcoholic fatty liver disease (NAFLD) affects 25% of adults in the general population and is a disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) to end-stage liver disease. NAFLD is an independent risk factor for cardiovascular disease, diabetes mellitus, and all-cause mortality, and NASH cirrhosis is a frequent indication for liver transplantation. In persons with human immunodeficiency virus (PWH), chronic liver disease is the second leading cause of non-human immunodeficiency virus-related mortality. Between 20% and 63% of PWH have NASH, and 14% to 63% have NASH with fibrosis. However, little is known about the optimal diagnostic strategies, risk factors for, and treatment of NAFLD in PWH. Here, we review current data on and identify knowledge gaps in the epidemiology, pathophysiology, diagnosis, and management of NAFLD in PWH and highlight priorities for research.
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http://dx.doi.org/10.1016/j.cgh.2020.10.018DOI Listing
October 2020

Weight gain during early adulthood, trajectory of body shape and the risk of nonalcoholic fatty liver disease: A prospective cohort study among women.

Metabolism 2020 12 12;113:154398. Epub 2020 Oct 12.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America; Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America. Electronic address:

Background & Aims: Obesity is established as a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD). However, the influence of dynamic changes in adiposity over the life course on NAFLD risk remains poorly understood.

Methods: We collected data from 110,054 women enrolled in the Nurses' Health Study II cohort. Early adulthood weight was ascertained at age 18 years, and weight gain since early adulthood was defined prospectively every 2 years. We used a group-based modeling approach to identify five trajectories of body shape from age 5 years up to age 50 years. NAFLD was defined by physician-confirmed diagnoses of fatty liver, after excluding excess alcohol intake and viral hepatitis, using validated approaches.

Results: We documented 3798 NAFLD cases over a total of 20 years of follow-up. Compared to women who maintained stable weight (±2 kg), women with ≥20 kg of adulthood weight gain had the multivariable aHR of 6.96 (95% CI, 5.27-9.18), and this remained significant after further adjusting for early adulthood BMI and updated BMI (both P trend <0.0001). Compared to women with a medium-stable body shape trajectory, the multivariable aHRs for NAFLD were, 2.84 (95% CI, 2.50-3.22) for lean-marked increase, 2.60 (95% CI, 2.27-2.98) for medium-moderate increase, and 3.39 (95% CI, 2.95-3.89) for medium-marked increase.

Conclusions: Both early adulthood weight gain and lifetime body shape trajectory were significantly and independently associated with excess risk of developing NAFLD in mid-life. Maintaining both lean and stable weight throughout life may offer the greatest benefit for the prevention of NAFLD.
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http://dx.doi.org/10.1016/j.metabol.2020.154398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680436PMC
December 2020

Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

Liver Int 2020 11;40(11):2602-2611

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background & Aims: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters.

Methods: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted.

Results: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa.

Conclusions: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.
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http://dx.doi.org/10.1111/liv.14658DOI Listing
November 2020

Epoxygenase-Derived Epoxyeicosatrienoic Acid Mediators Are Associated With Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Fibrosis.

Gastroenterology 2020 12 5;159(6):2232-2234.e4. Epub 2020 Aug 5.

Harvard Medical School, Boston, Massachusetts; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725909PMC
December 2020

Low Complement C4 Predicts Improvement of Kidney Function After Direct-Acting Antiviral Therapy for Hepatitis C Virus.

Hepatol Commun 2020 Aug 4;4(8):1206-1217. Epub 2020 Jun 4.

Gastrointestinal Division Department of Medicine Massachusetts General Hospital Boston MA.

Direct-acting antiviral therapies (DAAs) may improve kidney function and proteinuria in certain patients with hepatitis C infection (HCV) and chronic kidney disease (CKD). To improve our understanding of HCV-mediated kidney dysfunction, we aimed to evaluate the baseline predictors of improvement in proteinuria after DAAs in a single-arm, pilot, clinical trial of ledipasvir 90 mg/sofosbuvir 400 mg once daily for patients with HCV genotype 1 or 4 infection and proteinuric CKD (≥300 mg proteinuria per gram creatinine). Plasma biomarkers of complement system (C3 and C4) and urinary kidney injury biomarkers were measured at baseline, 8 weeks on treatment, 12 weeks following treatment, and 1 year following treatment. We then conducted a retrospective cohort study of patients at Partners Healthcare who had baseline complement component 4 (C4) measured before DAAs for HCV and evaluated the change in estimated glomerular filtration rate (eGFR) before and after therapy. Ten patients with HCV and proteinuric CKD were enrolled in the trial. The mean age was 64 years, 70% male, 70% white, and 30% black. Baseline creatinine was 1.25 mg/dL (SD 0.44), eGFR was 65 mL/min/1.73 m (SD 29), and proteinuria was 0.98 g/g creatinine (SD 0.7). Sustained virologic response at 12 weeks was achieved by 80% of patients. Patients with low baseline C4 had improved proteinuria, urinary neutrophil gelatinase-associated lipocalin, and interleukin-18 after ledipasvir and sofosbuvir treatment. The retrospective study included 50 patients with CKD and HCV. Twenty patients (40%) had low baseline C4; these patients significantly improved their eGFR (+3.4 ± 11.2 mL/min/1.73 m) compared to those with normal baseline C4 (-4.4 ± 12.2 mL/min/1.73 m;  = 0.028). Low C4 may be a marker of kidney dysfunction that improves with DAA therapy.
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http://dx.doi.org/10.1002/hep4.1528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395066PMC
August 2020

