Hepatology Highlights
Vax On, Vax Off
Kavitha M. Nair* and Ravi S. Vora1
National guidelines recommend vaccination of adults at high risk for hepatitis B (HBV) infection, but the prevalence of undetectable immunity in this population is unknown. Yeo et al. analyzed a sample using the National Health and Nutrition Examination Survey to evaluate the prevalence of undetectable vaccine-induced antibodies against HBV surface antigen (HBsAg) among high risk adults from 2003 to 2014. They found that the prevalence of undetectable immunity decreased from 83.2% to 69.4% from 2003 to 2014. Improved immunity was noted in patients with multiple sex partners and in pregnant women. Interestingly, there were no changes in men who have sex with men, intravenous drug users, patients with hepatitis C virus, patients with diabetes, and patients with elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Older age, lower educational level, those without health insurance, and patients born abroad were also more likely to have undetectable immunity. Despite our efforts to increase screening and vaccination of HBV in high-risk groups, the prevalence of immunity remains low. This highlights the importance of better identifying high-risk populations in order to improve screening, vaccination, and eradication of hepatitis B. (Hepatology 2019;69:1385-1397).
Terminate PAPD5/7 to Eradicate HBV
Omar Y Mousa,** Harmeet Malhi,2 and Robert E. Schwartz3
Since the discovery of HBV in 1967 and development of the first vaccine, the hope for a cure for HBV continues to grow. Currently available standard-of-care treatments effectively reduce viremia, but rarely result in sustained HBsAg loss or a functional cure. A better understanding of virus-host interactions is essential to develop new therapeutic targets. Mueller et al. previously discovered RG7834, a potent orally bioavailable inhibitor of HBV gene expression that uniquely blocks the production of both viral DNA and antigens. In this study, they identified poly(A) RNA polymerase (PAP)-associated domain-containing protein 5 and 7 using a yeast three-hybrid system. PAPD5 and PAPD7 are protein targets for HBV-active dihydroquinolizinone (DHQ) compounds, and their knockdown phenocopied the effect of RG7834. A specific and selective interaction was confirmed between the DHQ component of the Y3H-DHQ molecule and PAPD5/PAPD7. PAPD5 and PAPD7 are cellular dependency factors required for HBV mRNA stabilization and efficient regulation of gene expression by posttranscriptional mechanism. PAPD5 and PAPD7 serve as a novel therapeutic host target for RG7834 and HBV cure. (Hepatology 2019;69:1398-1411).
Up in Smoke
Joseph F. Pisa and Robert S. Brown, Jr.3
Globally, chronic HBV infection is responsible for 50% of hepatocellular carcinoma (HCC). High HBV viral load increases the risk of HCC. The impact and mechanism of environmental factors, including cigarette smoking, is less known. Wang et al. investigated the role of smoking in a cohort of 4,841 male HBV carriers, including 209 HCC cases and 1,256 controls. They found that the effect of smoking on HCC risk was substantially mediated through viral load (percent mediated, 32%). Furthermore, among the 1,143 subjects with serial measurements of viral load and ALT over periods of up to 16 years, increasing pack-years of smoking was associated with an increased viral load, maintenance of a high viral load, more severe hepatotoxicity grade, and increased likelihood of ALT ≥80 U/L, suggesting that cigarette cessation may decrease HCC risk directly and indirectly. (Hepatology 2019;69:1412-1425).
Fat, Back in the Cardio Groove
Hirsh D. Trivedi*** and Daryl T.Y. Lau4
Cardiovascular disease (CVD) is known to be associated with nonalcoholic fatty liver disease (NAFLD), but understanding the causal relationship is challenging given multiple shared risk factors. Pais et al. studied 2,554 individuals with >1 traditional cardiac risk factors but without previous CVD to evaluate the relationship between hepatic steatosis (HS), using the validated Fatty Liver Index (FLI), and atherosclerosis in the carotid, femoral, and coronary arteries and to predict CVD events based on the Framingham Risk Score (FRS). Steatosis was found to be an independent risk factor for carotid, coronary artery, and multisite atherosclerosis and additive to traditional cardiovascular risk factors or individual site atherosclerosis with the 10-year FRS. Even though the study was limited by using FLI as a surrogate marker for steatosis, the findings suggest including HS to improve CVD risk prediction models. (Hepatology 2019;69:1453-1463).
Low SALT Is Good for Transplantation
Nicole Shen**** and Akhil Shenoy5
Identifying transplanted patients with alcohol-related liver disease at risk for sustained alcohol use post–liver transplantation is imperative. Lee et al. used a retrospective, multicenter cohort of 134 highly selected transplanted patients with severe alcohol-related hepatitis and no previous liver decompensation to create a predictive model, the Sustained Alcohol use post-Liver Transplantation (SALT) score, with four simple inputs—drinks per day, failed rehabilitation, history of alcohol-related legal issues, and illicit substance abuse. Though the SALT score had poor positive predictive value, the negative predictive value of a score <5 was 95%. Whereas the score requires external validation and a method for stratifying higher-risk individuals is needed, the SALT score appears to be a reasonable tool to identify patients at low risk for sustained alcohol use posttransplantation. (Hepatology 2019;69:1477-1487).
