Publications by authors named "Christopher Koh"

93 Publications

Identifying who best tolerates moderate sedation: Results from a national database of gastrointestinal endoscopic outcomes.

World J Gastrointest Endosc 2021 Apr;13(4):97-110

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States.

Background: With increasing volume and cost of gastrointestinal endoscopic procedures, the proper selection of patients for moderate sedation becomes increasingly relevant. The current literature lacks consistent findings that allow for appropriate selection of patients for moderate sedation.

Aim: To analyze a nationwide registry of patients to identify patient and procedural factors associated with lower sedation requirements for endoscopy.

Methods: The Clinical Outcomes Research Initiative National Endoscopic Database was queried to assess adult patients undergoing moderate sedation for esophagogastroduodenoscopy (EGD) and colonoscopy from 2008 to 2014. Patients were stratified into two groups [low dose (LD) and high dose sedation] based on sedation requirements. Anthropometric, procedural, and anesthesia data were compared, and multivariable analysis was performed to identify factors associated with LD sedation.

Results: Of the 371102 patients included in the study, 63137 where stratified into the LD sedation group and 307965 were in the high dose group. Moderate sedation was managed primarily by endoscopists (50%) and anesthesia providers (47%). Patients undergoing EGDs and procedures performed in the inpatient setting, in ambulatory surgery centers, intensive care units or hospital wards, required less sedation than colonoscopies, outpatient procedures and procedures done in endoscopy suites, respectively ( < 0.0001 for all). On multivariable analysis, factors predictive of tolerance with lower sedation requirements for EGDs and colonoscopies were female gender, age ≥ 50, non-White race, Hispanic descent, body mass index ≤ 25 kg/m, and higher American Society of Anesthesia Class ( < 0.0001 for all).

Conclusion: Clinicians should consider these patient profiles in determining which patients will better tolerate moderate sedation those better suited for alternative sedation methods.
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http://dx.doi.org/10.4253/wjge.v13.i4.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080537PMC
April 2021

Professional Use of Social Media by Hepatology Providers.

Hepatology 2021 Mar 20. Epub 2021 Mar 20.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

In 2018, we challenged the readers of HEPATOLOGY to lead the international conversation about hepatology on social media. And you stepped up. The AASLD has seen a near doubling of Facebook followers since 2017 (6,173 to 12,047) and an even greater increase in Twitter followers over the same period (7,649 to over 19,000). On Twitter, #LiverTwitter is increasingly used to centralize discussions of the hepatology community.
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http://dx.doi.org/10.1002/hep.31824DOI Listing
March 2021

The response to vedolizumab in chronic granulomatous disease-related inflammatory bowel disease.

Gastroenterol Rep (Oxf) 2020 Oct 10;8(5):404-406. Epub 2020 Mar 10.

Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1093/gastro/goaa005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603867PMC
October 2020

Recurrent nodular regenerative hyperplasia post-liver transplantation in common variable immunodeficiency.

Hepatology 2021 Feb 27. Epub 2021 Feb 27.

Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.

Liver involvement is well described in common variable immunodeficiency (CVID) and is an important prognostic marker. While multiple etiologies for liver disease have been reported, nodular regenerative hyperplasia (NRH) is being increasingly recognized with an overall prevalence above 5% (1). In this case series we describe the pre and post-transplant evolution of CVID-related liver disease (CVID-ld). (Table 1.).
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http://dx.doi.org/10.1002/hep.31775DOI Listing
February 2021

Acute oesophageal necrosis in multiple endocrine neoplasia type 1: an undescribed complication.

BMJ Case Rep 2021 Jan 7;14(1). Epub 2021 Jan 7.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Acute oesophageal necrosis (AEN) is a rare entity that most commonly presents as upper gastrointestinal bleeding. Complex pathophysiology may include oesophageal ischaemia as well as reflux of acidic gastric contents causing oesophageal mucosal injury. Management is supportive and directed at underlying comorbidities however prognosis is poor with complications such as oesophageal perforation, stricture and stenosis. Here we present the case of a 56-year-old man with multiple endocrine neoplasia type 1 (MEN1) and gastro-oesophageal reflux disease who developed AEN as a result of undiagnosed Zollinger-Ellison syndrome (ZES), duodenal ulcer-induced obstruction and hypotension from new-onset atrial fibrillation. AEN as the presentation of MEN1-associated ZES is an unusual presentation of this disease which clinicians, particularly endocrinologists and endoscopists, should be aware of.
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http://dx.doi.org/10.1136/bcr-2020-238214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797279PMC
January 2021

COVID-19: An analysis of social media and research publication activity during the early stages of the pandemic.

medRxiv 2020 Dec 22. Epub 2020 Dec 22.

