Publications by authors named "Don C Rockey"

334 Publications

Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1.

PLoS One 2022 14;17(1):e0261789. Epub 2022 Jan 14.

Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261789PLOS
January 2022

Infection in Hospitalized Cirrhosis Patients: Changing Epidemiology and Clinical Features.

Am J Med Sci 2022 Jan 4. Epub 2022 Jan 4.

Division of Gastroenterology and Hepatology, and the Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina. Electronic address:

Background: Patients with cirrhosis are uniquely predisposed to infections, which can lead to acute decompensation and an increase in mortality rates. We hypothesized that not only are cirrhotic patients more likely to develop certain infections, but that specific infections are associated with poorer outcomes. Therefore, we aimed to examine the epidemiology, bacteriology, and outcomes of infections in cirrhotic patients admitted to the hospital.

Methods: In this single center observational retrospective cohort study, we identified admissions in which patients had an infection from a group of all admissions of cirrhotics from 2011-2016. Infections were categorized by the primary source of infection, and rigorous clinical and bacteriologic definitions were used.

Results: We identified 1,208 unique admissions in 877 unique patients during the study period. The most common infections identified were as follows: urinary tract infections (33%), pneumonia (23%), spontaneous bacterial peritonitis (14%), and bacteremia (11%). Gram-positive organisms were most commonly isolated in patients with spontaneous bacterial peritonitis and bacteremia, whereas gram negative bacteria were most prevalent in urinary tract infections and pneumonia. Candida infections were common and identified in the following proportions: spontaneous bacterial peritonitis (16%), pneumonia (14%), bacteremia (13%), and urinary tract infections (9%). Pneumonia, spontaneous bacterial peritonitis, and meningitis were associated with increased mortality rates (29%, 32%, and 67%, respectively), compared to the overall mortality rate of 20% (p-value<0.05).

Conclusions: In summary, infections were common in patients with cirrhosis and were associated with poor outcomes, particularly in the presence of evidence of sepsis. Spontaneous bacterial peritonitis and bacteremia are now most commonly due to gram-positive organisms and fungal infections appear to be rising in prevalence.
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http://dx.doi.org/10.1016/j.amjms.2021.10.023DOI Listing
January 2022

Improved Mortality But Increased Economic Burden of Disease in Compensated and Decompensated Cirrhosis: A US National Perspective.

J Clin Gastroenterol 2021 Dec 31. Epub 2021 Dec 31.

Division of Gastroenterology, Hepatology and Motility, University of Kansas-School of Medicine, Kansas City, KS Prisma Health, Gastroenterology & Liver Center Division of Gastroenterology & Hepatology, Department of Internal Medicine, University of South Carolina School of Medicine Greenville Campus, Greenville Digestive Disease Research Center, Medical University of South Carolina, Charleston, SC Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas at San Antonio, San Antonio, TX Division of Gastroenterology, Department of Internal Medicine, East Tennessee State University, Johnson City, TN.

Introduction: Cirrhosis remains a major burden on the health care system despite substantial advances in therapy and care. Studies simultaneously examining mortality, readmission, and cost of care are not available. Here, we hypothesized that improved patient care in the last decade might have led to improved outcomes and reduced costs in patients with cirrhosis.

Materials And Methods: We identified compensated cirrhosis (CC) and decompensated cirrhosis (DC) patients using carefully chosen ICD-9/ICD-10 codes from the Nationwide Readmission Database (NRD) (years 2010 to 2016). We evaluated trends of 30-day all-cause mortality, 30-day readmission, and inflation-adjusted index hospitalization and readmission costs. Factors associated with mortality and readmission were identified using regression analyses.

Results: A total of 3,374,038 patients with cirrhosis were identified, of whom nearly 50% had a decompensating event on initial admission. The 30-day inpatient mortality rate for both CC and DC patients decreased from 2010 to 2016. The 30-day readmission rate remained stable for DC and declined for CC. Over the study period, 30-day readmission costs increased for DC and remained unchanged for CC. The median cost for index hospitalization remained nearly unchanged, but the cost of readmission increased for both CC and DC groups. Gastrointestinal diseases and infections were the leading cause of readmission in CC and DC patient groups.

