Hepatology Highlights
Authors: Jean-François Dufour
Journal: Hepatology (2013)

Nuclear receptors regulate hepatocellular metabolism and are attractive targets to treat nonalcoholic steatohepatitis (NASH). Randomized, control trials have demonstrated some benefits with peroxisome proliferator-activated receptor (PPAR)-γ agonists. GFT505, a compound developed by Genfit, is a dual PPAR-α and -δ agonist. Hanf et al. report that GFT505 improves the characteristic features of NASH in a combined genetic and diet-induced NASH mouse model and that these effects remain in mice lacking PPAR-α receptors. In a rat model of fibrosis, GFT505 demonstrated antifibrotic properties. Furthermore, the investigators report improvement of serum liver tests in patients treated in phase II studies. Based on these results, a clinical trial testing GFT505 in patients with NASH has been launched. (Hepatology 2013;58:1941-1952.) Clinical research on NASH is limited by the need to perform liver biopsies, which are invasive and subject to random sampling. Noninvasive imaging methods are of great interest in this regard. Noureddin et al. used magnetic resonance imaging to estimate hepatic proton density fat fraction in 50 patients in a randomized, clinical trial. In a detailed comparison with magnetic resonance spectroscopy and histology, this method appears sensitive enough to detect small changes in hepatic fat content, which correlated with changes in circulating aminotransferase levels and which could not be detected by histology. Because such a method is potentially widely available, it deserves further attention. (Hepatology 2013;58:1930-1940.) Extreme adaptation stresses normal physiology and reveals regulatory mechanisms. High altitude induces erythropoiesis and stresses iron demand. In a textbook set of experiments, Goetze et al. investigated how hypoxia affects the expression of iron transporters in the duodenal mucosa. Twenty-five healthy alpinists had a duodenal biopsy by unsedated transnasal small-caliber duodenoscopy in Zürich and 4,000 m higher in Capanna Margherita. Hypoxemia was associated with a 10-fold increase in duodenal expression of divalent metal-ion transporter 1– and ferroportin 1–promoting iron intake. This was associated with decreased serum hepcidin levels and increased duodenal expression of hypoxia inducible factor 2a (HIF-2a). Understanding the respective role and possible cross-talk between hepcidin and HIF-2a in iron transporter regulation could be addressed in future cell-based experiments. (Hepatology 2013;58:2153-2162.) The metabolism of acetaminophen (APAP) and its toxicity have been studied extensively. Administration of N-acetyl cysteine is both liver- and life-saving if administered early. In recent years, the crucial role of host enzymes driving necroapotosis has been found to be involved in APAP-induced liver injury. Receptor-interacting protein 3 (RIP3) is a pivotal kinase in orienting cell death to necrosis, a hallmark of APAP-induced liver damage. Ramachandran et al. report that genetic and pharmacologic ablation of RIP3 activity is protective against the deleterious mitochondrial effects of APAP. This observation brings us closer to being able to use kinase inhibitors to treat drug-induced liver failure. (Hepatology 2013;58:2099-2108.) Primary sclerosing cholangitis (PSC) is a challenging disease for hepatologists: There is no effective pharmacological treatment and it carries substantial carcinogenic risks. Counseling patients and management decisions are based on knowledge of the natural history of the disease. In a remarkable population-based study covering half the population of the Netherlands (>7 million persons), Boonstra et al. found a prevalence of only 6 in 100,000, albeit increasing, and a longer survival than previously reported from tertiary center-based cohorts. This study confirms that PSC patients have a substantial risk of developing cholangiocarcinoma (CCA; nearly 400-fold increased risk) as well as colorectal carcinoma (5-fold increased risk). Regular colonoscopies should be performed, and the fact that CCA occurs linearly over time, and not predominantly in the first years after diagnosis, argues for a surveillance regimen, which remains to be defined. (Hepatology 2013;58:2045-2055.) Intrahepatic CCA bears a very poor prognosis. We are lacking effective treatment, and major questions remain about its carcinogenic mechanisms that could direct clinical research. It is appreciated that this tumor is characterized by an abundant stromal component, so Sulpice et al. performed gene expression profiling of laser-captured stroma and tissue microarray analysis in two independent cohorts of patients with intrahepatic CCA. Multivariate analysis identified stromal expression of osteopontin as an independent prognostic marker. It remains to be investigated whether this correlates with circulating levels of osteopontin and whether these have prognostic significance, as has already been suggested for hepatocellular carcinoma (HCC). (Hepatology 2013;58:1992-2000.) Triple therapy with the first generation of protease inhibitors is the current standard of care for chronic hepatitis C genotype 1. This treatment is demanding and requires unusual commitment from patients. In this era of “informed deferral,” it is particularly relevant to identify factors affecting sustained virological response. Insulin resistance (IR) has been suggested to be such a factor for double therapy with pegylated interferon/ribavirin. Younossi et al. review the data of the phase III REALIZE trial regarding the predictive value of homeostatic model assessment for IR (HOMA-IR). In this population of patients who failed previous double therapy, HOMA-IR was not associated with response in multivariate analysis and therefore is not helpful in clinical decision making in this context. (Hepatology 2013;58:1897-1906.) Treatment of hepatitis B with nucleos(t)ide analogs is very effective and easy to initiate, but much more difficult to stop. The optimal duration of the treatment has important compliance and cost implications. Jeng et al. investigated the “APASL stopping rule” based on hepatitis B virus (HBV) viremia. They assessed the outcome of hepatitis B e antigen–negative patients who stopped entecavir after three negative HBV viremia determinations 6 months apart. In the year after cessation of treatment, hepatitis B relapsed in 45% of the patients. The relapse rate was 29% in patients with a baseline viremia lower than 2 × 105 IU/mL, the only identified predictive factor. These results may provide some guidance regarding when to stop oral treatment of HBV, but one should remain cautious, particularly with patients with cirrhosis. Rarely, withdrawal can trigger a flare with liver failure. (Hepatology 2013;58:1888-1896.) Survival of patients treated for HCC can be divided into two distinct periods: the time up to progression and the time after progression. Since the SHARP trial, time to progression (TTP) has been used as the surrogate endpoint for overall survival. However, the factors determining postprogression survival have not been investigated. Intuitively, the pattern of progression should affect postprogression survival. Reig et al. performed this analysis in their collection of sorafenib-treated patients who demonstrated a progression. First, they show that TTP is indeed an independent predictor of overall survival, along with Child-Pugh progression. Second, they report that the Barcelona Clinic Liver Cancer stage at progression and the presence of new extrahepatic lesions or vascular invasion are independent predictors of postprogression survival. In an era of second-line trials, these results have evident implications. (Hepatology 2013;58:2023-2031.) Studies investigating variceal bleeding typically exclude patients with HCC, so the outcome of variceal bleeding in these patients is unknown. Ripoll et al. matched 146 HCC patients with 146 without HCC for age and Child-Pugh class; all were admitted for variceal bleeding. Patients with HCC received secondary prophylaxis significantly less frequently and this was associated with shorter survival on multivariate analysis. Patients with HCC receive a significant amount of medical treatment for their tumor. Because this work associates secondary prophylaxis with longer survival in HCC patients who bled from varices, this treatment measure should not be forgotten. (Hepatology 2013;58:2079-2088.)