Hepatology Highlights
Potential conflict of interest: Nothing to report.
One Pill a Day May Keep HBV Away After Liver Transplant
Nicholas Russo1 and Robert S. Brown, Jr.1
Potent antiviral nucleos(t)ides with high barriers to resistance have made the use of hepatitis B immunoglobulin (HBIG) to prevent hepatitis B virus (HBV) recurrence controversial. Fung et al. performed a prospective study of 265 patients without lamivudine resistance receiving entecavir monotherapy without any HBIG after liver transplantation (LT) for a median of 59 months. Though over 60% had positive HBV DNA at the time of transplant, HBV DNA was undetectable in 100% at 8 years after transplantation with very few requiring tenofovir add-on therapy. The hepatitis B surface antigen (HBsAg) negativity rate was 85%-92%, though only a minority had hepatitis B surface antibodies (HBsAb). Long-term survival was excellent long-term. Patients had normal FibroScan readings and no deaths were attributed to recurrent HBV. These data suggest that potent oral antiviral monotherapy without HBIG may be sufficient to prevent recurrent HBV long term in most patients. (Hepatology 2017;66:1036-1044)
preS1, a New Target for HBV Vaccination and Treatment?
Robert E. Schwartz1
Tolerance to the HBV surface antigens in patients with chronic hepatitis B (CHB) viral infection has limited the clinical benefit of conventional HBsAg vaccination. Bian et al. examined whether targeting the preS1 domain of the HBV large surface antigen (which presents less immune tolerance in CHB patients) could have clinical benefit. Vaccination with the long peptide of the preS1 domain generated immune responses in HBV carrier mice and led to HBV virion clearance. Administration of the preS1 polypeptide and then HBsAg induced clearance of HBV infection and HBsAg to HBsAb seroconversion in HBV carrier mice. The ability to translate these findings to chronic HBV infection in humans remains to be seen; however, these findings suggest that preS1 may be used as a therapeutic vaccination in CHB. (Hepatology 2017;66:1067-1082)
HCV Is Targeted for Cure After Transplant
Russell Rosenblatt1* and Robert S. Brown, Jr.1
Direct-acting antivirals (DAAs) have been used extensively in pre-LT patients with hepatitis C virus (HCV), but posttransplant data are lacking. Saxena et al. investigated the efficacy of DAAs in a large, prospective, observational cohort of post-LT, post–kidney transplant, and dual liver kidney transplant patients. Of the 415 patients, most (347) of whom had LTs, 87% were genotype 1 and 95.7% achieved sustained virological response (SVR), despite high-risk features, with over half of patients failed before therapy and 42% with cirrhosis. Various treatment regimens were used, and ribavirin did not appear to influence SVR. Rejection was rare and occurred in only 6 patients. Overall, DAA therapy in posttransplant patients appears safe and effective, with the possibility to cure almost all after transplant. (Hepatology 2017;66: 1090-1101)
Fatty Liver Disease: Dodging Degradation
Nicholas Russo1 and Robert S. Brown, Jr.1
Human genomic association studies have found that a single amino acid substitution in patatin-like phospholipase-domain containing protein 3 (PNPLA3) is highly associated with increased hepatic fat, inflammation, and fibrosis; however, the mechanism through which this occurs has been debated. Mice expressing the variant protein and fed a high-sucrose diet recapitulate the disease process, developing hepatic steatosis. BasuRay et al. found that triglyceride synthesis, secretion, and oxidation were not altered in mutant mice. Interestingly, they found that mice with the variant PNPLA3 protein showed marked accumulation of this protein during feeding, which remained elevated during fasting for several hours before declining to wild-type levels. Using antibody-mediated proteasome inhibition, they found that wild-type PNPLA3 could undergo marking for degradation whereas the variant PNPLA3 avoided degradation. The cellular consequences of inadequate degradation of PNPLA3 remain to be seen; however, these findings shed new light on our understanding and potential avenues of treatments for fatty liver disease. (Hepatology 2017;66:1111-1124)
Protein Pearls of Wisdom
Shirley Cohen-Mekelburg1* and Robert E. Schwartz1
Noninvasive tools for the early detection of primary sclerosing cholangitis (PSC), cholangiocarcinoma (CCA), and hepatocellular carcinoma (HCC) are currently unavailable. Arbelaiz et al. explore serum extracellular vesicles for markers of PSC, CCA, and HCC. The protein content of these vesicles was characterized by mass spectrometry, showing features distinct for PSC, CCA, and HCC. Of note, the proteomic analysis revealed a greater number of oncogenic proteins in extracellular vesicles from CCA. In an orthotopic CCA mouse model, the presence of these characteristic proteins was evident in the serum extracellular vesicles. These distinct proteomic signatures may allow us to more accurately diagnose PSC, CCA, and HCC using noninvasive techniques in the future. (Hepatology 2017;66:1125-1143)