Conclusion: Inpatient mortality has decreased for CC and DC patients. Readmission has declined for CC patients and remained stable for DC patients. However, the economic burden of cirrhosis is rising.
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http://dx.doi.org/10.1097/MCG.0000000000001652DOI Listing
December 2021

The relationship between portal hypertension and portal hypertensive gastropathy.

Scand J Gastroenterol 2021 Dec 14:1-5. Epub 2021 Dec 14.

Digestive Disease Research Center, Medical University of South Carolina, Charleston, SC, USA.

Background And Aim: Portal hypertensive gastropathy (PHG) most commonly occurs in the setting of increased portal pressure in patients with cirrhosis. Here, we aimed to understand the correlation between hepatic venous pressure gradient (HVPG) and the presence and severity of PHG in patients with cirrhosis.

Methods: We examined patients with cirrhosis who underwent HVPG measurement at the Medical University of South Carolina between 2014 and 2020. Extensive demographic, clinical, laboratory, procedural (including precise grading of PHG severity using standard definitions), and outcome data were abstracted at the time of HVPG measurement.

Results: Three hundred and ten patients with HVPG measurements and cirrhosis were identified. Seventy-three patients having endoscopy within 6 months of HVPG measurement were included (mean age 54 ± 11, 44% female). The most common causes of cirrhosis were alcohol (41%) and non-alcoholic steatohepatitis (32%). The average HVPG was 15 mmHg (±6) and 62 patients had clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mmHg). Of the 73 patients with HVPG measured, 45 (62%) had PHG, including 40 (89%) of whom had CSPH. Out of the 45 patients with PHG, 41 and four had mild or severe PHG, respectively. MELD scores were similar in patients with and without PHG [15 ± 9 (SD) and 17 ± 9, respectively;  = .37]. HVPG was higher in patients with PHG (17 ± 7 mmHg) than those without PHG (13 ± 4 mmHg) ( = .01) but did not differ between mild and severe PHG.

Conclusion: A weak correlation exists between HVPG level and the presence of PHG.
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http://dx.doi.org/10.1080/00365521.2021.2012591DOI Listing
December 2021

Retraction Note to: Akt2-Dependent Phosphorylation of Radixin in Regulation of Mrp-2 Trafficking in WIF-B Cells.

Dig Dis Sci 2022 Jan;67(1):354

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, 803 CSB, MSC 623, Charleston, SC, USA.

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http://dx.doi.org/10.1007/s10620-021-07350-2DOI Listing
January 2022

From Coronaries to Cirrhosis: The Role of Percutaneous Coronary Intervention and Dual Antiplatelet Therapy in End-Stage Liver Disease.

J Investig Med High Impact Case Rep 2021 Jan-Dec;9:23247096211005097

Medical University of South Carolina, Charleston, SC, USA.

Drug-eluting stents (DES) have superior efficacy compared with bare metal stents (BMS) for treatment of coronary artery lesions. However, BMS continue to play an important role in percutaneous coronary intervention for patients who are at a high bleeding risk, because they require a shorter duration of dual antiplatelet therapy. However, new developments in DES and understanding of the optimal time required for dual antiplatelet therapy after percutaneous coronary intervention may further limit the use of BMS. Furthermore, the use of dual antiplatelet therapy is complicated in patients with cirrhosis, who may have coagulopathy. In this article, we present the case of a patient with cirrhosis and end-stage chronic liver disease with coronary artery disease and a proximal left anterior descending stenosis who received a DES and had multiple episodes of gastrointestinal bleeding. We review the literature addressing DES and BMS in patients at high risk of bleeding. We also review the optimal duration of dual antiplatelet therapy.
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http://dx.doi.org/10.1177/23247096211005097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606929PMC
November 2021

Correction: The function of integrin-linked kinase in normal and activated stellate cells.

Lab Invest 2022 Jan;102(1):112-114

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

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http://dx.doi.org/10.1038/s41374-021-00659-6DOI Listing
January 2022

Normal or Near Normal Aminotransferase Levels in Patients with Alcoholic Cirrhosis.

Am J Med Sci 2021 Oct 4. Epub 2021 Oct 4.