“miR”ror Mirror in the Liver
Jessica L. Maiers2 and Harmeet Malhi2
Evidence for abnormally regulated microRNAs in NAFLD and nonalcoholic steatohepatitis (NASH) is increasingly prevalent; however, the mechanisms mediating their dysregulation at a transcriptional level are relatively unexplored. Zhang et al. identified a critical transcriptional uncoupling of an embedded intronic microRNA, miR-378, from its host gene, peroxisome proliferator-activated receptor γ coactivator 1-beta (Ppargc1β). miR-378 and Ppargc1β have mirroring functions in lipid regulation, with miR-378 repressing genes involved in fatty acid oxidation (FAO) and Ppargc1β (through encoding PGC1β), promoting FAO. Thus, the group hypothesized that the two transcripts were differentially regulated. This study elegantly shows that the transcription factor, liver X receptor alpha (LXRα), binds to a previously unidentified promoter upstream of miR-378 and promotes its transcription while repressing Ppargc1β, thus reducing FAO and promoting lipid accumulation. Furthermore, the LXRα agonist, GW3965, enhanced hepatosteatosis through enhanced miR-378 transcription and simultaneous repression of Ppargc1β. Together, this work provides unique insight into pathological mechanisms of NAFLD and NASH through microRNA transcriptional regulation. (Hepatology 2019;69:1488-1503).
The Secret Activity of HSD17B13: A New Player in Liver Disease
Enis Kostallari2 and Harmeet Malhi2
The genetic susceptibility to NAFLD is complex. Recently, a large-scale genome-wide association study identified that a new single-nucleotide polymorphism (SNP) in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) was associated with lower plasma ALT, suggestive of a protective biological role for this SNP. However, a direct relationship between this SNP and NAFLD has not yet been shown. The study from Ma et al. demonstrated that unique SNPs near the HSD17B13 gene were associated with NAFLD histological features, suggesting a functional role for HSD17B13 protein in the pathogenesis of the disease. HSD17B13 expression was higher in NAFLD and NASH patients compared to healthy individuals. Moreover, HSD17B13 protein localized to lipid droplets and had retinol dehydrogenase activity in vitro. Genetic variation of HSD17B13 had complex consequences that the researchers are currently investigating. Overall, the data suggest a role for HSD17B13 in mediating NAFLD-associated injury through its enzymatic activity, which might represent a novel therapeutic target. (Hepatology 2019;69:1504-1519).
The Inflammatory Plot Thickens in NASH-HCC
Petra Hirsova,2 Harmeet Malhi,2 and Robert E. Schwartz3
The chronic inflammatory state in NASH appears to play a key role in the initiation and development of HCC. To better understand the interplay between inflammation and HCC, Kumar et al. investigated the role of apoptosis antagonizing transcription factor (AATF), a gene overexpressed in mouse and human NASH-related HCC. Tumor necrosis factor, a NASH-associated cytokine, was identified to increase AATF expression in HCC cells. In turn, AATF increased expression of chemokine C-C motif chemokine ligand 2 through signal transducer and activator of transcription 3, linking AATF to two well-known NASH/HCC drivers. Knockdown of AATF in HCC cells inhibited proliferation, migration, invasion, colony formation, and anchorage-dependent growth. In mouse xenografts, HCC cells with AATF knockdown displayed decreased tumorigenesis and metastases. Hepatocyte AATF overexpression thus likely contributes to hepatocarcinogenesis in NASH and may represent a potential therapeutic target. Additional mechanistic studies are needed to delineate the role of AATF in inflammation-associated carcinogenesis in NASH. (Hepatology 2019;69:1520-1534).
For HCC, It’s Magnetic!
Nicholas Russo and Robert S. Brown, Jr.3
While current guidelines for surveillance for HCC in patients at risk is biannual ultrasonography (US), the sensitivity of US for early-stage HCC is only 18%-28%, and the same modality is used regardless of inherent HCC risk. Kim et al. used a cohort-based Markov model to compare expected costs and quality-adjusted life-years of US and magnetic resonance imaging (MRI) with a 20-year time horizon in a higher-risk group, HBV-associated compensated cirrhosis. Biannual MRI, with a sensitivity of 85%, was more cost-effective than US provided the annual HCC incidence is >1.8%. These findings highlight the importance of accurately stratifying the risk of HCC in patients with HBV and with cirrhosis and tailoring the HCC surveillance based on the expected HCC incidence. (Hepatology 2019;69:1599-1613).
Granisetron Grinds Inflammation to a Halt to Save the Liver From Sepsis
Tasha B. Kulai,** Harmeet Malhi,2 and Robert E. Schwartz3
Liver injury is commonly observed in sepsis; however, the role of gut microbiota in mediating this injury is unknown. Gong et al. utilized cecal ligation and puncture (CLP) in mice to generate polymicrobial sepsis and its associated liver damage. Sepsis-resistant mice were identified as those surviving to 7 days after CLP, whereas sepsis-sensitive mice were moribund within 24 hours after CLP, and demonstrated more severe liver injury. Although the gut microbiota composition was similar, metabolomic analysis revealed different functional profiles between the two groups. Sepsis-resistant mice produced markedly more granisetron, a 5-HT3 receptor antagonist generated by gut microbiota. Mice treated with granisetron demonstrated increased survival and decreased ALT elevations when challenged with CLP. In humans with sepsis, stool granisetron levels were inversely associated with plasma ALT and AST levels. Harnessing the anti-inflammatory properties of granisetron may be a promising approach to the management of sepsis-induced liver injury. (Hepatology 2019;69:1751-1767).