Hepatology highlights

Vitamin D, like coffee, is a trendy topic in hepatology. Vitamin D has been reported to have antifibrotic properties. García-Álvarez et al. performed a meta-analysis to investigate whether vitamin D status was associated with fibrosis and response to antiviral treatment in chronic hepatitis C (CHC). The investigators identified 18 studies covering more than 2,500 patients. Low plasma levels of 25-hydroxyvitamin D were associated with more advanced fibrosis. Given that this advanced fibrosis is associated with decreased response to antiviral treatment, it is not surprising that low vitamin D levels were also associated with poor response. Patients with CHC frequently have low levels of vitamin D. This work falls short of showing that supplementation is beneficial. This is not the famous battle of Lodi, but the battle of low D! (Hepatology 2014;60:1541-1550.) Regulatory T cells (Tregs), which control against excessive immune response, are heterogeneous. Tregs demonstrate plasticity: They can acquire specialized suppressive functions or be subverted into cytokine-producing cells contributing to, rather than suppressing, the inflammatory response. This tuning depends on cues from the microenvironment. Piconese et al. characterized the hepatic Tregs in different stages of CHC. Noncirrhotic liver contained relatively few Tregs, and these cells produced interferon-gamma. Cirrhotic livers and hepatocellular carcinoma (HCC) contained more Tregs, and these cells expressed OX40 and had a Th1-suppressing phenotype. OX40, also known as CD134, fosters proliferation. OX40 ligand expression correlated with hepatitis C virus (HCV) viremia. It would appear that the profile of hepatic Tregs changes as CHC progresses: These cells seem to contribute to inflammation at the noncirrhotic stage and favor immune tolerance at the cirrhotic stage. (Hepatology 2014;60:1494-1507.) With the availability of safer, more potent direct antiviral agent combinations, indication to treat CHC will take into account societal aspects, such as risk of secondary transmission. Jacka et al. performed a detailed analysis of factors associated with phylogenetic clustering among people who inject drugs. This retrospective study enrolled 655 participants from the Vancouver Injection Drug Users Study. One third of participants demonstrated phylogenetic clustering. Factors associated with clustering were age, human immunodeficiency virus infection, HCV seroconversion, and syringe borrowing. This work identifies individuals whose treatment may be particularly beneficial from an epidemiological perspective. (Hepatology 2014;60:1571-1580.) Liver transplantation while patients are viremic for HCV always leads to rapid infection of the new liver. Recurrence of CHC occurs, which can affect the outcome of the transplant. HCV docks on specific surface proteins to enter into hepatocytes. Drugs impairing this binding may prevent infection. Vercauteren et al. used mice transplanted with human hepatocytes to show that the administration of monoclonal antibodies against the scavenger receptor class B type I, which acts as an HCV receptor, successfully inhibits infection. Interestingly, this effect persisted even when the antibodies are administered after exposure to the virus and was also effective with HCV variants that are relatively resistant in vitro to this strategy. This is an intriguing approach that adds a new host therapeutic target and, as discussed by the investigators, it can be particularly helpful in the transplantation setting. (Hepatology 2014;60:1508-1518.) The discovery of the receptor for hepatitis B virus (HBV) on hepatocytes has been long awaited; its identity came as a surprise given that it is the bile acid transporter, Na+-taurocholate cotransporting polypeptide (NTCP). In a fascinating article, Oehler et al. used HBV-infected humanized mice to show that the binding of HBV to NTCP stimulates the expression of enzymes responsible for bile acid synthesis. The pre-S1-derived peptide, Myrcludex-B, which binds to both human and murine NTCP, also induces the expression of enzymes responsible for bile acid synthesis. The investigators confirmed the increased messenger RNA abundance of these enzymes in liver biopsy samples from patients infected with HBV. This was accompanied by a decreased nuclear localization of the bile-acid–regulated transcription factor, farnesoid X receptor. The investigators hypothesize that these changes occur in response to a reduction of bile acid import into hepatocytes resulting from the binding of HBV to NTCP. (Hepatology 2014;60:1483-1493.) Radiological contrast agents can provide not only morphological information, but also functional information. Magnetic resonance imaging (MRI) can be performed with contrast agents (e.g., gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid) that define arterial and venous perfusion and which are later taken up into