Division of Gastroenterology and Hepatology; Digestive Disease Research Center, Medical University of South Carolina, Charleston, SC, USA. Electronic address:

Background: Alcoholic liver disease is caused by excessive alcohol consumption that results in an inflammatory response and fibrosis. We have recognized that patients with alcoholic cirrhosis often have unremarkable liver enzyme values.

Methods: In this retrospective cohort analysis, we identified consecutive patients with documented alcoholic cirrhosis at an academic medical center who were admitted between January 1 2016 and December 1 2018. We examined clinical outcomes of patients as a function of whether the aspartate transaminase (AST) or alanine aminotransferase (ALT) was normal or abnormal. Likelihood chi-square analyses were utilized for group comparisons and t-tests were used for numerical data.

Results: In the cohort of 78 patients with alcoholic cirrhosis (age 55, 26-75; 58% male) 70 had a normal ALT and 12 had a normal AST. The average AST for all patients was 59U/L ± 34U/L (ULN=35U/L), and the average ALT was 27U/L ± 13U/L (ULN=45U/L). The average INR was 1.5 ± 0.5 and total bilirubin was 3.7mg/dL ± 4.9mg/dL, and 20 patients had a normal bilirubin level, including only one with an abnormal ALT level. The average model for end-stage liver disease (MELD) score was 19 ± 8 and 32% of patients died during the follow-up time period of 5 months. Decompensating events were identified in 78 (100%) patients. There was no correlation between complications or death and aminotransferase levels.

Conclusions: Aminotransferase levels are often unremarkable in patients with alcohol related cirrhosis and bear no relationship to clinical events or outcomes. Clinicians should be cautious when interpreting aminotransferases in patients with alcoholic cirrhosis.
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http://dx.doi.org/10.1016/j.amjms.2021.09.012DOI Listing
October 2021

Acute Liver Injury in Patients Hospitalized with COVID-19.

Dig Dis Sci 2021 Sep 6. Epub 2021 Sep 6.

Division of Gastroenterology and Hepatology, The Medical University of South Carolina, Charleston, SC, USA.

Introduction: The prevalence and significance of acute liver injury in patients with COVID-19 are poorly characterized.

Methods: Patients with confirmed COVID-19 who were hospitalized in geographically diverse medical centers in North America were included. Demographics, symptoms, laboratory data results, and outcomes were recorded. Linear and logistic regression identified factors associated with liver injury, in-hospital mortality, and length of stay (LOS).

Results: Among 1555 patients in the cohort, most (74%) had an elevated alanine aminotransferase (ALT) during hospitalization, which was very severe (> 20 × upper limit of normal [ULN]) in 3%. Severe acute liver injury (ALI) was uncommon, occurring in 0.1% on admission and 2% during hospitalization. No patient developed acute liver failure (ALF). Higher ALT was associated with leukocytosis (per mL) (β 10.0, 95% confidence interval (CI) 6.7-12.6, p < 0.001) and vasopressors use (β 80.2, 95%CI 21.5-138.8, p = 0.007). In-hospital mortality was associated with ALT > 20 × ULN (unadjusted OR 6.0, 95%CI 3.1-11.5, p < 0.001), ALP > 3 × ULN (unadjusted OR 4.4, 95%CI 2.5-7.7, p < 0.001), and severe ALI (unadjusted OR 6.8, 95%CI 3.0-15.3, p < 0.001) but lost significance after adjusting for covariates related to severe COVID-19 and hemodynamic instability. Elevated ALP and ALT were associated with longer LOS, admission to intensive care, mechanical ventilation, vasopressor use, and extracorporeal membrane oxygenation use (p < 0.001).

Conclusions: Transaminase elevation is common in hospitalized patients with COVID-19. Severe ALI is rare, and ALF may not be a complication of COVID-19. Extreme elevations in liver enzymes appear to be associated with mortality and longer LOS due to more severe systemic disease rather than SARS-CoV-2-related hepatitis.
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http://dx.doi.org/10.1007/s10620-021-07230-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419385PMC
September 2021

Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury.

Clin Gastroenterol Hepatol 2021 Aug 14. Epub 2021 Aug 14.

Department of Medicine, Einstein Healthcare Network, Philadelphia, Pennsylvania. Electronic address:

Background & Aims: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial.

Methods: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS.

Results: Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13-223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10).

