Publications by authors named "Raymond T Chung"

496 Publications

Association of Statins and 28-Day Mortality in Patients Hospitalized with SARS CoV-2 Infection.

J Infect Dis 2021 Oct 19. Epub 2021 Oct 19.

Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.

Background: Statins may be protective in SARS-CoV-2 infection. The aim of this study was to evaluate the effect of in-hospital statin use on 28-day mortality and ICU admission among patients with SARS-CoV-2 stratified into 4 groups: those who used statins prior to hospitalization (continued, discontinued) and those who did not (newly initiated, never).

Methods: In a cohort study of 1179 patients with SARS-CoV-2, chart review was used to assess demographics, laboratory measurements, comorbidities, and time from admission to death, ICU admission, or discharge. Using marginal structural Cox models, we estimated hazard ratios for mortality and ICU admission.

Results: Among 1179 patients, 676 (57 %) were male, 443 (37 %) were at least 65 years old, and 493 (46%) had a BMI ≥30. Inpatient statin use reduced the hazard of death (HR 0.566, P = 0.008). This association held among patients who did and did not use statins prior to hospitalization (HR 0.270, P=0.003; HR 0.493, P=0.038). Statin use was associated with improved time-to-death for patients >65 years, but not patients ≤65 years.

Conclusion: Statin use during hospitalization for SARS-CoV-2 infection was associated with reduced 28-day mortality. Well-designed randomized control trials are needed to better define this relationship.
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http://dx.doi.org/10.1093/infdis/jiab539DOI Listing
October 2021

Association of donor hepatitis C virus infection status and risk of BK polyomavirus viremia after kidney transplantation.

Am J Transplant 2021 Oct 6. Epub 2021 Oct 6.

Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.
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http://dx.doi.org/10.1111/ajt.16834DOI Listing
October 2021

Terlipressin and the Treatment of Hepatorenal Syndrome: How the CONFIRM Trial Moves the Story Forward.

Am J Kidney Dis 2021 Oct 1. Epub 2021 Oct 1.

Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Hepatorenal syndrome (HRS) is a form of acute kidney injury occurring in patients with advanced cirrhosis and is associated with significant morbidity and mortality. The pathophysiology underlying HRS begins with increasing portal pressures leading to the release of vasodilatory substances which result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and release of arginine vasopressin serve to defend mean arterial pressure but at the cost of severe constriction of the renal vasculature, leading to a progressive, often fulminant form of AKI. While there are no approved treatments for HRS in the United States, multiple countries, including much of Europe, utilize terlipressin, a synthetic vasopressin analogue, as first-line therapy. The recently published CONFIRM trial, the third randomized trial based in North America evaluating terlipressin, met its primary endpoint, showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about apparent increased rates of respiratory adverse events and a lack of evidence for mortality benefit, terlipressin was not approved by the Food and Drug Administration (FDA). In this Perspective, we explore the history of regulatory approval for terlipressin in the United States, examine the results from CONFIRM and the concerns they raised and consider the future role of terlipressin in this critical clinical area of continued unmet need.
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http://dx.doi.org/10.1053/j.ajkd.2021.08.016DOI Listing
October 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

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.

Nat Commun 2021 09 17;12(1):5525. Epub 2021 Sep 17.

Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2, CLEC5A, MARCO liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.
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http://dx.doi.org/10.1038/s41467-021-25468-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448834PMC
September 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

Type I, II, and III Interferon Signatures Correspond to Coronavirus Disease 2019 Severity.

J Infect Dis 2021 09;224(5):777-782

Liver Center, GI Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.
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http://dx.doi.org/10.1093/infdis/jiab288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244575PMC
September 2021

Hepatic Encephalopathy is Associated With Slow Speech on Objective Assessment.

Am J Gastroenterol 2021 09;116(9):1950-1953

Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

Introduction: There are no available low-burden, point-of-care tests to diagnose, grade, and predict hepatic encephalopathy (HE).

Methods: We evaluated speech as a biomarker of HE in 76 English-speaking adults with cirrhosis.