Objectives: The COVID-19 pandemic has highlighted the importance of rapid dissemination of scientific and medical discovery. Social media (SoMe) has become an invaluable platform in science and medicine. This study analyzed activity of SoMe (Twitter), preprints, and publications related to COVID-19 and gastroenterology (GI) during the COVID-19 pandemic.

Methods: Data from Twitter, preprint servers and PubMed was collected and analyzed from December 2019 through May 2020. Global and regional geographic and gastrointestinal organ specific social media trends were compared to preprint and publication activity; any associations were identified.

Results: Over the 6-month period, there were 73,079 tweets from 44,609 users, 7,164 publications, and 4,702 preprints. Twitter activity peaked during March while preprints and publications peaked in April 2020. Strong correlations were identified between Twitter and both preprints and publications activity (p<0.001 for both). While COVID-19 data across the 3 platforms concentrated on pulmonology/critical care, the majority of GI tweets pertained to pancreatology, most publications focused on hepatology, and most preprints covered hepatology and luminal GI (LGI). There were significant associations between Twitter activity and research for all GI subfields (p=0.009 for LGI, p=0.006 for hepatology and IBD, p=0.007 for endoscopy), except pancreatology (p=0.2). Twitter activity was highest in the US (7,331 tweets) whereas PubMed activity was highest in China (1,768 publications).

Conclusions: The COVID-19 pandemic has highlighted the utility of SoMe as a vehicle for disseminating scientific information during a public health crisis. Scientists and clinicians should consider the use of SoMe in augmenting public awareness of their scholarly pursuits.
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http://dx.doi.org/10.1101/2020.12.20.20248517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781340PMC
December 2020

Enhanced endoscopic detection of occult gastric cancer in carriers of pathogenic CDH1 variants.

J Gastroenterol 2021 Feb 18;56(2):139-146. Epub 2020 Nov 18.

Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.

Background: Germline inactivating variants in the CDH1 tumor suppressor gene impart an elevated lifetime risk of diffuse gastric cancer. The current endoscopic surveillance method depends upon random gastric biopsies for early cancer detection.

Methods: Asymptomatic adults with pathogenic or likely pathogenic CDH1 variants referred for endoscopic gastric cancer surveillance were included in this retrospective cohort. Upper gastrointestinal endoscopy was performed according to the consensus Cambridge method, in the early period, or a systematic (Bethesda) protocol as part of an ongoing natural history study. The primary outcome measure was cancer detection.

Results: Collectively, 135 endoscopic surveillance procedures were performed in 120 patients. Twenty-six (19%, 26/135) procedures were performed using Cambridge method and 109 (81%) using the Bethesda protocol. Gastric signet ring cell carcinomas were detected in 15% (4/26) using the Cambridge method and 36% (40/109) using the Bethesda protocol (p < 0.05). Almost half (44.2%, 53/120) of patients later elected for prophylactic total gastrectomy, of whom 51 (96%, 51/53) had a signet ring cell carcinoma (T1a) discovered by histopathology. On a per endoscopy basis, the false-negative rates of detection using Cambridge method and Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively (p < 0.01).

Conclusions: Gastric cancer detection was more frequent with implementation of a systematic surveillance protocol in CDH1 variant carriers. Given the decision for prophylactic surgery is often made by patients in the context of family history and pathologic result of surveillance biopsies, we propose the Bethesda protocol offers patients an opportunity to make more informed decisions.
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http://dx.doi.org/10.1007/s00535-020-01749-wDOI Listing
February 2021

Risk Factors for Delta Hepatitis in a North American Cohort: Who Should Be Screened?

Am J Gastroenterol 2021 01;116(1):206-209

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: The American Association for the Study of Liver Diseases recommends hepatitis D virus (HDV) screening in certain high-risk groups; however, the effectiveness is unknown.