Conclusions: The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. Clinical Trials.gov number: NCT00345930.
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http://dx.doi.org/10.1016/j.cgh.2021.08.015DOI Listing
August 2021

Hepatitis C virus treatment with direct-acting antivirals induces rapid changes in the hepatic proteome.

J Viral Hepat 2021 Nov 19;28(11):1614-1623. Epub 2021 Aug 19.

Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC, USA.

Treatment of chronic hepatitis C virus with direct-acting antivirals usually eradicates infection, but liver fibrosis does not resolve concurrently. In patients who develop cirrhosis prior to hepatitis C virus treatment, hepatic decompensation and hepatocellular carcinoma can still occur after viral elimination due to residual fibrosis. We hypothesized the liver proteome would exhibit meaningful changes in inflammatory and fibrinogenic pathways change upon hepatitis C virus eradication, which could impact subsequent fibrosis regression. We analysed the liver proteome and phosphoproteome of paired liver biopsies obtained from 8 hepatitis C virus-infected patients before or immediately after treatment with direct-acting antivirals. Proteins in interferon signalling and antiviral pathways decreased concurrent with hepatitis C virus treatment, consistent with prior transcriptomic analyses. Expression of extracellular matrix proteins associated with liver fibrosis did not change with treatment, but the phosphorylation pattern of proteins present within signalling pathways implicated in hepatic fibrinogenesis, including the ERK1/2 pathway, was altered concurrent with hepatitis C virus treatment. Hepatitis C virus treatment leads to reduced expression of hepatic proteins involved in interferon and antiviral signalling. Additionally, changes in fibrosis signalling pathways are detectable before alteration in extracellular matrix proteins, identifying a putative chronology for the dynamic processes involved in fibrosis reversal.
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http://dx.doi.org/10.1111/jvh.13593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530867PMC
November 2021

A Machine Learning Approach to Liver Histological Evaluation Predicts Clinically Significant Portal Hypertension in NASH Cirrhosis.

Hepatology 2021 12;74(6):3146-3160

Virginia Commonwealth University, Richmond, VA.

Background And Aims: The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm.

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

Conclusions: An ML model based on trichrome-stained liver biopsy slides can predict CSPH in patients with NASH with cirrhosis.
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http://dx.doi.org/10.1002/hep.32087DOI Listing
December 2021

An AI Approach for Identifying Patients With Cirrhosis.

J Clin Gastroenterol 2021 Jul 8. Epub 2021 Jul 8.

Department of Public Health Sciences Division of Gastroenterology and Hepatology Medical University of South Carolina Digestive Disease Research Center, Medical University of South Carolina, Charleston, SC.

Goal: The goal of this study was to evaluate an artificial intelligence approach, namely deep learning, on clinical text in electronic health records (EHRs) to identify patients with cirrhosis.

Background And Aims: Accurate identification of cirrhosis in EHR is important for epidemiological, health services, and outcomes research. Currently, such efforts depend on International Classification of Diseases (ICD) codes, with limited success.

Materials And Methods: We trained several machine learning models using discharge summaries from patients with known cirrhosis from a patient registry and random controls without cirrhosis or its complications based on ICD codes. Models were validated on patients for whom discharge summaries were manually reviewed and used as the gold standard test set. We tested Naive Bayes and Random Forest as baseline models and a deep learning model using word embedding and a convolutional neural network (CNN).

Results: The training set included 446 cirrhosis patients and 689 controls, while the gold standard test set included 139 cirrhosis patients and 152 controls. Among the machine learning models, the CNN achieved the highest area under the receiver operating characteristic curve (0.993), with a precision of 0.965 and recall of 0.978, compared with 0.879 and 0.981 for the Naive Bayes and Random Forest, respectively (precision 0.787 and 0.958, and recalls 0.878 and 0.827). The precision by ICD codes for cirrhosis was 0.883 and recall was 0.978.

Conclusions: A CNN model trained on discharge summaries identified cirrhosis patients with high precision and recall. This approach for phenotyping cirrhosis in the EHR may provide a more accurate assessment of disease burden in a variety of studies.
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http://dx.doi.org/10.1097/MCG.0000000000001586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741865PMC
July 2021

Silvio O. Conte Digestive Disease Research Core Centers-Connecting People, Creating Opportunities, Developing Careers.