Association of Hepatic Steatosis With Major Adverse Cardiovascular Events, Independent of Coronary Artery Disease.

Clin Gastroenterol Hepatol 2021 07 21;19(7):1480-1488.e14. Epub 2020 Jul 21.

Cardiovascular Imaging Research Center, Massachusetts General Hospital, Boston, Massachusetts; Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon.

Background & Aims: Hepatic steatosis has been associated with increased risk of major adverse cardiovascular events (MACE) but it is not clear whether steatosis is independently associated with risk of MACE. We investigated whether steatosis is associated with risk of MACE independently of the presence and extent of baseline coronary artery disease, assessed by comprehensive contrast-enhanced computed tomography angiography (CTA).

Methods: We conducted a nested cohort study of 3756 subjects (mean age, 60.6 years; 48.4% men) who underwent coronary CTA at 193 sites in North America, from July 2010 through September 2013, as part of the PROMISE study, which included noninvasive cardiovascular analyses of symptomatic outpatients without coronary artery disease. Independent core laboratory readers measured hepatic and splenic attenuation, using non-contrast computed tomography images to identify steatosis, and evaluated coronary plaques and stenosis in coronary CTA images. We collected data on participants' cardiovascular risk factors, presence of metabolic syndrome, and body mass index. The primary endpoint was an adjudicated composite of MACE (death, myocardial infarction, or unstable angina) during a median follow-up time of 25 months.

Results: Among the 959 subjects who had steatosis (25.5% of the cohort), 42 had MACE (4.4%), whereas among the 2797 subjects without steatosis, 73 had MACE (2.6%) (hazard ratio [HR] for MACE in subjects with steatosis, 1.69; 95% CI, 1.16-2.48; P = .006 for MACE in subjects with vs without steatosis). This association remained after adjustment for atherosclerotic cardiovascular disease risk scores, significant stenosis, and metabolic syndrome (adjusted HR, 1.72; 95% CI, 1.16-2.54; P = .007) or obesity (adjusted HR, 1.75; 95% CI, 1.19-2.59; P = .005). Steatosis remained independently associated with MACE after adjustment for all CTA measures of plaques and stenosis.

Conclusions: Hepatic steatosis is associated with MACE independently of other cardiovascular risk factors or extent of coronary artery disease. Strategies to reduce steatosis might reduce risk of MACE. ClinicalTrials.gov no: NCT01174550.
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http://dx.doi.org/10.1016/j.cgh.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855524PMC
July 2021

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.
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http://dx.doi.org/10.1172/jci.insight.140134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455119PMC
August 2020

Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices.

Aliment Pharmacol Ther 2020 08 29;52(3):513-526. Epub 2020 Jun 29.

Washington, DC, USA.

Background: Primary care practitioners (PCPs) and diabetologists are at the frontline of potentially encountering patients with NASH. Identification of those at high risk for adverse outcomes is important.

Aim: To provide practical guidance to providers on how to identify these patients and link them to specialty care.

Methods: US members of the Global Council on NASH evaluated the evidence about NASH and non-invasive tests and developed a simple algorithm to identify high-risk NASH patients for diabetologists and primary care providers. These tools can assist frontline providers in decision-making and referral to gastroenterology/hepatology practices for additional assessments.

Results: The presence of NASH-related advanced fibrosis is an independent predictor of adverse outcomes. These patients with NASH are considered high risk and referral to specialists is warranted. Given that staging of fibrosis requires a liver biopsy, non-invasive tests for fibrosis would be preferred. Consensus recommendation from the group is to risk-stratify patients based on metabolic risk factors using the FIB-4 as the initial non-invasive test due to its simplicity and ease of use. A FIB-4 score ≥1.3 can be used for further assessment and linkage to specialty care where additional technology to assess liver stiffness or serum fibrosis test will be available.