Methods: A study of North American patients with hepatitis B (HBV) referred to the NIH was performed to identify risk factors associated with HDV infection. Active HDV was "confirmed" by serum HDV RNA or histologic HDV antigen staining.

Results: Six hundred fifty-two were studied, of which 91 were HDV "confirmed." Independent risk factors for HDV included: intravenous drug users, HBV-DNA <2,000 IU/mL, alanine aminotransferase >40 U/L, and HDV endemic country of origin.

Disussion: North American patients with HBV and significant risk factors should be screened for HDV.
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http://dx.doi.org/10.14309/ajg.0000000000000954DOI Listing
January 2021

Characterization and timing of gastrointestinal bleeding in continuous flow left ventricular assist device recipients.

Heliyon 2020 Sep 1;6(9):e04695. Epub 2020 Sep 1.

Department of Gastroenterology, University of Missouri, Kansas-School of Medicine, USA.

Background And Aims: Heart failure is one of the leading causes of morbidity and mortality in the United States. The advent of left ventricular assist devices (LVAD) has improved the survival and quality of life in patients with end stage heart failure. Gastrointestinal bleeding (GIb) remains one of the limitations of LVADs.

Methods: A single center, retrospective review of records was performed for patients who underwent LVAD implantation between 2010 and 2015. All patients who survived more than 30 days were followed till March 2016 and are described below.

Results: A total of 79 patients were included in the study. The rate of GIb was 34.1% (27 patients) with a mean time to bleed of 267 days. Older patients were more likely to bleed. Upper GI bleeding was the source of bleeding in 54% patients. Arteriovenous malformations (AVM) were the source of bleeding in 74% bleeders and 80% of these patients had AVM formation. 14/27 (51%) patients had a re-bleeding event. Thrombotic events were 4.5 times more likely to occur in patients who also had a GI bleed.

Conclusions: GI bleeding in LVAD patients is common with the source of bleeding more commonly being in the upper GI tract. GI bleeding may occur as early as 10 days post procedure, despite previous negative screening endoscopies. There is an increased risk of thrombotic events in patients who have experienced a GI bleed.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479277PMC
September 2020

HLA-B*35:01 and Green Tea Induced Liver Injury.

Hepatology 2020 Sep 5. Epub 2020 Sep 5.

Department of Medicine, Einstein Healthcare Network, Philadelphia, PA, United States.

Background: Herbal supplements and particularly multi-ingredient products have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial.

Methods: Among 1414 patients enrolled in the U.S. Drug Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1142 to conventional drugs. The clinical features of green tea cases and representation of HLA class I and II alleles in cases and control groups were analyzed in detail.

Results: Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15 to 448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% CI: 58% to 87%) of green tea cases but only 15% (95% CI: 10% to 20%) caused by other supplements and 12% (95% CI: 10% to 14%) attributed to drugs, the latter rate being similar to population controls (95% CI: 11%: 10.5% to 11.5%).

Conclusions: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01 suggesting that it is idiosyncratic and immune-mediated.
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http://dx.doi.org/10.1002/hep.31538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052949PMC
September 2020

Hepatocellular Carcinoma Where You Least Expect It.

Am J Gastroenterol 2020 07;115(7):1134-1136

National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Liver Diseases Branch, Bethesda, Maryland, USA.

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http://dx.doi.org/10.14309/ajg.0000000000000616DOI Listing
July 2020

APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.

Hepatology 2021 Mar;73(3):1088-1104

Translational, Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

Background And Aims: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas.

Approach And Results: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH.

Conclusions: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.
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http://dx.doi.org/10.1002/hep.31421DOI Listing
March 2021

Coronavirus Disease-19 Has Come Home to Roost in Gastroenterology.

Gastroenterology 2020 07 12;159(1):36-38. Epub 2020 Jun 12.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1053/j.gastro.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290204PMC
July 2020

A Viral Exposure Signature Defines Early Onset of Hepatocellular Carcinoma.

Cell 2020 07 10;182(2):317-328.e10. Epub 2020 Jun 10.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87-0.96] at baseline and 0.98 [95% CI 0.97-1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.
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http://dx.doi.org/10.1016/j.cell.2020.05.038DOI Listing
July 2020

Hepatitis D infection: from initial discovery to current investigational therapies.