Gastroenterology 2021 10 24;161(4):1085-1089. Epub 2021 Jun 24.

Medical University of South Carolina Digestive Disease Research Core Center, Medical University of South Carolina, Charleston, South Carolina.

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http://dx.doi.org/10.1053/j.gastro.2021.06.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463423PMC
October 2021

Flavin Adenine Dinucleotide Depletion Caused by Haploinsufficiency Leads to Hepatic Steatosis and Injury in Zebrafish.

Hepatol Commun 2021 Jun 2;5(6):976-991. Epub 2021 Mar 2.

Department of Medicine Medical University of South Carolina Charleston SC USA.

The electron transfer flavoprotein (ETF) complex, made up of the ETF alpha subunit (ETFA), ETF beta subunit (ETFB), and ETF dehydrogenase (ETFDH), regulates fatty acid β-oxidation activity while scavenging leaked electrons through flavin adenine dinucleotide (FAD)/reduced form FAD (FADH) redox reactions in mitochondria. Here, we hypothesized that ETF dysfunction-mediated FAD deficiency may result in increased mitochondrial oxidative stress and steatosis and subsequent liver injury. We report that haploinsufficiency caused hyperlipidemia, hypercholesterolemia, and hepatic steatosis and injury in adult zebrafish. Further, mutant livers had reduced levels of FAD and glutathione and an increase in reactive oxygen species. Because FAD depletion might be critical in the pathogenesis of the liver lesion identified in mutants, we used riboflavin to elevate FAD levels in the liver and found that riboflavin supplementation significantly suppressed hepatic steatosis and injury in mutants through suppression of oxidative stress and lipogenesis in the liver. Additionally, we found that adenosine triphosphate-linked mitochondrial oxygen consumption and mitochondrial membrane potential were reduced in primary hepatocytes and that riboflavin supplementation corrected these defects. FAD depletion caused by haploinsufficiency plays a key role in hepatic steatosis and oxidative stress-mediated hepatic injury in adult zebrafish. This raises the possibility that people with haploinsufficiency have a high risk for developing liver disease.
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http://dx.doi.org/10.1002/hep4.1691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183174PMC
June 2021

Letter to the Editor: Complications Associated With Anesthesia Services in Endoscopic Procedures Among Patients With Cirrhosis.

Hepatology 2021 10 25;74(4):2313-2314. Epub 2021 Aug 25.

Department of Medicine, Medical University of South Carolina, Charleston, SC.

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http://dx.doi.org/10.1002/hep.31892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627583PMC
October 2021

Letter: Confounders and outcomes in studies of beta-blockers in liver disease-role of PPIs? Authors' reply.

Aliment Pharmacol Ther 2021 07;54(1):91

Digestive Disease Research Center, Medical University of South Carolina, Charleston, SC, USA.

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http://dx.doi.org/10.1111/apt.16355DOI Listing
July 2021

Trends in hospitalization, mortality, and timing of colonoscopy in patients with acute lower gastrointestinal bleeding.

Endosc Int Open 2021 Jun 27;9(6):E777-E789. Epub 2021 May 27.

Division of Gastroenterology, Department of Internal Medicine, Medical University of South Carolina, United States.

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http://dx.doi.org/10.1055/a-1352-3204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159619PMC
June 2021

A community of portal hypertension.

Hepatol Int 2021 Jun 12;15(3):575-578. Epub 2021 May 12.

Digestive Disease Research Center, Medical University South Carolina, Charleston, SC, USA.

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http://dx.doi.org/10.1007/s12072-021-10192-9DOI Listing
June 2021

Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study.

J Hepatol 2021 08 24;75(2):439-441. Epub 2021 Apr 24.

CHESS-COVID-19 Group, The Third People's Hospital of Zhenjiang City, Zhenjiang, China.

Background & Aims: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD.

Methods: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination.

Results: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m (IQR 23.8-28.1 kg/m). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained.

Conclusions: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD.

Lay Summary: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.
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http://dx.doi.org/10.1016/j.jhep.2021.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185617PMC
August 2021

Increased rebleeding and mortality in patients with gastrointestinal bleeding treated with anticoagulant drugs compared to antiplatelet drugs.

Eur J Gastroenterol Hepatol 2021 Apr 16. Epub 2021 Apr 16.