Results: Three speech features significantly correlated with the following neuropsychiatric scores: speech rate, word duration, and use of particles. Patients with low neuropsychiatric scores had slower speech (22 words/min, P = 0.01), longer word duration (0.09 seconds/word, P = 0.01), and used fewer particles (0.85% fewer, P = 0.01). Patients with a history of overt HE had slower speech (23 words/min, P = 0.005) and longer word duration (0.09 seconds/word, P = 0.005).

Discussion: HE is associated with slower speech.
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http://dx.doi.org/10.14309/ajg.0000000000001351DOI Listing
September 2021

A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis.

Med (N Y) 2021 Jul 21;2(7):836-850.e10. Epub 2021 Apr 21.

Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S.

Background: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need.

Methods: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection.

Findings: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively).

Conclusions: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.
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http://dx.doi.org/10.1016/j.medj.2021.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312635PMC
July 2021

Epigenetic scars of CD8 T cell exhaustion persist after cure of chronic infection in humans.

Nat Immunol 2021 08 26;22(8):1020-1029. Epub 2021 Jul 26.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8 T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8 T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.
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http://dx.doi.org/10.1038/s41590-021-00979-1DOI Listing
August 2021

Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

Nat Immunol 2021 08 26;22(8):1030-1041. Epub 2021 Jul 26.

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

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8 T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.
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http://dx.doi.org/10.1038/s41590-021-00982-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323980PMC
August 2021

An exploratory analysis of the competing effects of alcohol use and advanced hepatic fibrosis on serum HDL.

Clin Exp Med 2021 Jul 1. Epub 2021 Jul 1.

Division of Gastroenterology, MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.

While alcohol use has been shown to increase serum HDL, advanced liver disease associates with decreased serum HDL. The combined influence of alcohol consumption and liver fibrosis is poorly defined. In this study, we sought to investigate the competing effects of alcohol use and hepatic fibrosis on serum HDL and to determine if the presence of advanced hepatic fibrosis ablates the reported effect of alcohol consumption on serum HDL. We performed a cross-sectional, exploratory analysis examining the interaction between alcohol use and advanced hepatic fibrosis on serum HDL levels in 10,528 patients from the Partners Biobank. Hepatic fibrosis was assessed using the FIB-4 index. We excluded patients with baseline characteristics that affect serum HDL, independent of alcohol use or the presence or advanced hepatic fibrosis. We observed an incremental correlation between increasing HDL levels and amount of alcohol consumed (P < 0.0001), plateauing in those individuals who drink 1-2 drinks per day, Contrastingly, we found a negative association between the presence of advanced hepatic fibrosis and lower HDL levels, independent of alcohol use (beta coefficient: -0.011075, SEM0.003091, P value: 0.0001). Finally, when comparing subjects with advanced hepatic fibrosis who do not use alcohol to those who do, we observed that alcohol use is associated with increased HDL levels (54.58 mg/dL vs 67.26 mg/dL, p = 0.0009). This HDL-elevating effect of alcohol was more pronounced than that seen in patients without evidence of advanced hepatic fibrosis (60.88 mg/dL vs 67.93 mg/dL, p < 0.0001). Our data suggest that the presence of advanced hepatic fibrosis does not blunt the HDL-elevating effect of alcohol use.
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http://dx.doi.org/10.1007/s10238-021-00736-6DOI Listing
July 2021

Comparison of HBV RNA and Hepatitis B Core Related Antigen With Conventional HBV Markers Among Untreated Adults With Chronic Hepatitis B in North America.

Hepatology 2021 Nov 9;74(5):2395-2409. Epub 2021 Sep 9.

Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA.

Background And Aims: The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear.

Approach And Results: Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg and 58% of HBeAg participants; HBcrAg was quantifiable in 20% of HBeAg (above linear range in the other 80%) and 51% of HBeAg participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg and HBeAg immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg and HBeAg phases (HBV RNA: e ρ = 0.84; e ρ = 0.78; HBcrAg: e ρ = 0.66; e ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg phases only (HBV RNA: e ρ = 0.71; P < 0.001; e ρ = 0.18; P = 0.56; HBcrAg: e ρ = 0.51; P < 0.001; e ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg , but not HBeAg , phases.