Gastroenterol Rep (Oxf) 2019 Aug 23;7(4):231-245. Epub 2019 Jun 23.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Hepatitis D is the most severe form of viral hepatitis associated with a more rapid progression to cirrhosis and an increased risk of hepatocellular carcinoma and mortality compared with hepatitis B mono-infection. Although once thought of as a disappearing disease, hepatitis D is now becoming recognized as a serious worldwide issue due to improvement in diagnostic testing and immigration from endemic countries. Despite these concerns, there is currently only one accepted medical therapy (pegylated-interferon-α) for the treatment of hepatitis D with less than desirable efficacy and significant side effects. Due to these reasons, many patients never undergo treatment. However, increasing knowledge about the virus and its life cycle has led to the clinical development of multiple promising new therapies that hope to alter the natural history of this disease and improve patient outcome. In this article, we will review the literature from discovery to the current investigational therapies.
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http://dx.doi.org/10.1093/gastro/goz023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691517PMC
August 2019

Hepatitis Delta: Prevalence, Natural History, and Treatment Options.

Gastroenterol Clin North Am 2020 06;49(2):239-252

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Room 4-5722, Bethesda, MD 20892, USA.

Half a century after its discovery, hepatitis delta remains a pertinent global health issue with a major clinical impact in endemic regions and an underestimated prevalence worldwide. Hepatitis delta virus infection follows a challenging clinical course and is responsible for significant liver-related morbidity. Although the only currently available treatment (pegylated interferon) does not provide consistent results, emerging therapeutic options are promising. This article explores the epidemiology, natural history, as well as current and potential therapeutic options for hepatitis delta virus infection.
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http://dx.doi.org/10.1016/j.gtc.2020.01.004DOI Listing
June 2020

Hepatocellular Carcinoma Where You Least Expect It.

Am J Gastroenterol 2020 Apr 10. Epub 2020 Apr 10.

National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Liver Diseases Branch, Bethesda, Maryland, USA.

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http://dx.doi.org/10.14309/ajg.0000000000000616DOI Listing
April 2020

United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts.

Toxicol Rep 2020 15;7:386-402. Epub 2020 Feb 15.

United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA.

As part of the United States Pharmacopeia's ongoing review of dietary supplement safety data, a new comprehensive systematic review on green tea extracts (GTE) has been completed. GTEs may contain hepatotoxic solvent residues, pesticide residues, pyrrolizidine alkaloids and elemental impurities, but no evidence of their involvement in GTE-induced liver injury was found during this review. GTE catechin profiles vary significantly with manufacturing processes. Animal and human data indicate that repeated oral administration of bolus doses of GTE during fasting significantly increases bioavailability of catechins, specifically EGCG, possibly involving saturation of first-pass elimination mechanisms. Toxicological studies show a hepatocellular pattern of liver injury. Published adverse event case reports associate hepatotoxicity with EGCG intake amounts from 140 mg to ∼1000 mg/day and substantial inter-individual variability in susceptibility, possibly due to genetic factors. Based on these findings, USP included a cautionary labeling requirement in its Powdered Decaffeinated Green Tea Extract monograph that reads as follows: ")."
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http://dx.doi.org/10.1016/j.toxrep.2020.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044683PMC
February 2020

Spontaneous Clearance of Chronic Delta Hepatitis.

Hepatology 2020 05;71(5):1873-1875

Liver Disease Branch, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1002/hep.31073DOI Listing
May 2020

The Delta-4 fibrosis score (D4FS): A novel fibrosis score in chronic hepatitis D.

Antiviral Res 2020 02 16;174:104691. Epub 2019 Dec 16.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Chronic Hepatitis D virus (HDV) infection results in the most severe form of viral hepatitis with a rapid progression to cirrhosis. However, non-invasive fibrosis tests that can accurately predict cirrhosis have not been adequately validated. We aimed to develop a clinically useful non-invasive score that can accurately detect cirrhosis.

Material And Methods: Patients with chronic HDV diagnosed by liver histology or serum PCR were evaluated. Data regarding demographics, laboratory, imaging, vibration-controlled transient elastography (VCTE), and liver biopsy were collected. The total cohort was randomized into a training and validation cohort. The training cohort was used to develop a novel score, the Delta-4 fibrosis score (D4FS) which was then compared to other non-invasive tests in the validation cohort by area under receiver operating characteristics (AUROC).