Division of Gastroenterology and Hepatology Biostatistics Support Unit, Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA.

Background/aim: We determined the effect of antiplatelet and anticoagulant agents on rebleeding and mortality in patients with gastrointestinal bleeding.

Methods: This was a prospective study of patients admitted with gastrointestinal bleeding between 2013 and 2018. Outcomes were compared among patients on antiplatelet agents only, anticoagulant drugs only, combination therapy, and none. The association between mortality, rebleeding, and type of antithrombotic medication on admission and discharge was determined using multivariate analysis.

Results: A total of 509 patients were followed up for a median of 19 months. End of follow-up rebleeding and mortality rates were 19.4% and 23.0%, respectively. Independent predictors of mortality were age [hazard ratio (HR) = 1.025 per year increase, P = 0.002], higher Charlson Comorbidity Index (HR = 1.4, P < 0.0001), severe bleeding (HR = 2.1, P < 0.0001), and being on anticoagulants (HR = 2.3, P = 0.002). Being on antiplatelets was protective against rebleeding (HR = 0.6, P = 0.047). Those on anticoagulants were more likely to die (HR = 2.5, P < 0.0001) and to rebleed (HR = 2.1, P = 0.01) than those on antiplatelets. Antithrombotic drug discontinuation upon discharge was associated with increased mortality in patients with cardiovascular disease.

Conclusion: In gastrointestinal bleeding, rebleeding and mortality were associated with being on anticoagulant drugs, while being on antiplatelet agents was protective against rebleeding. Discontinuation of antithrombotics upon discharge increased the risk of death. The findings inform risk stratification and decisions regarding continuation or discontinuation of antithrombotics.
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http://dx.doi.org/10.1097/MEG.0000000000002148DOI Listing
April 2021

Updated strategies in the management of acute variceal haemorrhage.

Curr Opin Gastroenterol 2021 05;37(3):167-172

Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA.

Purpose Of Review: This article reviews the most recent studies regarding the management of acute esophageal variceal haemorrhage.

Recent Findings: New randomized control trials and meta-analyses confirmed the role of early transjugular intrahepatic portosystemic shunt (TIPS) in the management of acute variceal haemorrhage in Child-Pugh C (10-13) and B patients with active bleeding. A recent randomized controlled trial focused on the duration of vasoactive therapy showed no difference between 2 and 5 days of octreotide. A randomized trial showed decreased use of blood products for the correction of coagulopathy using a thromboelastography-guided approach (vs. conventional parameters) as well as decreased bleeding rates when compared with standard of care. A meta-analysis found that for rescue of variceal bleeding, self-expanding metallic stents were more efficacious and safer than balloon tamponade. In addition, studies showed that Child-Pugh C patients and those with hepatic vein pressure gradient more than 20 were at the highest risk of treatment failure, while model for end-stage liver disease was highly predictive of in-hospital mortality.

Summary: In patients with severe coagulopathy and uncontrolled bleeding, TEG-based transfusion strategies are recommended. Antibiotics should be used for all cirrhotic patients presenting with upper gastrointestinal bleeding, but should be tailored in accordance to local resistance patterns. Early TIPS for high-risk patients has been shown to have a significant survival benefit. Certain aspects of the management of variceal bleeding remain poorly studied such as the role of early TIPS in Child-B patients as well as strategies for rescue therapy in patients who are not TIPS candidates, and require further investigation.
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http://dx.doi.org/10.1097/MOG.0000000000000723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8691141PMC
May 2021

Editorial: Advances in hepatology - 2021.

Authors:
Don C Rockey

Curr Opin Gastroenterol 2021 05;37(3):165-166

Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA.

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http://dx.doi.org/10.1097/MOG.0000000000000728DOI Listing
May 2021

Advanced liver fibrosis and the metabolic syndrome in a primary care setting.

Diabetes Metab Res Rev 2021 Nov 9;37(8):e3452. Epub 2021 Apr 9.

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Aims: The fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) are noninvasive and accessible methods for assessing advanced liver fibrosis risk in primary care. We evaluated the distribution of FIB-4 and NFS scores in primary care patients with clinical signals for nonalcoholic fatty liver disease (NAFLD).

