Hepatology Highlights.

Potential conflict of interest: Nothing to report. There Is No “E” in sEx Joseph F. Pisa and Robert S. Brown, Jr.1 The fecal‐oral transmission of the hepatitis E virus (HEV) is established, but sexual transmission is unknown. The large outbreaks of hepatitis A virus (HAV) between 2015 and 2017 that disproportionally affected human immunodeficiency virus (HIV)‐positive men who have sex with men (MSM) allowed Lin et al. to study sexual transmission of HEV in a retrospective cohort of 3,293 HIV‐positive patients. One hundred twenty‐three were positive for anti‐HEV immunoglobulin G by enzyme‐linked immunosorbent assay, resulting in 3.7% HEV prevalence, and all were confirmed by either western blotting or PCR. Statistical analysis revealed that HEV infection was low and had no significant association with sexual orientation or practices among HIV‐positive MSM, indicating that HEV was rarely transmitted by sexual contact. (Hepatology 2019;70:1892‐1902). Making Something Out of Nothing Lauren M. Yang* and Daryl T.Y. Lau2 Out of the ashes of the negative simtuzumab nonalcoholic steatohepatitis (NASH) trial, Sanyal et al. used prospective data on 475 patients with NASH and bridging fibrosis (F3) or compensated cirrhosis (F4) to evaluate fibrosis progression and decompensation. Over a median of 29 months, 22% of F3 patients progressed to F4 and 12% with F4 experienced liver‐related clinical events. Higher baseline and greater increases in hepatic fibrosis by histology or serum markers were associated with progression to cirrhosis. In F4, higher baseline and greater increases in hepatic venous pressure gradient correlated with liver‐related complications. In multivariate models, Nonalcoholic Fatty Liver Disease Activity Score did not predict disease progression. These findings suggest that the natural history of fibrosis progression attributable to NASH may be more rapid than previously described. (Hepatology 2019;70:1913‐1927). Don't Go Breaking My Heart Brett E. Fortune1 Billey et al. performed a prospective cohort study of cardiac dysfunction after elective transjugular intrahepatic portosystemic shunt (TIPS) in 100 patients. Twenty percent were hospitalized because of cardiac decompensation in the first year at a median of 30 days. Preexistent cardiac disease was common, and surrogate markers for cardiac remodeling, prolonged QTc interval, and diastolic dysfunction (termed cirrhotic cardiomyopathy) as well as fluid overload were strongly associated with poor post‐TIPS outcomes. The investigators developed a suggested algorithm for pre‐TIPS risk stratification using brain natriuretic peptide (BNP), N‐terminal pro‐BNP, and echocardiographic findings. These conclusions support the importance of proper assessment of cardiac function and volume status before TIPS insertion. External validation of risk models is needed, and other strategies, such as small caliber TIPS stent, need further investigation. (Hepatology 2019;70:1928‐1941). Three SMADs, a Hepcidin, and the Tale of Iron Overload and Hepatic Fibrosis Sayed Obaidullah Aseem3 and Robert E. Schwartz1 Hereditary hemochromatosis is defined by iron overload, which can be attributed to dysregulated hepatic hepcidin production. Whereas suppressor of mothers against decapentaplegic (SMAD)1/5 transcription factors are known regulators of hepcidin, Wang et al. sought further mechanistic insight into hepcidin regulation and iron overload in vivo by generating triple hepatocyte‐specific genetic knockdown of Smad1, 5, and 8 in mice. Whereas Smad8 deficiency alone did not have an effect, Smad1/5/8 triple knockdown showed significantly reduced hepcidin levels and increased multisystem iron overload compared to Smad1/5 double knockdown. Unlike other models, these mice lacked sex‐related differences between male and female mice in hepcidin and iron levels. Finally, Smad1/5/8 knockdown resulted in liver injury and fibrosis, which were both prevented with a low‐iron diet. The investigators conclude that SMAD8 has a redundant role in regulating hepcidin and iron levels, but the combined Smad1/5/8 knockout mice are a robust model given that they better phenocopy the severe iron overload, liver injury, and fibrosis observed in human disease. (Hepatology 2019;70:1986‐2002). Time to PPAiR up in PBC Nicholas Russo and Robert S. Brown, Jr.1 Honda et al. performed a retrospective cohort study of 118 patients with primary biliary cholangitis (PBC) with inadequate response to ursodeoxycholic acid (UDCA) for at least a year treated with UDCA plus bezafibrate (BF) dual therapy for at least a year, to elucidate the effectiveness of long‐term combination therapy in patients. GLOBE scores, used to estimate transplant‐free survival, improved significantly from 0.50 to 0.12 on UDCA + BF. The UK‐PBC score was also significantly reduced with BF; however, a significant reduction in actual events of liver transplant or liver‐related death was not detected. Cox regression did demonstrate a significantly reduced risk in patients with normal serum bilirubin (hazard ratio, 0.09). This study supports the use of second‐line, dual therapy with UDCA + BF. A large, randomized control trial in PBC is warranted. (Hepatology 2019;70:2035‐2046). Hereditary Cholestasis: A piggyBac Ride to Therapy Vikas Gupta** and Robert E. Schwartz1 Progressive familial intrahepatic cholestasis type 3 is characterized by mutations in ATP‐binding cassette subfamily B member 4 (ABCB4), which encodes a lipid transporter that secretes phosphatidylcholine into bile. The