hepatocytes by a transporter. Focal lesions composed of cells devoid of this transporter do not accumulate this contrast agent. Yamashita et al. report that the majority of HCCs do not accumulate this contrast agent, and that only well-differentiated HCCs (i.e., 15%) demonstrate uptake. These lesions are not associated with elevated alpha-fetoprotein (AFP). The investigators were able to show that the transcription factor, hepatocyte nuclear factor 4, is responsible for this phenotype. Based on an external validation cohort, they confirmed that uptake of MRI contrast agent in combination with low AFP is associated with good survival. Uptake of such an MRI contrast agent does not exclude the diagnosis of HCC and, in this case, bears clinically relevant information. (Hepatology 2014;60:1674-1685.) Even if metastases tend to occur late in the natural history of HCC, their presence radically changes the therapeutic options. Little is known about the molecular mechanisms underlying the HCC metastatic process. For other tumor types, it has been shown that cross-linking of collagen by lysyl oxidases favors colonization of potential metastatic sites. Wong et al. report increased expression of lysyl oxidase-like 2 (LOXL-2) in HCC samples, compared to nontumor tissues, and in the sera of patients with HCC, compared to the sera of those without HCC. In vitro, media from hepatocytes expressing LOXL2 favors invasion of bone marrow cells through Matrigel-coated transwell. Hepatic implantation of HCC cells expressing LOXL2 resulted in intra- and extrahepatic metastases. The investigators identified factors regulating the expression of LOXL2; among them, hypoxia increased the expression of LOXL2. This illuminating work has many implications, one of which is to suggest how transarterial chemoembolization (TACE), a major hypoxia inducer, may negatively affect tumor biology. (Hepatology 2014;60:1645-1658.) Patients with intermediary-stage HCC are treated with TACE. This is a palliative treatment that may profit from combination with a systemic therapy. Evidence in support of this is lacking, at least with sorafenib. Kudo et al. report the results of a randomized, control trial testing brivanib in combination with TACE. When it came to light that the trials testing brivanib in first and second lines were negative, this third trial was stopped. Consequently, the results are based on only 32% of the required events, which represents a major limitation of this work. Nevertheless, patients receiving brivanib after the first TACE needed fewer TACE sessions and had a delayed time to extrahepatic spread or vascular invasion. Unfortunately, this did not translate into an improvement of overall survival. The upshot of this is that we are left with a negative, terminated trial, and so, support for combination treatment with TACE is still lacking. (Hepatology 2014;60:1697-1707.) What has been the evolution in HCC stage at diagnosis and which treatments have been selected at the beginning of this century? Ulahannan et al. studied the cases identified in the Surveillance, Epidemiology, and End Results (SEER 18) cancer registries from January 2000 to December 2010. They assembled an impressive collection of more than 47,000 cases, which covers approximately 28% of the cases in the U.S. population. Until 2005, more tumors >5 cm were diagnosed, but, in the second half of the decade, more tumors ≤5 cm were diagnosed. In terms of treatment selection, 52% (at best) of the patients eligible for a curative option received it. Resection was the most common treatment over the years. Transplantation increased up to 2006 only. Radiofrequency ablation increased dramatically to establish itself as the second-most common modality in 2010. The selection of treatments with a curative intent more than doubled from 2000 to 2005, but since then, there has been a plateau; understanding this observation will require more research. (Hepatology 2014;60:1637-1644.) Increased consumption of fructose has been implicated in the epidemic of nonalcoholic steatohepatitis. To better understand the mechanism underlying this association, Sapp et al. studied an unusual model for metabolic liver diseases, namely, the zebrafish. Exposure to fructose induced steatosis in zebrafish. There was an increase in the expression of genes related to lipogenesis, oxidative stress, and endoplasmic reticulum stress. Pharmacological induction of these stresses resulted in steatosis. The investigators observed an activation of mammalian target of rapamycin complex 1 (mTORC1) in these steatogenic experimental conditions. Administration of the mTORC1 inhibitor, rapamycin, prevented steatosis. The investigators took care to relate their finding to humans by showing phosphorylation of a downstream target of mTORC1 in biopsy samples of nonalcoholic fatty liver disease. (Hepatology 2014;60:1581-1592.)

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