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

Patients with cirrhosis with chronic hepatitis C (CHC) are at risk of complications. Different factors may influence this risk, among them alcohol abuse, human immunodeficiency virus, or hepatitis B virus coinfection, and diabetes. Elkrief et al. followed 348 patients with cirrhosis with CHC who were hospitalized between 2006 and 2008. At baseline, 29% of the patients had diabetes, a cofactor much more frequent than alcohol abuse (6%) or coinfection (6%). Baseline diabetes was independently associated with development of ascites, bacterial infections, and hepatocellular carcinoma (HCC). Diabetes affected transplant-free survival only in patients with a Model for End-Stage Liver Disease score below 10. This French study confirms diabetes as an important negative prognostic factor in hepatitis C cirrhosis. This observation is likely to be true beyond hepatitis C and suggests, but did not show, that better management of diabetes may improve cirrhosis outcome. (Hepatology 2014;60:823-831.) This work is looking at the role of diabetes in the natural history of CHC before the development of cirrhosis. This is a large, epidemiologic study from Taiwan. Huang et al. selected hepatitis C virus–positive patients without diabetes and without cirrhosis from a randomly sampled 1 million Taiwanese of the national health insurance database. They then compared the evolution of patients who developed diabetes with those who did not. The cumulative incidence of cirrhosis and decompensated cirrhosis was significantly higher in patients with new-onset diabetes. Diabetes remains a predictor after adjustment for several relevant parameters. This complements and extends the results of the Elkrief et al. French study. (Hepatology 2014;60:807-814.) Hepatitis E is no longer a viral hepatitis confined to specific geographic locations. Hepatitis E has gone worldwide and should always be included in the differential diagnosis of an acute hepatitis, although acute hepatitis E should be excluded from the diagnostic algorithm of drug-induced liver injury. Recently, very high seroprevalences have been reported in some areas of Europe. Ditah et al. took advantage of the National Health and Nutrition Examination Survey database, which is representative of the U.S. population, to test 8,814 individuals for hepatitis E. They looked for immunoglobulin (Ig)G and IgM antibodies to hepatitis E using a commercially available enzyme-linked immunosorbent assay, described as having very high sensitivity and specificity. They report a seroprevalence of “only” 6%. Older age was the only parameter predictive of seropositivity by multivariate analysis. If this is a seroprevalence lower than previously reported, it is far from rare. Do not forget hepatitis E. (Hepatology 2014;60:815-822.) We still do not have an approved pharmaceutical treatment for primary sclerosing cholangitis (PSC). The trials that tested ursodeoxycholic acid (UDCA) have been negative, and a trial of high-dose UDCA even suggested deleterious effects. Nevertheless, many physicians offer PSC patients a UDCA therapy expecting an amelioration of the liver tests. Wunsch et al. took the reverse approach. They prospectively withdrew UDCA in 26 PSC patients and followed them for 3 months. As expected, this resulted in a significant deterioration of the liver tests. Serum levels of fibroblast growth factor 19, the ileum feedback hormone that regulates hepatic bile acid synthesis, remained unexpectedly unchanged. Interestingly, there was a significant decrease in lithocholic acid after ursodeoxycholic withdrawal. This is a small study with a short follow-up, but if future clinical trials of PSC require stopping UDCA for inclusion, this study suggests that this is safe. (Hepatology 2014;60:931-940.) Patients with suspected acute variceal bleeding should receive a vasoacting drug, even before endoscopy. Three drugs are possible: terlipressin, sandostatin, and octreotide. Selection of one of these depends on several parameters, but efficacy is certainly an important criterion. Seo et al. conducted a randomized, comparative trial. One thousand thirty-four patients were randomized to receive either terlipressin, sandostatin, or octreotide. The investigators restricted their analysis to patients who bled from variceal bleeding, and so, 780 patients were analyzed. On all the efficacy endpoints of the trial—active bleeding at initial endoscopy, bleeding control without rescue treatment, rebleeding, and 5- and 42-day mortality—no significant difference was shown between the three drugs. There was also no difference in the side effects, except for hyponatremia, which, as expected, was more frequent with terlipressin. These are solid results based on a