Results: 77 patients with chronic HDV were evaluated: mean age 42.6 (SD:11.1) years, 59.7% male, and 57.1% Asian. The total cohort was then separated into a training (n = 45) and validation (n = 32) cohort with no significant differences in terms of clinical characteristics between the two. From the training cohort, the D4FS was derived from variables of statistical and clinical interest (gamma-glutamyl transpeptidase (GGT), platelet count, alanine aminotransferase (ALT), and liver stiffness measurement (LSM)). The D4FS demonstrated the best AUROC in the validation cohort (0.94) followed by VCTE (0.90), FIB-4 (0.86), APRI (0.81), and AAR (0.71).

Discussion: The D4FS is a clinically useful non-invasive fibrosis score that can accurately detect cirrhosis in patients with chronic HDV infection. Further studies should be performed to further validate clinical utility.
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http://dx.doi.org/10.1016/j.antiviral.2019.104691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560973PMC
February 2020

Vibration-controlled transient elastography for the detection of cirrhosis in chronic hepatitis D infection.

J Viral Hepat 2020 04 9;27(4):428-436. Epub 2019 Dec 9.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Noninvasive detection of cirrhosis via vibration-controlled transient elastography (VCTE) has revolutionized the management of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, VCTE has not been studied in chronic hepatitis D virus (HDV) infection and accuracy remains in question due to the significant hepatic inflammation associated with this infection. Consecutive HBV, HCV and HDV patients who underwent VCTE (2006-2019) were evaluated. Diagnosis of cirrhosis was made via liver biopsy or clinical findings. VCTE was compared with other noninvasive serum fibrosis tests using AUROC curves. The performance of VCTE in HBV/HCV/HDV was also compared. We evaluated 319 patients (HBV-112; HCV-132; HDV-75), 278(87%) patients had histology for evaluation. HDV patients had evidence of higher hepatic inflammation as evidence by aspartate aminotransferase, alanine aminotransferase and histology activity index. Cirrhotic HDV patients had higher mean liver stiffness measurements compared with noncirrhotic patients (29.0 vs 8.3 kPa, P < .0001). VCTE demonstrated excellent diagnostic accuracy for the detection of cirrhosis with an AUROC of 0.90 compared with APRI (0.83), FIB-4 (0.88), AAR (0.73) and RPR (0.85). Performance of VCTE in HDV was comparable with HBV (0.93) and HCV (0.94). At the optimized cut-off value of ≥14.0 kPa for determining cirrhosis in HDV, VCTE had a sensitivity of 0.78, specificity of 0.86, NPV of 0.93 and PPV of 0.64. Hence, VCTE is a useful noninvasive test in HDV for determining cirrhosis despite the presence of significant hepatic inflammation.
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http://dx.doi.org/10.1111/jvh.13235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080586PMC
April 2020

Reply.

Hepatology 2020 01 24;71(1):397-398. Epub 2019 Dec 24.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1002/hep.30955DOI Listing
January 2020

Chronic hepatitis delta: A state-of-the-art review and new therapies.

World J Gastroenterol 2019 Aug;25(32):4580-4597

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States.

Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.
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http://dx.doi.org/10.3748/wjg.v25.i32.4580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718034PMC
August 2019

Twitter As a Noninvasive Bio-Marker for Trends in Liver Disease.

Hepatol Commun 2019 Sep 13;3(9):1271-1280. Epub 2019 Jul 13.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD.