Conclusions: Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators.
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http://dx.doi.org/10.1002/hep.32018DOI Listing
November 2021

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

Cell Mol Gastroenterol Hepatol 2021 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

Serum HMGB1 associates with liver disease and predicts readmission and mortality in patients with alcohol use disorder.

Alcohol 2021 09 10;95:37-43. Epub 2021 Jun 10.

MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States; Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States. Electronic address:

Identifying the minority of patients with alcohol use disorder (AUD) who develop the wide spectrum of alcohol-associated liver disease (ALD), and risk-stratifying these patients, is of critical importance. High-Mobility Group Box 1 protein (HMGB1) is an alarmin that has been implicated in the pathogenesis of multiple liver diseases. Its use as a biomarker for liver disease in those with AUD has not been studied. In this report, we investigated the association between serum HMGB1 and the presence, severity, and progression of ALD in two well-characterized cohorts of patients with AUD. In our discovery cohort of 80 patients, we found that patients with AUD and ALD exhibited higher serum HMGB1 levels compared to patients with AUD only (p = 0.0002). Additionally, serum HMGB1 levels were positively associated with liver disease severity (p < 0.0001). We found that index serum HMGB1 levels were associated with liver disease progression, defined by an increase in MELD score at 120 days (p = 0.0397). Serum HMGB1 was notable for its diagnostic and prognostic ability; it proved able to distinguish accurately between severe and non-severe forms of ALD in both our discovery cohort (AUC = 0.8199, p = 0.0003) and an independent validation cohort of 74 patients with AUD (AUC = 0.8818, p < 0.0001). Moreover, serum HMGB1 levels effectively predicted both liver-related readmission (AUC = 0.8849, p < 0.0001) and transplantation/death (AUC = 0.8614, p = 0.0002) at 90 days. The predictive potential of HMGB1 was also validated in an independent cohort of patients with AUD. Taken together, our results suggest that serum HMGB1 shows promise as a biologically relevant biomarker for ALD in patients with AUD.
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http://dx.doi.org/10.1016/j.alcohol.2021.05.003DOI Listing
September 2021

The risk of hepatitis C virus recurrence in hepatitis C virus-infected patients treated with direct-acting antivirals after achieving a sustained virological response: A comprehensive analysis.

Liver Int 2021 Oct 16;41(10):2341-2357. Epub 2021 Jun 16.

Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background & Aims: The risk for hepatitis C virus (HCV) recurrence persists after HCV eradication with direct-acting antivirals (DAAs), particularly in patients with ongoing high-risk behaviours. Our aim was to assess the risk of HCV recurrence (late relapse and/or reinfection) post-sustained virological response (SVR).

Methods: We searched the literature for studies reporting HCV recurrence rates post-SVR in PubMed, Web of Science and the Cochrane Library. Identified publications were divided into groups based on patient risk for HCV reinfection: low-risk HCV mono-infection, high-risk HCV mono-infection and a human immunodeficiency virus (HIV)/HCV coinfection. The HCV recurrence rate for each study was calculated by using events divided by the person-years of follow-up (PYFU). HCV recurrence was defined as confirmed, detectable HCV RNA post-SVR.

Results: In the 16 studies of low-risk patients, the pooled recurrence rate was 0.89/1000 PYFU (95% confidence interval [CI], 0.16-2.03). For the 19 studies of high-risk patients, the pooled recurrence rate was 29.37/1000 PYFU (95% CI, 15.54-46.91). For the eight studies of HIV/HCV-coinfected patients, the pooled recurrence rate was 23.25/1000 PYFU (95% CI, 4.24-53.39). The higher pooled estimates of recurrence in the high-risk and HIV/HCV-coinfected populations were predominantly driven by an increase in reinfection rather than late relapse.

Conclusions: The HCV recurrence risk after achieving SVR with all-oral DAAs therapy is low, and the risk of HCV recurrence in high-risk and HIV/HCV-coinfected populations was driven by an increase in reinfection rather than late relapse.
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http://dx.doi.org/10.1111/liv.14976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455436PMC
October 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

Urinary NGAL as a Diagnostic and Prognostic Marker for Acute Kidney Injury in Cirrhosis: A Prospective Study.