Materials And Methods: This retrospective cohort study of electronic record data between 2007 and 2018 included adults with at least one abnormal aminotransferase and no known (non-NAFLD) liver disease. We calculated patient-level FIB-4 and NFS scores, the proportion of patients with mean values exceeding advanced fibrosis thresholds (indeterminate risk: FIB-4 > 1.3, NFS > -1.455; high-risk: FIB-4 > 2.67, NFS > 0.676), and the proportion of patients with a NAFLD International Classification of Diseases-9/10 code. Logistic regression models evaluated the associations of metabolic syndrome (MetS) components with elevated FIB-4 and NFS scores.

Results: The cohort included 6506 patients with a median of 6 (interquartile range: 3-13) FIB-4 and NFS scores per patient. Of these patients, 81% had at least two components of MetS, 29% had mean FIB-4 and NFS scores for indeterminate fibrosis risk, and 11% had either mean FIB-4 or NFS scores exceeding the high advanced fibrosis risk thresholds. Regression models identified associations of low high-density lipoprotein, hyperglycemia, Black race and male gender with high-risk FIB-4 and NFS values. Only 5% of patients had existing diagnoses for NAFLD identified.

Conclusions: Many primary care patients have FIB-4 and NFS scores concerning for advanced fibrosis, but rarely a diagnosis of NAFLD. Elevated FIB-4 and NFS scores may provide signals for further clinical evaluation of liver disease in primary care settings.
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http://dx.doi.org/10.1002/dmrr.3452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458479PMC
November 2021

Reply.

Gastroenterology 2021 07 20;161(1):365-366. Epub 2021 Mar 20.

Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina.

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http://dx.doi.org/10.1053/j.gastro.2021.03.032DOI Listing
July 2021

Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials.

Drug Saf 2021 Jun 16;44(6):619-634. Epub 2021 Mar 16.

Otsuka Pharmaceutical Development and Commercialization, Inc., 508 Carnegie Center Dr, Princeton, NJ, 08540, USA.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.
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http://dx.doi.org/10.1007/s40264-021-01051-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184702PMC
June 2021

The Utility of Liver Biopsy in the Evaluation of Liver Disease and Abnormal Liver Function Tests.

Am J Clin Pathol 2021 07;156(2):259-267

Department of Internal Medicine, Medical University of South Carolina, Charleston, SC, USA.

Objectives: We aimed to assess the value of liver biopsy in the evaluation of abnormal liver tests.

Methods: We analyzed consecutive liver biopsy specimens performed for evaluation of unexplained abnormal liver tests from 2014 to 2018. Diagnoses were categorized histologically and clinically. We determined whether histologic examination led to a specific diagnosis and whether prebiopsy laboratory variables predicted the underlying etiology.

Results: Among the 383 liver biopsy specimens included, chronic hepatitis was the most common histologic (25%) and clinical (17%) diagnosis. Liver biopsy led to a clinical diagnosis in 87% of patients. The most likely clinical diagnoses were autoimmune hepatitis, nonalcoholic fatty liver disease, and drug-induced liver injury (38, 33, and 32 patients, respectively). Using sensitivity, specificity, and positive and negative predictive values, we found that liver tests were not predictive of a specific diagnosis. In patients with no history of liver disease or clinical features of portal hypertension, biopsy specimens revealed histologic cirrhosis in 5% of patients.

Conclusions: Histopathologic diagnoses were made in 85% of patients undergoing liver biopsy for investigation of unexplained liver tests, leading to a clinical diagnosis in 87% of patients. However, neither liver tests themselves nor their patterns were useful in predicting histologic or clinical diagnoses.
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http://dx.doi.org/10.1093/ajcp/aqaa225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259499PMC
July 2021

Statins for treatment of chronic liver disease.

Curr Opin Gastroenterol 2021 05;37(3):200-207

Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA.

Purpose Of Review: Statins are a class of lipid lower medications used primarily in patients with high-risk cardiovascular disease. Since their development, statins have been considered to be harmful in patients with liver disease, and many of the prescribing information labels consider them to be contraindicated in patients with active liver disease. However, recent studies have shown the contrary, warranting further investigation and discussion. This review aims to describe the latest literature on the mechanism, safety profile and potential benefits of statins use on the natural history of chronic liver disease (CLD) progression and its complications.

