Hepatology Highlights
Authors: Jean‐François Dufour
Journal: Hepatology (2016)

The burden of chronic hepatitis C (CHC) is expected to decrease thanks to the introduction of the direct-acting antivirals (DAAs). Chhatwal et al. used a validated model (HEP-SIM), which takes into account key steps in the care cascade, to predict that the prevalence of CHC will be halved in the United States by 2020, and to predict that the prevalence of hepatocellular carcinoma (HCC) and decompensated cirrhosis attributed to hepatitis C virus (HCV) will decrease by a factor of 4 by 2050. As discussed by the researchers, one can and should do better. Not only should access to care be improved, but also access to diagnosis. According to their model, half a million of infected individuals will remain undiagnosed in the United States by 2020. To further shrink CHC, better screening policies have to be put in place. (Hepatology 2016;64:1442-1450) Administration of enriched immunoglobulins has been, and still is, used to prevent graft infection after liver transplantation in recipients infected with hepatitis B virus (HBV). Such an approach is currently being tested for HCV with a polyclonal antibody preparation derived from hundreds of samples of human plasma enriched with anti-HCV antibodies. Tawar et al. tested this preparation in vitro and found that it can prevent entry into hepatocytes of all the HCV variants including those resistant to DAAs that were investigated. The investigators attribute this broad neutralizing activity to the high antibody diversity of the preparation. This work may suggest a potentially valuable therapeutic approach. (Hepatology 2016;64:1495-1506) Despite passive and active immunization at birth, a residual risk remains for mother-to-child transmission of HBV. In the last few years, it has become clear that administration of an oral antiviral therapy to mothers with high HBV viremia during the last trimester of pregnancy can prevent this transmission. This requires determination of viral load at the end of the second trimester of pregnancy; however, such a strategy is not applicable in many parts of the world. Wen et al. studied a group of 526 mother-infant pairs from Taiwan, and report that a high quantitative determination of hepatitis B surface antigen (HBsAg) accurately identifies mothers with a high viremia and at high risk of transmitting HBV. HBsAg quantification is easier and cheaper to perform and could therefore replace HBV viremia to select mothers who should receive an oral antiviral therapy. (Hepatology 2016;64:1451-1461) Hepatitis delta virus (HDV) lags far behind HBV and HCV: In terms of prevalence, HDV infects approximately 10 times fewer individuals worldwide than HBV; and in terms of management, there are no effective treatments. HDV also lags behind in term of diagnosis, which is the focus of the report from Le Gal et al. The researchers asked 28 laboratories across the globe to quantify HDV in two sets of plasma samples. One set of 20 plasma samples included two negative controls and 18 different HDV strains, and a second set of eight samples included two negative controls and two dilutions in triplicate of the World Health Organization standard. More than half of the laboratories failed to detect HDV in at least one sample, and, frequently, HDV viremia was underestimated. HDV has a high genetic variability, which may explain these poor results. In order to accelerate therapeutic development, one needs to be able to monitor HDV viremia reliably. It is time to introduce standard assays. (Hepatology 2016;64:1483-1494) The ability of N-acetylcysteine (NAC) to prevent liver failure after acetaminophen intoxication depends heavily on its early administration. If not administered hours after acetaminophen ingestion, NAC cannot stop the destructive inflammatory process. High mobility group box 1 (HMGB1) is secreted by innate immune cells and is a key mediator of sterile inflammation. Neutralizing antibodies against HMGB1 protect tissues against a wide range of inflammatory diseases. Lundbäck et al. treated mice that had been overdosed with acetaminophen with humanized anti-HMGB1 antibodies. This ameliorated the histological lesions, as well as the rise in serum aminotransferase levels and cytokine levels. Importantly, a beneficial effect was also observed after late administration when NAC was no longer protective. This needs to be translated in the clinic! (Hepatology 2016;64:1699-1710) An unanswered question with nonalcoholic fatty liver disease (NAFLD) is whether patients with only steatosis may develop fibrosis and progress. Recently, data in support of this concept have accumulated. Cui et al. add a genetic piece of evidence. The researchers performed a cross-sectional analysis of a prospective cohort of 45 monozygotic and 20 dizygotic pairs of twins. They have previously reported that steatosis and fibrosis are heritable. In their current research, they specifically investigated whether there is a shared gene effect between steatosis and fibrosis. They used a statistical approach that measures whether phenotypic variance is accounted for by additive genetic effects. The researchers discovered a significant genetic correlation between steatosis and fibrosis. Patients genetically predisposed to steatosis seem to be also predisposed to fibrosis. (Hepatology 2016;64:1547-1558) In order to assess the impact of NAFLD in the Western world, Younossi et al. constructed a steady-state prevalence model with transition through nine stages (NAFL, nonalcoholic steatohepatitis [NASH] without and with fibrosis, cirrhosis not decompensated or decompensated, HCC, transplantation, posttransplantation, and death). They predict that in the United States, there are 1.3 million persons affected by NASH with fibrosis, half a million with compensated cirrhosis, and more than 5,000 with HCCs. This results in an annual direct medical cost of $103 billion. The researchers also present estimates for European countries. Even if, like every model, this one depends on a number of assumptions, the economic burden of NAFLD is massive. (Hepatology 2016;64:1577-1586) Death of hepatocytes is an important component of NASH. Apoptosis favors fibrosis and NASH progression. Necroptosis is a different form of programmed cell death, which is caspase independent and regulated by receptor interacting protein 3 (RIP3). Mice lacking RIP3 were reported to develop fewer lesions when exposed to a methionine-choline-deficient diet. Roychowdhury et al. exposed mice lacking RIP3 to a high-fat diet. These mice developed more inflammation, apoptosis, and fibrosis in comparison to wild-type mice on the high-fat diet. Whether necroptosis is protective or deleterious in NASH appears to be context dependent; this represents an important finding for a possible therapeutic target. (Hepatology 2016;64:1518-1533) Beta-catenin and Met are two oncogenes that activate the Wnt and Met signaling pathways, respectively. These two oncogenes are frequently up-regulated in HCC. Tao et al. investigated their concomitant activation. They found that simultaneous Met overexpression or activation, along with beta-catenin-activating mutations, occurs in around 10% of human HCCs. The investigators were able to coexpress Met and mutated beta-catenin in hepatocytes of mice using Sleeping Beauty transposon technology and hydrodynamic tail-vein injection. These animals develop HCCs that display a gene expression pattern close to the gene expression pattern observed in human HCCs with concomitant activation of both pathways. Interestingly, introduction of a dominant-negative form of the transcription factor, T-cell factor 4, in the mouse model abrogated the development of tumors. This work outlines an experimental model specific for around 10% of human HCCs and suggests a therapeutic target. (Hepatology 2016;64:1587-1605) Redundancy is an important safety feature of airplanes, whereby critical components are duplicated. Similarly, liver regeneration is wired redundantly. Until now, inhibition and ablation of key factors resulted, at most, in delaying liver regeneration. Paranjpe et al. observed, as expected, delayed regeneration after two-thirds hepatectomy when the kinase activity of epidermal growth factor receptor was inhibited pharmacologically with canertinib or when the kinase activity of MET was genetically ablated. However, surprisingly, when both pathways were eliminated simultaneously, the liver completely failed to regenerate and mice died of liver decompensation. The investigators identified genes that were affected only in the combined situation. Interestingly, many of these genes coded for enzymes associated with hepatic metabolic and synthetic functions. This is the first description of a model with inhibition of signal transduction pathways grounding liver regeneration. (Hepatology 2016;64:1711-1724)