Clin Transl Gastroenterol 2021 05 11;12(5):e00359. Epub 2021 May 11.

Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Introduction: Urinary neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in differentiating acute tubular necrosis (ATN) from other types of acute kidney injuries (AKIs) in cirrhosis, particularly hepatorenal syndrome (HRS). However, NGAL is not currently available in clinical practice in North America.

Methods: Urinary NGAL was measured in a prospective cohort of 213 US hospitalized patients with decompensated cirrhosis (161 with AKI and 52 reference patients without AKI). NGAL was assessed for its ability to discriminate ATN from non-ATN AKI and to predict 90-day outcomes.

Results: Among patients with AKI, 57 (35%) had prerenal AKI, 55 (34%) had HRS, and 49 (30%) had ATN, with a median serum creatinine of 2.0 (interquartile range 1.5, 3.0) mg/dL at enrollment. At an optimal cutpoint of 244 μg/g creatinine, NGAL distinguished ATN (344 [132, 1,429] μg/g creatinine) from prerenal AKI (45 [0, 154] μg/g) or HRS (110 [50, 393] μg/g; P < 0.001), with a C statistic of 0.762 (95% confidence interval 0.682, 0.842). By 90 days, 71 of 213 patients (33%) died. Higher median NGAL was associated with death (159 [50, 865] vs 58 [0, 191] μg/g; P < 0.001). In adjusted and unadjusted analysis, NGAL significantly predicted 90-day transplant-free survival (P < 0.05 for all Cox models) and outperformed Model for End-Stage Liver Disease score by C statistic (0.697 vs 0.686; P = 0.04), net reclassification index (37%; P = 0.008), and integrated discrimination increment (2.7%; P = 0.02).

Discussion: NGAL differentiates the type of AKI in cirrhosis and may improve prediction of mortality; therefore, it holds potential to affect management of AKI in cirrhosis.
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http://dx.doi.org/10.14309/ctg.0000000000000359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116001PMC
May 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

Statins Are Associated with Improved 28-day Mortality in Patients Hospitalized with SARS-CoV-2 Infection.

medRxiv 2021 Apr 6. Epub 2021 Apr 6.

Background: Statins may be protective in viral infection and have been proposed as treatment in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

Objective: We evaluated the effect of statins on mortality in four groups hospitalized with (SARS-CoV-2) infection (continued statin, newly initiated statin, discontinued statin, never on statin).

Design: In a single center cohort study of 1179 patients hospitalized with SARS-CoV-2 infection, the outcome of death, Intensive Care Unit (ICU) admission or hospital discharge was evaluated. Patients' statin use, laboratory data, and co-morbidities were determined via chart review and electronic health records. Using marginal structural models to account for timing of statin initiation and competing risks, we compared the likelihood of severe outcomes in the four statin exposure groups.

Setting: Academic medical center in the United States.

Participants: Patients hospitalized with SARS-CoV-2 infection.

Measurements: 28-day mortality, ICU admission, or discharge.

Results: Among 1179 patients, 360 were never on a statin, 311 were newly initiated on a statin, 466 were continued on a statin, and 42 had a statin discontinued. In this cohort, 154 (13.1%) patients died by 28-days. With marginal structural model analysis, statin use reduced the hazard of 28-day mortality (HR 0.566 [CI 0.372, 0.862], p = 0.008). Both new initiation of statins (HR 0.493 [CI 0.253, 0.963], p=0.038) and continuing statin therapy reduced the hazard of 28-day mortality (HR 0.270 [CI 0.114, 0.637], p=0.003). Sensitivity analysis found that statin use was associated with improved mortality for patients > 65 years, but not for patients 65 years or younger.

Limitation: Observational design.

Conclusion: Statin therapy during hospitalization for SARS-CoV-2 infection, including new initiation and continuation of therapy, was associated with reduced short-term mortality.
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http://dx.doi.org/10.1101/2021.03.27.21254373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043489PMC
April 2021

Hepatic Steatosis and Steatohepatitis in a Large North American Cohort of Adults With Chronic Hepatitis B.

Am J Gastroenterol 2021 08;116(8):1686-1697

University of Michigan, Ann Arbor, Michigan, USA.