lack of this phospholipid causes progressive biliary fibrosis, with 50% of patients progressing to cirrhosis requiring liver transplantation at a median age of 7.5 years. Siew et al. examined whether recombinant adeno‐associated viral vectors (rAAV) could correct this deficiency in an ABCB4 null mouse model. However, they found that transduction of an rAAV vector carrying the missing gene was not efficient. To overcome this, they utilized a piggyBac transposase that integrates genetic information into the genome of a cell through a “cut and paste” mechanism. They found that injection of rAAV vectors containing the missing gene and the transposase lead to the secretion of phosphatidylcholine into bile with a functional cure of the disease. While risks of genotoxicity exist because of disruption of genes near the integration site, it will be interesting to see if such an approach can be made safe and efficient for human disease. (Hepatology 2019;70:2047‐2061). Scoping for Quality Muhammad Amir*** and Giorgio Roccaro4 Decompensated cirrhosis is associated with significant morbidity, mortality, and health care costs. Serper et al. assessed adherence to six specific quality measures recently proposed by a Veterans Affairs (VA) Advanced Liver Disease Technical Advisory Group and the impact of adherence on outcomes in a large cohort of veterans. Care by a specialist, appropriate variceal screening within 12 months after diagnosis of cirrhosis, postdischarge care by a specialist or a primary care provider within 30 days after an inpatient admission, and timely screening for hepatocellular carcinoma led to lower all‐cause mortality and health care utilization. Readmission within 30 or 90 days after a discharge was associated with higher all‐cause mortality. Overall, five of six proposed VA cirrhosis quality measures were associated with mortality and health care utilization, suggesting promise as markers of quality of cirrhosis care. (Hepatology 2019;70:2062‐2074). Trans(it) to Liver Regeneration Nidhi Jalan‐Sakrikar3 and Robert E. Schwartz1 Interleukin (IL)‐6 signals by binding to either the membrane‐bound IL‐6 receptor subunit alpha (IL‐6Rα; classic signaling) or soluble (s)IL‐6Rα (trans‐signaling) that then form a complex with gp130 to activate downstream pathways. Trans IL‐6 signaling is critically involved in liver regeneration after partial hepatectomy (PHX). Fazel Modares et al. generated mice which exhibit enhanced IL‐6 trans‐signaling and abrogated classical signaling. These mice were able to fully compensate for the loss of classical IL‐6 signaling to ensure appropriate liver regeneration following PHX. Furthermore, global and selective inhibition of IL‐6 trans‐signaling resulted in poor survival after PHX. Mechanistically, IL‐6 trans‐signaling increased phosphorylation of signal transducer and activator of transcription 3 in the liver as well as proliferation of hepatocytes. IL‐6 further works in synergy with hepatocyte growth factor by stimulating its expression in hepatic stellate cells following PHX. These findings suggest that IL‐6 trans signaling is the main driver of liver regeneration and might have therapeutic potential in the clinic. (Hepatology 2019;70:2075‐2091). Autophagy and the miR‐acle Messengers Enis Kostallari3 and Robert E. Schwartz1 Alcoholic liver disease (ALD) impairs liver homeostasis, where autophagy plays a crucial role. Chronic alcohol consumption also increases exosome release, a type of extracellular vesicle important in cell‐to‐cell communication. In this study, Babuta et al. describe a new mechanism in hepatocytes and macrophages which regulates both autophagy and exosome production in ALD. Indeed, in ALD and alcoholic hepatitis mouse models, both autophagy and mammalian target of rapamycin (mTOR) signaling were impaired in hepatocytes and macrophages because of increased microRNA (miR)‐155 levels. Interestingly, miR‐155 knockout mice exhibited attenuated exosome release in ALD. Moreover, exosome release was increased by lysosomal dysfunction, lysosomes being crucial for autophagic degradation. The investigators show that there is, in part, an association between autophagy, miR‐155, and exosome release in ALD. This study opens the door to further investigations into how autophagy regulates extracellular vesicle release in other hepatic cell types and liver diseases. (Hepatology 2019;70:2123‐2141). mTOR and RapTOR: Good or Bad acTORs? Amaia Navarro‐Corcuera3 and Robert E. Schwartz1 Autophagy is a lysosomal degradation pathway that regulates the homeostasis of cellular proteins in the liver. Loss of hepatic autophagy leads to the activation of mTOR complex 1 (mTORC1) components, such as mTOR and Raptor, key nutrient sensors that regulate anabolic processes. Impaired hepatic autophagy causes hepatomegaly, liver injury, and fibrosis and has been linked to tumorigenesis. Ni et al. investigated the role of mTOR in impaired autophagy‐induced liver pathogenesis by using liver‐specific autophagy related 5 knockout (L‐ATG5 KO) mice, L‐ATG/mTOR, and L/ATG5/Raptor double‐knockout mice. They observed that overproduction of proteins attributable to mTOR and Raptor activation in autophagy‐deficient mice livers may contribute to hepatomegaly, inflammation, and liver tumorigenesis. Paradoxically, the deletion of either mTOR or Raptor attenuated hepatomegaly and liver injury, but promoted early liver tumorigenesis. The balance of the activity of mTORC1 components appears critical to maintaining normal physiology of the liver. (Hepatology 2019;70:2142‐2155).