Conclusion: Due to the growing burden of NAFLD and NASH, PCPs and diabetologists are faced with increased patient encounters in their clinical practices necessitating referral decisions. To assist in identifying high-risk NASH patients requiring specialty care, we provide a simple and easy to use algorithm.
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http://dx.doi.org/10.1111/apt.15830DOI Listing
August 2020

The Role of Bone Morphogenetic Protein Signaling in Non-Alcoholic Fatty Liver Disease.

Sci Rep 2020 06 19;10(1):9831. Epub 2020 Jun 19.

Cardiovascular Research Center and Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.
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http://dx.doi.org/10.1038/s41598-020-66770-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305229PMC
June 2020

Development of an Algorithm to Identify Cases of Nonalcoholic Steatohepatitis Cirrhosis in the Electronic Health Record.

Dig Dis Sci 2021 05 13;66(5):1452-1460. Epub 2020 Jun 13.

Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Liver Center, 110 Francis St. Suite 8E, Boston, MA, 02215, USA.

Background And Aims: Current genetic research of nonalcoholic steatohepatitis (NASH) cirrhosis is limited by our ability to accurately identify cases on a large scale. Our objective was to develop and validate an electronic health record (EHR) algorithm to accurately identify cases of NASH cirrhosis in the EHR.

Methods: We used Clinical Query 2, a search tool at Beth Israel Deaconess Medical Center, to create a pool of potential NASH cirrhosis cases (n = 5415). We created a training set of 300 randomly selected patients for chart review to confirm cases of NASH cirrhosis. Test characteristics of different algorithms, consisting of diagnosis codes, laboratory values, anthropomorphic measurements, and medication records, were calculated. The algorithms with the highest positive predictive value (PPV) and the highest F score with a PPV ≥ 80% were selected for internal validation using a separate random set of 100 patients from the potential NASH cirrhosis pool. These were then externally validated in another random set of 100 individuals using the research patient data registry tool at Massachusetts General Hospital.

Results: The algorithm with the highest PPV of 100% on internal validation and 92% on external validation consisted of ≥ 3 counts of "cirrhosis, no mention of alcohol" (571.5, K74.6) and ≥ 3 counts of "nonalcoholic fatty liver" (571.8-571.9, K75.81, K76.0) codes in the absence of any diagnosis codes for other common causes of chronic liver disease.

Conclusions: We developed and validated an EHR algorithm using diagnosis codes that accurately identifies patients with NASH cirrhosis.
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http://dx.doi.org/10.1007/s10620-020-06388-yDOI Listing
May 2021

Acyl-Coenzyme A Thioesterase 9 Traffics Mitochondrial Short-Chain Fatty Acids Toward De Novo Lipogenesis and Glucose Production in the Liver.

Hepatology 2020 09;72(3):857-872

Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY.

Background And Aims: Obesity-induced pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is associated with increased de novo lipogenesis (DNL) and hepatic glucose production (HGP) that is due to excess fatty acids. Acyl-coenzyme A (CoA) thioesterase (Acot) family members control the cellular utilization of fatty acids by hydrolyzing (deactivating) acyl-CoA into nonesterified fatty acids and CoASH.

Approach And Results: Using Caenorhabditis elegans, we identified Acot9 as the strongest regulator of lipid accumulation within the Acot family. Indicative of a maladaptive function, hepatic Acot9 expression was higher in patients with obesity who had NAFLD and NASH compared with healthy controls with obesity. In the setting of excessive nutrition, global ablation of Acot9 protected mice against increases in weight gain, HGP, steatosis, and steatohepatitis. Supportive of a hepatic function, the liver-specific deletion of Acot9 inhibited HGP and steatosis in mice without affecting diet-induced weight gain. By contrast, the rescue of Acot9 expression only in the livers of Acot9 knockout mice was sufficient to promote HGP and steatosis. Mechanistically, hepatic Acot9 localized to the inner mitochondrial membrane, where it deactivated short-chain but not long-chain fatty acyl-CoA. This unique localization and activity of Acot9 directed acetyl-CoA away from protein lysine acetylation and toward the citric acid (TCA) cycle. Acot9-mediated exacerbation of triglyceride and glucose biosynthesis was attributable at least in part to increased TCA cycle activity, which provided substrates for HGP and DNL. β-oxidation and ketone body production, which depend on long-chain fatty acyl-CoA, were not regulated by Acot9.

Conclusions: Taken together, our findings indicate that Acot9 channels hepatic acyl-CoAs toward increased HGP and DNL under the pathophysiology of obesity. Therefore, Acot9 represents a target for the management of NAFLD.
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http://dx.doi.org/10.1002/hep.31409DOI Listing
September 2020
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