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

There is an abundant literature describing an association between hepatitis C virus (HCV) and diabetes mellitus. The virus seems to directly interfere with insulin signaling, and patients with chronic hepatitis C frequently present with insulin resistance. Ruhl et al. revisit this association and their results actually challenge it. The researchers used the National Health and Nutrition Examination Survey data of more than 15,000 adults to test whether the prevalences of diabetes and prediabetes (American Diabetes Association criteria) were different in HCV-positive, compared to HCV-negative, patients. The prevalences of diabetes and prediabetes did not differ by HCV status, but they were higher in patients with elevated liver tests. The researchers conclude that elevated liver tests may account for the previously reported associations between HCV and diabetes. (Hepatology 2014;60:1139-1149.) Vitamin D deficiency has been associated with increased risk of several cancers, in particular, colorectal cancer. What about hepatocellular carcinoma (HCC)? Fedirko et al. used the EPIC cohort, which enrolled more than 500,000 Europeans, to build a prospective, nested case-control study around the 138 individuals who developed an HCC. They measured prediagnostic circulating levels of 25-hydroxyvitamin D (on average, 6 years before HCC diagnosis). Lower 25-hydroxyvitamin D levels were associated with a 49% increase in the risk of HCC. This association remained after adjustment for several possible confounding factors. Mechanistically, vitamin D has been reported to inhibit hepatic fibrogenesis and have direct antineoplastic properties. These data suggest that vitamin D supplementation might be hepatoprotective. (Hepatology 2014;60:1222-1230.) Surveillance for HCC is essential. Individuals at risk can be identified and have access to curative treatments only at early asymptomatic stages. Alfa-fetoprotein (AFP) is far from perfect, and surveillance relies on biannual sonography. In this context, the work of Ladep et al., from the PROLIFICA consortium, is a welcome opening. They compared the urinary metabolite phenotypes of patients with HCC, cirrhosis without HCC, liver disease without cirrhosis, and healthy volunteers. The investigators were able to identify a rather simple urinary metabolite signature associated with HCC, which outperformed AFP. These findings were duplicated in a validation cohort. This work was conducted with samples collected in West Africa, a region where HCC is particularly prevalent because of hepatitis B virus and exposure to aflatoxin. It will be interesting to find out whether the same signature applies in other geographic regions, where other factors are at play. In any case, such a metabolite-centric approach seems promising. (Hepatology 2014;60:1291-1301.) Given that hepatocytes are resistant to conventional chemotherapeutics, antiangiogenic drugs, which target vascular cells, may prove efficacious. This logic rings true for sorafenib; its beneficial effects in HCC have been primarily considered antiangiogenic. Peng et al. challenge this concept. Their data show that some HCCs express vascular endothelial growth factor (VEGF) and its receptors in tumor cells, and that, in this case, VEGF stimulates its own production and promotes cell proliferation. In tumor cells expressing VEGF and its receptors, sorafenib decreases VEGF production as well as cell proliferation. This work complements recent work showing that HCCs characterized by an amplification of the VEGFA locus are particularly sensitive to sorafenib. (Hepatology 2014;60:1264-1277.) The enzyme, aspartyl-(asparaginyl)-β-hydroxylase (ASPH), promotes cell migration and metastasis and is overexpressed in various cancers, including HCC. Its mechanism of action involves calcium homeostasis and hydroxylation of various receptors, including Notch. Aihara et al. designed inhibitors of ASPH based on the crystal structure of its active site. A small molecule that inhibits ASPH activity was identified. It suppresses HCC cell migration and HCC progression in animal models by disrupting Notch signaling. This is an original approach, which hopefully will be further investigated. (Hepatology 2014;60:1302-1313.) Acetaminophen (APAP) remains a frequent cause of acute liver injury. Specific criteria to decide when to list a patient with acute liver failure resulting from APAP for a liver transplant were proposed many years ago. These very useful criteria are based on parameters evaluating the gravity of the liver failure. They do not take into account the pathophysiology of APAP-induced liver failure. McGill et al., from the Acute Liver Study Group, investigated whether damage-associated molecular patterns can be helpful in predicting outcome of APAP-induced liver injury. Serum activity of the mitochondrial enzyme, glutamate dehydrogenase, serum levels of mitochondrial DNA, and nuclear DNA were higher in nonsurvivors than survivors. However, the results between survivors and nonsurvivors showed considerable overlap, indicating limited predictive value for these markers. This work emphasizes the extent of mitochondrial damage in APAP-induced acute liver failure. (Hepatology 2014;60:1336-1345.) Drug-induced liver injury, also known as DILI, appears to be too restrictive a concept at present. Many people take herbal preparations and supplements, which are not innocuous, as Navarro et al. remind us. These researchers used the database of the DILI network to retrieve cases of hepatotoxicity attributed to herbal and dietary supplements. They found 130 cases, which represents 16% of the database. The researchers classified these cases into two categories: (1) young bodybuilders who developed jaundice for several months, but recovered, and (2) older individuals, mostly women, with a hepatocellular injury that resulted in death or transplantation in more than 10% of cases. So, herbals-induced liver injury (HILI) and supplement-induced liver injury (SILI) do exist! (Hepatology 2014;60:1399-1408.) There is a lack of data showing an effect of omega-3 fatty acids in nonalcoholic steatohepatitis. The combination of eicosapentaenoic acid and docosahexaenoic acid is an approved treatment of hypertriglyceridemia. Scorletti et al. randomized 103 patients with nonalcoholic fatty liver disease to the combination or placebo. Steatosis was assessed by magnetic resonance spectroscopy, rather than histologically. The combination failed to significantly improve steatosis, but interestingly, several patients in the placebo arm showed enrichment in erythrocyte omega-3. After correcting for this unexpected confounding factor, the investigators detected an improvement of steatosis. This trial highlights the importance of measuring exposure to intervention drug not only to evaluate compliance, but also to assess exposure in the control arm. (Hepatology 2014;60:1211-1221.) Despite its peculiar features, the molecular pathophysiology of primary biliary cirrhosis (PBC) remains to be understood. Recent genome-wide association studies (GWASs) proposed pathways involving immunological and apoptotic genes. Lleo et al. also chose an unbiased, discovery approach, but with a completely different perspective. The investigators performed a detailed analysis of the proteome of apoptotic bodies from human intrahepatic biliary epithelial cells. They identified proteins specifically expressed or specifically missing in these apoptotic bodies. The data point to innate immune system and inflammatory response. It will be interesting to see how the identified proteins can be mechanistically implicated in the development of PBC. (Hepatology 2014;60:1314-1323.) Remote ischemic preconditioning consists of mechanically interrupting the blood flow to a limb repeatedly to induce cycles of local ischemia. This remote stress induces a systemic response that protects various organs against ischemia reperfusion (I/R). In a series of elegant experiments, Oberkofler et al. demonstrate that remote ischemic preconditioning activates platelets, which release serotonin, to stimulate VEGF secretion. These factors induce expression of the protective matrix metalloproteinase-8 and interleukin-10 in the liver and protect it against I/R injury. The investigators went on to show that this effect also applies to other organs and other insults. They conclude that platelet response to local stress primes the body against impending injury. (Hepatology 2014;60:1409-1417.)