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

Nonalcoholic steatohepatitis (NASH) is an entity defined by histological features suggestive of alcohol intake, in the absence of excess alcohol intake. This diagnostic definition bears major limitations. In an effort to identify noninvasive diagnostic biomarkers, Ajmera et al. measured 32 preselected plasma parameters in 648 individuals who participated in the NASH Clinical Research Network. Apart from several parameters that are significantly associated with fibrosis, the researchers found that activated plasminogen activator inhibitor 1 is increased in patients with NASH, as opposed to simple steatosis. This finding may bring us a step closer to a biomarker of NASH; however, the result must be replicated and also evaluated in patients with alcohol-induced liver disease. (Hepatology 2017;65:65-77) In patients diagnosed with NASH, hepatic fibrosis is associated with overall and liver-related morbidity and mortality. Several fibrosis scores have been shown to predict cardiovascular death, as well as liver-related morbidity and death. Decaris et al. devised a novel approach to measure the extracellular remodeling rate. In the weeks preceding liver biopsy, 21 patients drank heavy water daily. Using tandem mass spectrometry to determine the incorporation of heavy water in hepatic collagen and in circulating lumican, the investigators deduced the fractional synthesis rates for both. The two rates of synthesis (lumican and collagen) correlate and can be considered as a metric of hepatic fibrogenesis. This rather “heavy” approach may help to identify patients at risk of rapid progression. (Hepatology 2017;65:78-88) Hepatic macrophages play an essential role in clearing apoptotic cells and foreign material. Among the receptors responsible for this activity, the scavenger receptor A acts as an activator of the M2 polarization of macrophages, which is associated with anti-inflammatory properties. Labonte et al. infected mice with replication-defective recombinant adenovirus type 5 to induce liver injury. Mice that lacked scavenger receptor A suffered from exacerbated tissue damage and fibrosis. These adverse outcomes could be prevented by the adoptive transfer of macrophages expressing scavenger receptor A, which favors M2 polarization. This work stresses the importance of macrophage polarization to control hepatic damage attributed to hepatotropic viral infection. (Hepatology 2017;65:32-43) One of the functions of the liver is to detoxify ammonia. The liver accomplishes this by using two complementary systems: a periportal low-affinity mechanism, which converts ammonia to urea, and a pericentral high-affinity mechanism, which relies on glutamine synthetase to combine ammonia with glutamate to form glutamine. Hakvoort et al. used genetically modified mice that lack hepatic glutamine synthetase to show, in an elegant series of experiments, that the disposal to urea of the glutamine-bound ammonia is actually dependent on the rate of glutamine synthesis in the muscle. This emphasizes the role of glutamine synthesis in the muscle as a potential means to enhance hepatic periportal ammonia disposal. (Hepatology 2017;65:281-293) In order to better understand the benefit and cost-effectiveness of sorafenib—the only drug approved since 2007 for the treatment of advanced hepatocellular carcinoma (HCC)—Parikh et al. analyzed the Surveillance Epidemiology and End Results (SEER) Medicare-linked database. They identified 1,098 patients who were diagnosed with HCC from 2007 to 2009 (the years following the marketing of sorafenib), of whom 288 received sorafenib and 870 did not. Of note, the SEER database contains neither the Child-Pugh class nor the performance status, which are two essential pieces of information in staging HCC. The researchers found that sorafenib is associated with a survival benefit and that sorafenib is cost-effective. The researchers present deeper statistical analysis, which questioned this latter observation. More recent data, including Child-Pugh classification and performance status, would be of interest. (Hepatology 2017;65:122-133) Classically, interleukin (IL)−6 binds to its membrane-bound receptor and this complex engages the membrane-bound signal transducing protein, glycoprotein 130 (gp130). gp130 can also be activated by “trans-signaling”: The IL-6 receptor can be shed from the cell surface, and this now soluble receptor binds IL-6 and engages gp130. Specifically blocking IL-6 trans-signaling with soluble gp130 is possible. Bergmann et al. used transgenic mice expressing soluble gp130. These animals that lack IL-6 trans-signaling displayed markedly reduced tumor burden in a HCC model. The investigators were able to link IL-6 trans-signaling to reduced expression of p53 and activation of beta-catenin. This work uncovers a new side of IL-6 signaling in HCC. (Hepatology 2017;65:89-103) With the widespread determination of antimitochondrial antibodies (AMAs) as a diagnostic test for primary biliary cholangitis (PBC), every hepatologist is faced with their interpretation of the positive AMA test in patients without PBC. In a prospective, nation-wide French study, Dahlqvist et al. assembled 229 cases of patients with positive AMAs without PBC. This resulted in a prevalence of 16 per 100,000. After a mean follow-up of 4 years, only 10% of these patients developed PBC. More intriguing, the patients with positive AMAs without PBC had a significantly higher mortality than expected: none attributed to PBC, but many attributed to cancer. This observation warrants further investigation. (Hepatology 2017;65:152-163) Cirrhotic cardiomyopathy is a frequent condition. Elevation of circulating bile acids has long been suspected of playing a role. Desai et al. performed cardiac investigations in mice that lacked both farnesoid X receptor and small heterodimer partner. These animals are characterized by bile acid overload. The investigators report that these mice suffered from cardiac hypertrophy, bradycardia, and exercise intolerance. Importantly, however, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the phenotype. Moreover, they found that bile acids decrease cardiac fatty acid oxidation. This elegant work significantly adds to the literature on the cardiac toxicity of bile acids. (Hepatology 2017;65:189-201) Acute-on-chronic liver failure (ACLF) is associated with high mortality. It is thought that inflammation drives the severity of this condition. Alcaraz-Quiles analyzed six single-nucleotide polymorphisms in six inflammation-related genes from 279 patients with cirrhosis, of whom 178 had ACLF, with the remaining 101 not exhibiting ACLF. Polymorphisms in genes encoding IL-1 beta (IL-1β) and IL-1 receptor antagonist (IL-1ra) were associated with a reduced risk of ACLF and decreased ACLF-related mortality. The investigators further showed that these polymorphisms were also associated with lower circulating levels of IL-1 and C-reactive protein. These data suggest that recombinant IL-1ra is a possible anti-inflammatory therapy for ACLF patients. (Hepatology 2017;65:202-216) No doubt that hepatology has flourished as a specialty in the last few decades. Nevertheless, the standing of this discipline in outpatient and inpatient care should be stronger. Accomplishing this will rely heavily on our capacity to train liver specialists and ascertain expertise in imaging and liver-related interventions. In a special article, Russo et al. review the information relating to the specialty of hepatology, including compensation, which must be gathered in order to more precisely assess a workforce that clearly extends beyond liver-transplant–related activities. It is time to coordinate action across countries and health care systems to provide certification in hepatology. Russo et al. are to be commended for raising this important issue. (Hepatology 2017;65:336-340)