Hepatology highlights
Authors: Jean-François Dufour
Journal: Hepatology (2014)

Reactivation of hepatitis B virus (HBV) during chemotherapy is a potentially lethal situation. Currently, we have safe, potent drugs to block HBV replication and avoid this situation. In a prospective, multicenter study conducted in Taiwan, Hsu et al. monitored HBV viremia in 150 Hepatitis B core antibody (anti-HBc)-positive, Hepatitis B surface antigen (HBsAg)-negative patients diagnosed with non-Hodgkin's lymphoma. Entecavir was administered in case of reactivation. This study provides some interesting facts: HBV reactivation occurred in 11% of the patients; anti-HBs-positive patients were not spared because HBV reactivation occurred in 8% of these patients; the time between evidence of reactivation and hepatitis flare was only 49 days; and, despite the quick administration of entecavir, severe hepatitis occurred in more than 40% of patients with a flare. More information on the titers of anti-HBs antibody at baseline and during therapy would have been interesting. This work stresses, again, the absolute necessity to obtain a full hepatitis B serology before initiation of chemotherapy. It also provides strong support for prophylactic administration of therapy in anti-HBc-positive patients. If, within the tightly controlled environment of a prospective trial, 40% of patients have severe hepatitis, in daily practice, the risk is undoubtedly higher. It begs the question, why play with fire? (HEPATOLOGY; 2014;59:2092–2100.) What are the tricks that hepatitis C virus (HCV) employs to escape the vigilance of the innate immune system? Interferon (IFN) has been the cornerstone of anti-HCV treatments for more than a decade. So, it was unexpected to discover that many patients with chronic hepatitis C (CHC) infection express IFN-stimulated genes in abundance. One can then imagine that hepatocytes that express these genes are protected against HCV infection and that infected hepatocytes do not express these genes. Wrong! Wieland et al. were able to develop an in situ hybridization assay to identify HCV-infected hepatocytes. Only a minority of hepatocytes were infected and their number correlated with HCV viremia. Infected hepatocytes were found in clusters, suggesting a cell-cell spread. By colocalizing expression of IFN-stimulated genes with HCV hybridization, the researchers found that infected cells readily express these genes. The interactions between HCV and IFN signaling are clearly more complicated than anticipated. (HEPATOLOGY; 2014;59:2121–2130.) When a patient with portal hypertension (PH) turns out to have no cirrhosis and is diagnosed with idiopathic PH (IPH), many questions arise regarding management and outcome. Siramolpiwat et al. reviewed 69 biopsy-proven cases of IPH treated at the Barcelona Liver Unit. Their unique experience highlights important aspects of this rare disease. More than 40% of the patients had associated immunological, hematological, or thrombophilic conditions and 10% were human immunodeficiency virus positive. Fifty-eight percent of patients had no symptoms at presentation. Variceal bleeding was the most frequent presentation. The researchers recommend managing the varices as you would in cirrhosis. Portal vein thrombosis was a frequent complication, which occurred in 36% of patients. The prognosis was remarkable, with a 10-year survival above 80%. The pathophysiology of this disease is yet to be fully elucidated. Interestingly, the histology revealed nodular regenerative hyperplasia in nearly 20% of the cases, offering a possible mechanism, but not an etiologic treatment as yet. (HEPATOLOGY; 2014;59:2276–2285.) The nuclear receptor, farnesoid X receptor (FXR), is becoming an important therapeutic target in hepatology. Obeticholic acid (OCA) is an FXR agonist with therapeutic potential for primary biliary cirrhosis and nonalcoholic steatohepatitis (NASH). Patients with these diseases may present with PH. Verbeke et al. investigated the effects of OCA on PH in two experimental models of PH. They report on a significant amelioration of portal pressure and intrahepatic vascular resistance with OCA. These beneficial effects were mediated by an increased endothelial nitric oxide synthase activity. The researchers showed, surprisingly, a massive reduction in expression of FXR in the case of cirrhosis. So, it will be important to confirm that the reported effects of OCA are mediated by FXR. Whatever the mediator, these data add to the interesting properties of OCA. (HEPATOLOGY; 2014;59:2286–2298.) Primary sclerosing cholangitis (PSC) remains without an established medical treatment. Randomized, controlled trials have thus far been negative. New therapeutic directions may be proposed by investigating yet unexplored pathophysiologic processes. Tabibian et al. turned their attention to cellular senescence. Their results reveal that cholangiocytes of PSC patients express proteins and proinflammatory markers of senescence, in contrast to cholangiocytes of healthy controls. The researchers established an in vitro model of lipopolysaccharide-induced senescence of normal human cholangiocytes. With this model, they could demonstrate induction of senescence