Introduction: Fatty liver disease (FLD) influences liver disease progression and liver cancer risk. We investigated the impact of FLD on liver disease severity in a large North American cohort with chronic hepatitis B virus (HBV).

Methods: Liver biopsies from 420 hepatitis B surface antigen-positive adults enrolled in the Hepatitis B Research Network and who were not on HBV therapy in the previous month were evaluated for inflammation and fibrosis. Steatohepatitis was based on steatosis, hepatocyte ballooning ± Mallory-Denk bodies, and perisinusoidal fibrosis. Models evaluated factors associated with steatohepatitis, and the associations of steatohepatitis with fibrosis, and longitudinal alanine aminotransferase, aspartate aminotransferase, and Fibrosis-4.

Results: The median age was 42 years, 62.5% were male, and 79.5% were Asian. One hundred thirty-two (31.4%) patients had FLD (77 [18.3%] steatosis only, 55 [13.1%] steatohepatitis). Older age, overweight/obesity, and diabetes were associated with steatohepatitis. Steatohepatitis (vs no FLD) was associated with 1.68 times higher risk of advanced fibrosis at baseline (95% confidence interval, 1.12-2.51), and there was an indication of higher incident cirrhosis rate during follow-up. Steatohepatitis vs no FLD was also independently associated with, on average, 1.39 times higher alanine aminotransferase (P < 0.01) and 1.25 times higher Fibrosis-4 (P = 0.04) across 4 years.

Discussion: Coexisting steatosis occurred in nearly a third of adults (13% had steatohepatitis) with chronic HBV in this North American cohort who underwent liver biopsies. Steatohepatitis was associated with advanced fibrosis and higher biochemical measures of hepatic inflammation over time. Therefore, in addition to viral suppression, screening for and managing metabolic abnormalities is important to prevent disease progression in HBV.
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http://dx.doi.org/10.14309/ajg.0000000000001257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484018PMC
August 2021

The 2020 Nobel Prize for Medicine or Physiology for the Discovery of Hepatitis C Virus: A Triumph of Curiosity and Persistence.

Hepatology 2021 Nov 5;74(5):2813-2823. Epub 2021 Oct 5.

Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA.

The 2020 Nobel Prize in Medicine or Physiology was awarded to Drs. Harvey Alter, Michael Houghton, and Charles Rice for their contributions to the discovery and characterization of the hepatitis C virus (HCV). Their achievements represent a remarkable triumph of biomedical science which allowed the development of curative therapy for HCV, that will save countless lives. This tribute provides a historical perspective of the laureates' seminal work leading to the discovery of the HCV and a synopsis of a forum hosted by the American Association for the Study of Liver Diseases to honor the laureates in which they offered their perspectives, advice for young investigators and what's left to accomplish in the field. Finally, others in the research community who have worked closely with one or more of the laureates, share some of their personal reflections and anecdotes.
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http://dx.doi.org/10.1002/hep.31830DOI Listing
November 2021

Type I, II, and III interferon signatures correspond to COVID-19 disease severity.

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

We analyzed the plasma levels of interferons and cytokines, and the expression of interferon-stimulated genes in peripheral blood mononuclear cells in COVID-19 patients with different disease severity. Mild patients exhibited transient type I interferon responses, while ICU patients had prolonged type I interferon responses with hyper-inflammation mediated by interferon regulatory factor 1. Type II interferon responses were compromised in ICU patients. Type III interferon responses were induced in the early phase of SARS-CoV-2 infection, even in convalescent patients. These results highlight the importance of type I and III interferon responses during the early phase of infection in controlling COVID-19 progression.
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http://dx.doi.org/10.1101/2021.03.10.21253317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987053PMC
March 2021

A Prospective Study Evaluating Changes in Histology, Clinical and Virologic Outcomes in HBV-HIV Co-infected Adults in North America.

Hepatology 2021 Sep 25;74(3):1174-1189. Epub 2021 Aug 25.

National Cancer Institute, Bethesda, MD.

Background And Aims: Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined.