With the success of hepatitis C virus (HCV) direct-acting antiviral therapies, there has been a shift in research focus to the other major chronic liver diseases (CLDs). The use of social media, specifically Twitter, has become a popular platform for understanding public health trends and for performing health care research. To evaluate this, we studied the areas of public interest and social media trends of the following three major CLDs: hepatitis B virus (HBV), HCV, and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). Twitter activity data from January 1, 2013, through January 1, 2019, for HBV, HCV, and NAFLD/NASH were collected using the social media analytic tool Symplur Signals (Symplur LLC) software. Content and regression analyses were performed to understand and predict Twitter activity for each of the CLDs. Over the study period, there were 810,980 tweets generating 4,452,939,516 impressions. HCV tweet activity peaked in 2015 at 243,261 tweets, followed by a decline of 52.4% from 2015 to 2016 with a subsequent plateau through 2018. Meanwhile, NAFLD/NASH and HBV tweet activity has continued to increase, with projections that these two CLDs will surpass HCV by the second half of 2023 and 2024, respectively. Treatment and Management was the most popular content category for HCV and NAFLD/NASH, while Prevention was the most popular content category for HBV. Twitter is a useful social media tool to gauge public interest in liver disease over time. The information provided by Twitter can be used to identify gaps in public knowledge or highlight areas of interest that may need further research. Future studies on the use of Twitter in liver disease are warranted.
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http://dx.doi.org/10.1002/hep4.1394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719740PMC
September 2019

Exploring the Link Between Platelet Numbers and Vascular Homeostasis Across Early and Late Stages of Fibrosis in Hepatitis C.

Dig Dis Sci 2020 02 12;65(2):524-533. Epub 2019 Aug 12.

Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Dr. MSC 1800, Bethesda, MD, 20892-1800, USA.

Background: Thrombocytopenia is a hallmark of advanced liver disease. Platelets, growth factors (GFs), and vascular integrity are closely linked factors in disease pathogenesis, and their relationship, particularly in early disease stages, is not entirely understood. The aim was to compare circulating platelets, growth factors, and vascular injury markers (VIMs) in hepatitis C-infected (HCV) patients with early fibrosis and cirrhosis.

Methods: Retrospective evaluation of serum GFs and VIMs by ELISA were evaluated from twenty-six HCV patients. Analytes from an earlier time-point were correlated with MELD at a later time-point.

Results: Platelets and GFs decreased, and VIMs increased with fibrosis. Platelets correlated positively with PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selectin, and negatively with ICAM-3 and VCAM-1. P-selectin showed no correlations with VIMs but positively correlated with PDGF-AA, PDGF-BB, TGFB1, and EGF. Soluble VCAM-1 and ICAM-3 were linked to increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 and lower P-selectin at an earlier time-point were linked to higher MELD score at a later time-point.

Conclusion: In chronic HCV, progressive decline in platelets and growth factors with fibrosis and their associations suggest that platelets are an important source of circulating GFs and influence GF decline with fibrosis. Enhanced markers of vascular injury in patients with early fibrosis suggest an earlier onset of endothelial dysfunction preceding cirrhosis. Associations of VIMs with platelets suggest a critical link between platelets and vascular homeostasis. Circulating markers of vascular injury may not only have prognostic importance but emphasize the role of vascular dysfunction in liver disease pathogenesis (NCT00001971).
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http://dx.doi.org/10.1007/s10620-019-05760-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988415PMC
February 2020

Asparaginase-induced hepatotoxicity: rapid development of cholestasis and hepatic steatosis.

Hepatol Int 2019 Sep 7;13(5):641-648. Epub 2019 Aug 7.

Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, NIDDK, NIH, 6707 Democracy Blvd, Room 6005, Bethesda, MD, 20852, USA.

Background: L-Asparaginase is a bacterial enzyme used in the treatment of acute lymphoblastic leukemia. In the ongoing U.S. Drug-Induced Liver Injury Network (DILIN) prospective study, standard and pegylated asparaginase were the most frequent cause of liver injury with jaundice among anti-cancer agents (8 of 40: 20%). The unique features of this hepatotoxicity are described.

Methods: Eight cases from 5 DILIN centers were reviewed for clinical course, laboratory values, imaging, and histopathology.

Results: Seven females, aged 29-59 years, and one 8-year-old boy, all with leukemia, developed jaundice within 9-21 days (median 15 days) of starting asparaginase or pegaspargase, during the first (n = 6) or second (n = 2) cycle. Prominent symptoms were jaundice (n = 8), fatigue (6), abdominal pain (6) but rarely pruritus (1). Initial median ALT level was 284 U/L (range 83-1076), Alk P 159 U/L (64-452), and bilirubin 4.4 mg/dL (3.7-8.4). Bilirubin levels rose thereafter in all patients to median peak of 17.5 mg/dL (11.7-25.7), INR rose to 1.1-1.7 and serum albumin fell to 1.5-2.6 g/dL. Hepatic imaging revealed fatty liver in all patients. Liver biopsy showed steatosis but minimal hepatocyte necrosis. One patient restarted on pegaspargase re-developed less severe injury.