in bystander cholangiocytes by senescent cholangiocytes. The researchers found that this senescence depends on N-ras and can be prevented by an N-ras inhibitor. These are provocative results. We are eager to know whether they can be translated into a benefit for patients with PSC. (HEPATOLOGY; 2014;59:2263–2275.) The patatin-like phospholipase domain-containing 3 (PNPLA3) gene is a hot topic in hepatology. A single-nucleotide polymorphism (SNP) located in this gene has been consistently associated with progression of liver diseases, such as NASH, alcoholic liver disease (ALD), and CHC. This SNP has been associated with inflammation and fibrosis, two important features predisposing to hepatocellular carcinoma (HCC). In order to investigate whether this PNPLA3 SNP is also associated with HCC, Trépo et al. performed a meta-analysis based on 2,503 European patients with cirrhosis. Methodologically, they were able to access the individual participant data. Their results indicated an association between the PNPLA3 SNP and HCC. The association was stronger in patients with ALD, but also significant in patients with CHC after adjustment for age, sex, and body mass index. However, the magnitude of the association is not sufficient to provide a biomarker for HCC surveillance based on this SNP. That said, the mechanism should be further investigated, especially for a gene whose function is still controversial. (HEPATOLOGY; 2014;59:2170–2177.) Transplantation is an excellent option for eligible patients with HCC. These recipients are cured from the tumor and from cirrhosis. With the implementation of surveillance programs, more and more patients with HCC are listed. Wong et al. used the United Network for Organ Sharing registry to provide accurate numbers and proportions over a decade. From 2002 to 2012, the number of patients transplanted for HCC increased 10-fold, which represents a percentage increase from 3% to 23%. Not surprisingly, HCV was the leading etiology. NASH was the second etiology, but it was the most rapidly growing indication. It is only a matter of time for NASH to become the leading cause of HCC in transplanted patients, which is likely to come sooner with the development of new treatments against HCV. (HEPATOLOGY; 2014;59:2188–2195.) Fibrolamellar HCC is characterized by its abundant fibrous lamellar stroma and affects young individuals without underlying liver disease. This peculiar tumor is likely to present with unusual biological features that could be discovered by transcriptomic profiling. Malouf et al. performed gene expression arrays in 14 patients with fibrolamellar carcinoma (FLC). In comparison to normal liver and HCC arising in noncirrhotic liver, FLC has a distinct gene expression signature with activation of the ERBB2 pathway and overexpression of several neuroendocrine genes. An unsupervised clustering of gene expression profiles distinguished two subtypes of FLC with different clinical features. Recently, a chimeric transcript leading to deregulated activation of protein kinase A was reported in FLC. With these observations, our understanding of the molecular changes occurring in FLC increases dramatically and may lead to therapeutic advances. (HEPATOLOGY; 2014;59:2228–2237.) Ubiquitination is a posttranslational modification that alters the cellular location or function of proteins or targets proteins for proteasomal degradation. Ubiquitin is activated by ubiquitin-activating enzyme (E1), then transferred to ubiquitin-conjugating enzyme (E2), which works in concert with ubiquitin-protein ligase (E3), which recognizes the proteins to be ubiquitinated. Jiang et al. sequenced the exome of a dysplastic nodule, two HCCs, and peripheral blood from the same patient and identified mutations in the UBE3C gene, an E3 ligase. They found mutations in this gene in 16% of HBV-induced HCCs. It was also found that HCC cell lines expressing less UBE3C undergo epithelial-mesenchymal transition. Whether expression of a mutated UBE3C has similar effects has not been tested. Finally, overexpression of UBE3C was associated with HCC recurrence. Even if the role of the mutations in the UBE3C gene remains to be investigated, this work adds to the evidence that ubiquitination is involved in hepatocarcinogenesis. (HEPATOLOGY; 2014;59:2216–2227.) COP9 signalosome regulates the enzymatic complex responsible for ubiquitination. COP9 is composed of several proteins; among them, COPS5 removes NEDD8 adducts from Cullin-RING ubiquitin ligase. These ligases control other factors responsible for licensing sites of DNA replication. Panattoni et al. report that, in mice lacking hepatocellular COPS5, regenerative stimuli result in DNA rereplication, meaning that the genome is replicated more than once per cell cycle. This triggers replicative stress, which leads to cell-cycle arrest, polyploidy, and apoptosis. This striking phenotype could be rescued in mice lacking the cyclin-dependent kinase inhibitor 2A gene. Conversely, acute expression of c-Myc partially recapitulates the replicative stress observed in the absence of COPS5. This work highlights the complex interactions between DNA replication and ubiquitin ligases. (HEPATOLOGY; 2014;59:2331–2343.)