TGR5 Puts the Cyst in Polycystic Liver Disease
Russell Rosenblatt1* and Robert E. Schwartz1
What drives the progression of cysts in polycystic liver disease (PLD)? Masyuk et al. propose that TGR5, a G-protein-coupled bile acid receptor that is linked to cAMP and expressed in cholangiocytes, is linked to PLD. TGR5 stimulation enhanced cAMP, cell proliferation, and cyst growth by 40% in vitro and in vivo. Reduction of TGR5 levels in animal knockouts attenuated cyst progression in vivo. Treatment with SBI-115 (a novel TGR5 antagonist) decreased cAMP levels, cholangiocyte proliferation, and cyst growth in vitro. Taken together, TGR5 contributes to hepatic cystogenesis by increasing cAMP and promoting cholangiocyte proliferation, and is a new and novel target for treatment in patients with PLD. (Hepatology 2017;66:1197-1218)
Beta Blockers Strike Back
Monica Saumoy1* and Robert S. Brown, Jr.1
Preventing rebleeding after acute variceal hemorrhage is standard of care. Combination therapy with endoscopic variceal ligation and nonselective beta blockers (BB) has previously shown to prevent recurrent variceal hemorrhage, but not improve survival. Given the controversy regarding BB use in decompensated cirrhosis, Albillos et al. performed an individual patient meta-analysis comparing combination versus monotherapy, stratified by Child-Turcotte-Pugh classification. Combination therapy decreased overall rebleeding in all Child classes, but improved mortality only in Child B/C patients. This suggests that BB are key to variceal rebleeding prophylaxis and likely should be maintained even in patients with decompensated cirrhosis. (Hepatology 2017;66:1219-1231)
C the Future With Cystatin C?
Clara Tow2** and Robert S. Brown, Jr.1
The development of renal dysfunction (RD) and acute on chronic liver failure (ACLF) in patients with cirrhosis is associated with high short-term mortality. Early identification of at-risk patients could help guide early aggressive medical care, but no reliable biomarkers have been identified. Markwardt et al. analyzed 429 decompensated patients with cirrhosis in the multicenter CANONIC study to determine whether renal biomarkers cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) could predict RD, ACLF, and death. Both serum CysC and NGAL were predictors of death, but only CysC was predictive of developing RD, hepatorenal syndrome, and ACLF. This study suggests that CysC may be of value in clinical practice, but more data are needed to determine whether this predictive knowledge can translate into better clinical outcomes. (Hepatology 2017;66:1232-1241)
RNAi Block to Fibrosis
Yecheskel Schneider1* and Robert E. Schwartz1
Hepatic stellate cell (HSC) proliferation and activation are required for liver fibrogenesis. Activation and proliferation of HSCs depend on cyclin-dependent kinase 2, and inactivation of its regulatory subunit cyclin E1 (CcnE1) decreases HSC activation, proliferation, and fibrosis. Bangen et al. studied CcnE1 inhibition by an RNA interference (RNAi)-based approach. Using CcnE1-small interfering RNA (siRNA) to inhibit murine and human CcnE1 gene expression, they found decreased proliferation and increased cell death of primary HSCs and HSC cell lines. In C57BL/6 mice, a single injection of stabilized siRNA (by a liposome-based carrier) targeted a large percentage of HSCs and hepatocytes, reversed CcnE1 induction in mice with CCl4-mediated liver injury, and significantly diminished or prevented hepatic fibrosis and inflammation. RNAi has the potential to target CcnE1 in vivo and prevent/ameliorate liver fibrosis. (Hepatology 2017;66:1242-1257)
DILI May DILI-Dally Its Way to Disaster
Vikas Gupta1* and Robert E. Schwartz1
Drug-induced liver injury (DILI) has a reported mortality of up to 10%; however, its contribution to fatality is poorly characterized, and the impact of DILI in the nonacute setting is unknown. Hayashi et al. analyzed 1,089 likely DILI patients in the US DILIN prospective study for up to 2 years after DILI onset. Among 1,089 patients, 9.8% died, DILI had a primary or contributing cause in 78% of fatalities, and 40% of these had non-ALF (acute liver failure). For acute cases, fatality was predicted by the new-R ratio(nR) Hy's law and, to a lesser extent, the original Hy's law, but neither accurately predicted non-ALF death nor outperformed the Model for End-Stage Liver Disease. It is, however, clear that hepatologists need to watch their DILI patients closely even after the acute event seems to have passed. (Hepatology 2017;66:1275-1285)