Conclusion: Asparaginase is a common cause of antineoplastic-induced liver injury with jaundice, typically with short latency, marked steatosis, and prolonged jaundice, which can lead to delays in antileukemic therapy. The cause of injury is likely direct inhibition of hepatic protein synthesis caused by asparagine depletion.
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http://dx.doi.org/10.1007/s12072-019-09971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226930PMC
September 2019

Bacterial Translocation and Host Immune Activation in Chronic Hepatitis C Infection.

Open Forum Infect Dis 2019 Jul;6(7)

Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Hepatitis C virus (HCV) infects 71 million individuals, and barriers to treatment remain. Bacterial translocation is a complication of chronic HCV infection, and this study evaluated circulating microbial components including lipopolysaccharide, peptidoglycan, and β-D-glucan in addition to their pattern recognition receptors and degree of hepatic macrophage uptake. The findings suggest that regulation of serum peptidoglycan and β-D-glucan differs from that of lipopolysaccharide. Additionally, macrophage activation in the liver may be better reflected by the degree of macrophage uptake than by circulating levels of microbial markers. These findings allow for a greater understanding of bacterial translocation and host immune activation during HCV infection.
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http://dx.doi.org/10.1093/ofid/ofz255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667717PMC
July 2019

Portal Pressure in Noncirrhotic Portal Hypertension: To Measure or Not to Measure.

Hepatology 2019 12 9;70(6):2228-2230. Epub 2019 Oct 9.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1002/hep.30862DOI Listing
December 2019

HBV/HDV Coinfection: A Challenge for Therapeutics.

Clin Liver Dis 2019 08 24;23(3):557-572. Epub 2019 May 24.

Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR Building, Room 3115A, 269 Campus Drive, Stanford, CA 94305, USA; Department of Medicine Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR Building, Rm. 3115A, 269 Campus Drive, Stanford, CA 94305, USA.

Chronic hepatitis D (CHD) results from an infection with the hepatitis B virus and hepatitis D virus (HDV). CHD is the most severe form of human viral hepatitis. Current treatment options consist of interferon alfa, which is effective only in a minority of patients. Study of HDV molecular virology has resulted in new approaches entering clinical trials, with phase-3 studies the most advanced. These include the entry inhibitor bulevirtide, the nucleic acid polymer REP 2139-Ca, the farnesyltransferase inhibitor lonafarnib, and pegylated interferon lambda. This article summarizes the available data on these emerging therapeutics.
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http://dx.doi.org/10.1016/j.cld.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659751PMC
August 2019

Vibration Controlled Transient Elastography (Fibroscan®) in sickle cell liver disease - could we strike while the liver is hard?

Br J Haematol 2019 10 19;187(1):117-123. Epub 2019 Jun 19.

Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA.

Vibration controlled transient elastography (VCTE) is validated for the evaluation of hepatic fibrosis in different liver diseases. Sickle cell liver disease (SCLD) results from a cumulative hepatic injury and its lifelong and progressive nature raises the need for a non-invasive tool for fibrosis evaluation. Fifty patients, aged between 23 and 59 years with sickle cell disease and suspected SCLD underwent a VCTE followed by a liver biopsy. Biopsies were evaluated for various scores of liver disease that were then correlated to VCTE score. 90% of our patients had an Ishak Fibrosis (IF) score between 0-2 (Group A-minimal to no fibrosis) and 10% of the patients had IF score between 3-6 (Group B-advanced fibrosis). The median Transient Elastography (TE) for patients in Groups A and B was 4·8 kilopascals (kPa) and 17·6 kPa, respectively. A positive correlation was shown between TE and IF score, R = 0·0·68 (P = <0·0001); a positive correlation was also shown with Histology Activity Index fibrosis score, R = 0·64 (P = <0·0001). This study emphasises the need for further studies of non-invasive tools and their utility in liver fibrosis evaluation of patients with SCLD.
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http://dx.doi.org/10.1111/bjh.16047DOI Listing
October 2019