Approach And Results: Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)-funded prospective observational study (n = 139). Demographic, clinical, serological, and virological data were collected at entry and every 24 weeks for ≤ 192 weeks. Paired liver biopsies were obtained at study entry and at ≥ 3 years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n = 114), median age was 49 years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20 years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm and 93% had HIV < 400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20 IU/mL) in 61% and < 1,000 IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n = 1), alanine aminotransferase flare (n = 2), and HBeAg loss (n = 13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n = 62; median 3.6 years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2-4] to 3 [1-3]; P = 0.02) and no significant change in fibrosis score (1 [1-2] to 1 [0-3]; P = 0.58).

Conclusions: In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon.
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http://dx.doi.org/10.1002/hep.31823DOI Listing
September 2021

Loss of Coordinated Neutrophil Responses to the Human Fungal Pathogen, , in Patients With Cirrhosis.

Hepatol Commun 2021 03 5;5(3):502-515. Epub 2021 Jan 5.

Department of Medicine Massachusetts General Hospital Boston MA USA.

Neutrophils are the most abundant white blood cell in the body and are key participants in the defense against fungal infections. Fungal infections occur often in patients with cirrhosis and are associated with increased 30-day and 90-day mortality. Previous studies have shown that specific neutrophil functions are abnormal in patients with cirrhosis, although the extent of neutrophil dysfunction is not well understood. We tested the ability of neutrophils from 21 hospitalized patients with cirrhosis and 23 healthy control patients to kill , a common fungal pathogen in patients with cirrhosis. Using an assay, we also measured the ability of neutrophils to coordinate multicellular, synchronized control of hyphae through a process known as swarming. We found that neutrophils from patients with cirrhosis have significantly decreased fungicidal capacity compared with healthy control neutrophils (53% vs. 74%,  < 0.0001) and diminished ability to control hyphal growth normalized as a ratio to healthy control (0.22 vs. 0.65,  < 0.0001). Moreover, serum from patients with cirrhosis decreases the ability of healthy control neutrophils to kill (from 60% to 41%,  < 0.003). Circulating concentration of the inflammatory cytokines tumor necrosis factor α, interleukin-6, and interleukin-8 were found to be significantly elevated in patients with cirrhosis compared to healthy controls. Following pretreatment with granulocyte-colony stimulating factor and granulocyte-macrophage colony-stimulating factor, neutrophil function was restored to almost that of healthy controls. Our data establish profound neutrophil dysfunction against, and altered swarming to, in patients with cirrhosis. This dysfunction can be partially reversed with cytokine augmentation .
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http://dx.doi.org/10.1002/hep4.1645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917271PMC
March 2021

Deep stool microbiome analysis in cirrhosis reveals an association between short-chain fatty acids and hepatic encephalopathy.

Ann Hepatol 2021 Feb 20;25:100333. Epub 2021 Feb 20.

Department of Medicine, Harvard Medical School, United States; Liver Center, Gastroenterology Division, Massachusetts General Hospital, United States. Electronic address:

Introduction And Objectives: Hepatic encephalopathy (HE) is a complication of cirrhosis linked to the microbiome. We aimed to characterize the fecal microbiome of patients with prior and future overt HE, and explore the relationship between fecal species, short-chain fatty acids (SCFAs) and ammonia on HE pathogenesis.

Materials And Methods: Consecutive inpatients and outpatients with cirrhosis were recruited. A single stool sample was collected and underwent shallow shotgun sequencing, and SCFA and ammonia quantification. Patients were followed until the end of the study period. Prior and new overt HE was diagnosed by the treating hepatologist.

Results: Forty-nine patients with cirrhosis, mean MELD-Na 20 (SD = 9) and 33 (67%) with a history of OHE provided a stool sample. Over a median 85 days of follow up (interquartile range 34-181 days), 16 developed an OHE episode. Eight fecal bacterial species were associated with a history of OHE, and no species predicted future OHE. Bacterial species positively associated with SCFA content were inversely related to cirrhosis disease severity. Patients with a history of OHE had lower concentrations of 6 fecal SCFAs. Fecal ammonia concentrations were similar between those with and without a history of OHE (273 μmol/g ± 214 vs. 327 ± 234, P = 0.43).