Recent Findings: A number of recently published studies have added to the existing body of literature supporting the concept that statins are safe and likely to be beneficial for treating patients with CLD. Patients with CLD including hepatitis B virus infection, hepatitis C virus infection, nonalcoholic fatty liver disease and alcohol on statins have been shown to have a lower rate of decompensating events, lower incidence of hepatocellular cancer, a lower rate of infections, and increased survival. However, the majority of the available literature supporting statin use in patients with liver disease comes from retrospective observational studies with high potential for bias.

Summary: Statins appear to be safe in patients with compensated cirrhosis, and evidence suggests that they may reduce fibrosis, even in patients with advanced fibrosis and cirrhosis. Further high-quality research on this topic is needed to fully delineate the effect of statins in patients with liver disease.
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http://dx.doi.org/10.1097/MOG.0000000000000716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8691140PMC
May 2021

Role of Liver Biopsy in Assessment of Radiologically Identified Liver Masses.

Dig Dis Sci 2022 Jan 19;67(1):337-343. Epub 2021 Feb 19.

Digestive Disease Center, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 908, CSB, Charleston, SC, 29425, USA.

Background: Despite improvements in imaging techniques that have enhanced the ability to diagnose hepatocellular carcinoma (HCC), histopathological evaluation of many other types of liver masses is critical.

Aims: To evaluate the utility of liver biopsy in patients with radiologically undiagnosed liver masses.

Methods: We retrospectively analyzed 293 consecutive patients who had a liver biopsy for evaluation of an undiagnosed liver mass between January 2014 and January 2018.

Results: Out of 293 biopsies, 246 patients were found to have malignancy (84%), including 210 (72%) patients with metastatic malignancy and 36 with primary hepatic malignancies (20 HCC and 16 others). In the 47 patients without malignancy, 17 patients had necrotic abscess/granuloma, 16 patients had normal histology, eight patients had hepatic fibrosis/cirrhosis without malignant foci, and six patients had benign tumors. The most common primary lesion in patients with liver metastasis was breast carcinoma (32/293, 11%), followed by colon and pancreas (31 (each)/293, 11%), and lung (9%) adenocarcinomas. Histopathological analysis confirmed the presence of metastasis in 165/200 (83%) patients with a history of oncological malignancy and in 45/93 (48%) patients who had no malignancy history.

Conclusions: In patients with a radiologically identified liver mass of unclear etiology, liver biopsy/histology made a diagnosis in 95% (277/293) of patients, including 84% (246/293) found to have an oncological malignancy. Liver biopsy/histology also identified malignancy in a high proportion of patients without known underlying cancer. We conclude that liver biopsy is valuable for evaluation of radiologically identified liver masses of unclear etiology.
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http://dx.doi.org/10.1007/s10620-021-06822-9DOI Listing
January 2022

Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside.

Gastroenterology 2021 04 30;160(5):1502-1520.e1. Epub 2021 Jan 30.

Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York.

Hepatitis C virus (HCV) infection and its complications have been the major cause of cirrhosis and its complications for several decades in the Western world. Until recently, treatment for HCV with interferon-based regimens was associated with moderate success but was difficult to tolerate. More recently, however, an arsenal of novel and highly effective direct-acting antiviral (DAA) drugs has transformed the landscape by curing HCV in a broad range of patients, including those with established advanced fibrosis, cirrhosis, comorbidities, and even those with complications of cirrhosis. Fibrosis is a dynamic process comprising both extracellular matrix deposition, as well as its degradation. With almost universal sustained virologic response (SVR) (ie, elimination of HCV), it is timely to explore whether HCV eradication can reverse fibrosis and cirrhosis. Indeed, fibrosis in several types of liver disease is reversible, including HCV. However, we do not know with certainty in whom fibrosis regression can be expected after HCV elimination, how quickly it occurs, and whether antifibrotic therapies will be indicated in those with persistent cirrhosis. This review summarizes the evidence for reversibility of fibrosis and cirrhosis after HCV eradication, its impact on clinical outcomes, and therapeutic prospects for directly promoting fibrosis regression in patients whose fibrosis persists after SVR.
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http://dx.doi.org/10.1053/j.gastro.2020.09.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601597PMC
April 2021
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