large study with a strong design. (Hepatology 2014;60:954-963.) PIWI-interacting RNA sounds rather mysterious. Indeed, this class of small noncoding RNAs, also called piRNA, plays a role in genome stability in germline cells and had not previously been studied in liver pathophysiology. Rizzo et al. report first that the liver possesses the machinery associated with piRNAs (the PIWI proteins, among others) and describe important modifications of the piRNA profile after partial hepatectomy. Expression of 48 known and 24 putative new piRNAs changed significantly during liver regeneration. Whether piRNAs silence protein-coding genes and transposons, as discussed by the investigators, remains to be established. This work demonstrates the existence of a regulated hepatic piRNome. But, it still has mysterious aspects. (Hepatology 2014;60:798-806.) Both bile acid receptors farnesoid X receptor (FXR) and transmembrane G-protein-coupled receptor 5 (Tgr5) are expressed in the testes. It is unknown which bile acid effects they mediate in this organ. Baptissart et al. demonstrated that mice fed a diet supplemented with cholic acid have a lower sperm count. This is the result of structural alterations of the seminiferous epithelium with apoptosis of spermatids. The researchers were able to show that Tgr5-deficient mice are protected against this toxic effect of cholic acid. Regarding the second bile acid receptor, FXR, it has been reported that pharmacological stimulation of FXR decreases the testicular synthesis of testosterone. It is well known that female patients with advanced liver disease suffer from amenorrhea; currently, we are learning that bile acids also compromise male fertility. (Hepatology 2014;60:1054-1065.) It has finally been accepted that liver fibrosis is reversible and fibrosis is becoming a major therapeutic target. But, hepatic fibrogenesis is a complex process involving many players, and it is essential to identify those whose pharmacological manipulation leads to beneficial effects. Chiu et al. found that, in the experimental model of carbon tetrachloride–induced fibrosis, the expression of interleukin (IL)-20 is up-regulated. IL-20 stimulated the expression of transforming growth factor beta 1 and activated quiescent stellate cells. Mice lacking the IL-20 receptor were protected against fibrosis in this model. The investigators went on to show the pharmacological antifibrotic effects of an antibody against IL-20 and another antibody against the IL-20 receptor. Even though they report elevated amounts of IL-20 in the biopsies of human fibrotic livers, translation of this observation into the clinical arena is the critical step. Anti-IL-20 biologics are currently being tested in patients with rheumatoid arthritis. (Hepatology 2014;60:1003-1014.) Inflammation and cancer: This is a long story that has gone on for more than 100 years! An abundant literature explores the links that relate chronic inflammation with carcinogenesis. HCC is no exception, with many HCCs arising in the context of chronic (viral) hepatitis. Experimental work supported this concept. Mice lacking the IL-6 receptor, an important mediator of inflammation, developed less HCCs than their wild-type counterparts when exposed to obesity-induced inflammation. Now, Aleksandrova et al. provide evidence at an epidemiologic level. They performed a nested case-control study within the EPIC cohort, which enrolled 520,000 healthy Europeans between 1992 and 2000. During the follow-up, 125 patients developed HCC. Even after adjustment for viral hepatitis, diabetes, and adiposity, baseline serum concentrations of C-reactive protein and IL-6 were associated with a higher risk of HCC. Whether these simple markers could be used at screening to better stratify patients at risk needs to be further explored. (Hepatology 2014;60:858-871.) We have previously highlighted articles dealing with the difficulty in diagnosing cholangiocarcinoma (CCA). Tumor cells tend to be embedded in a dense stroma and therefore difficult to reach for histological analysis. Li et al. turned their attention to the bile and, more specifically, to biliary extracellular vesicles. They were able to isolate exosomes from bile collected during endoscopy and perform quantitative reverse-transcriptase polymerase chain reaction for microRNAs (miRNAs) on these isolates. They compared biliary exosome miRNA profiles obtained in 46 patients suffering from CCA to those obtained in 50 patients with nontumor biliary obstruction. Using a special bioinformatics approach, the investigators propose a five-miRNA panel to diagnose CCA with competitive accuracy. There was no validation set in this study. This intriguing work will certainly stimulate further investigations. (Hepatology 2014;60:896-907.)