Conclusions: We found 8 fecal species and 6 SCFAs linked to OHE. Many of the species inversely linked to OHE also have an association with SCFA production. Further work is needed to detail this relationship and to develop targeted interventions to treat HE.
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http://dx.doi.org/10.1016/j.aohep.2021.100333DOI Listing
February 2021

American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

Hepatology 2021 08;74(2):1049-1064

University of Michigan, Ann Arbor, MI, USA.

The aim of this document is to provide a concise scientific review of the currently available COVID-19 vaccines and those in development, including mRNA, adenoviral vectors, and recombinant protein approaches. The anticipated use of COVID-19 vaccines in patients with chronic liver disease (CLD) and liver transplant (LT) recipients is reviewed and practical guidance is provided for health care providers involved in the care of patients with liver disease and LT about vaccine prioritization and administration. The Pfizer and Moderna mRNA COVID-19 vaccines are associated with a 94%-95% vaccine efficacy compared to placebo against COVID-19. Local site reactions of pain and tenderness were reported in 70%-90% of clinical trial participants, and systemic reactions of fever and fatigue were reported in 40%-70% of participants, but these reactions were generally mild and self-limited and occurred more frequently in younger persons. Severe hypersensitivity reactions related to the mRNA COVID-19 vaccines are rare and more commonly observed in women and persons with a history of previous drug reactions for unclear reasons. Because patients with advanced liver disease and immunosuppressed patients were excluded from the vaccine licensing trials, additional data regarding the safety and efficacy of COVID-19 vaccines are eagerly awaited in these and other subgroups. Remarkably safe and highly effective mRNA COVID-19 vaccines are now available for widespread use and should be given to all adult patients with CLD and LT recipients. The online companion document located at https://www.aasld.org/about-aasld/covid-19-resources will be updated as additional data become available regarding the safety and efficacy of other COVID-19 vaccines in development.
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http://dx.doi.org/10.1002/hep.31751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014184PMC
August 2021

Performance of Serum-Based Scores for Identification of Mild Hepatic Steatosis in HBV Mono-infected and HBV-HIV Co-infected Adults.

Dig Dis Sci 2021 Feb 8. Epub 2021 Feb 8.

National Institutes of Health, Bethesda, USA.

Background: There are limited data on noninvasive methods to identify hepatic steatosis in coexisting hepatitis B virus (HBV) infection.

Aims: To evaluate the diagnostic performance of noninvasive serum-based scores to detect steatosis using two distinct chronic HBV cohorts with liver histology evaluation.

Methods: Chronic HBV cohorts with untreated HBV mono-infection (N = 302) and with treated HBV-HIV (N = 92) were included. Liver histology was scored centrally. Four serum-based scores were calculated: hepatic steatosis index (HSI), nonalcoholic fatty liver disease Liver Fat Score (NAFLD-LFS), visceral adiposity index (VAI), and triglyceride glucose (TyG) index. Optimal cutoffs (highest sensitivity + specificity) to detect ≥ 5% HS, stratified by cohort, were evaluated.

Results: HBV-HIV (vs. HBV mono-infected) patients were older (median 50 vs. 43 years), and a higher proportion were male (92% vs. 60%), were black (51% vs. 8%), had the metabolic syndrome (41% vs. 25%), and suppressed HBV DNA (< 1000 IU/mL; 82% vs. 9%). Applying optimal cutoffs, the area under the receiver operator curve for detecting ≥ 5% steatosis in HBV-only and HBV-HIV, respectively, was 0.69 and 0.61 for HSI, 0.70 and 0.76 for NAFLD-LFS, 0.68 and 0.64 for TyG, and 0.68 and 0.69 for VAI. The accuracy of optimal cutoffs ranged from 61% (NAFLD-LFS) to 67% (TyG) among HBV-only and 56% (HSI) to 76% (NAFLD-LFS) among HBV-HIV. Negative predictive values were higher than positive predictive values for all scores in both groups.

Conclusion: The relative utility of scores to identify steatosis in chronic HBV differs by co-infection/anti-HBV medication status. However, even with population-specific cutoffs, several common serum-based scores have only moderate utility. ClinicalTrials.gov NCT01924455.
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http://dx.doi.org/10.1007/s10620-021-06860-3DOI Listing
February 2021
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