Hepatology highlights
Authors: Jean‐François Dufour
Journal: Hepatology (2015)

Radiological assessment of hepatocellular carcinoma (HCC) is the method of choice to evaluate the response to antitumor treatment, although different criteria can be used. The Response Evaluation Criteria in Solid Tumor (RECIST) uses the change in size of the tumor to categorize the response to treatment. This is a crude measure that does not take into account the appearance of tumor necrosis. The modified RECIST (mRECIST) uses the size of the residual viable tumor instead of the size of the entire lesion. This approach might be more accurate, but less reproducible. Seyal et al. evaluated the response of 103 patients with HCC who underwent transarterial radioembolization at Northwestern University. Only 4% of patients demonstrated a response with the RECIST, whereas 41% demonstrated a response with the mRECIST. However, the intra- and interobserver reproducibility using the mRECIST was moderate in tumors with a homogeneous appearance and low in heterogeneous tumors. This work confirms that the mRECIST better captures the evolution of the tumor but that this advantage is mitigated by its moderate reproducibility. (Hepatology 2015;62:1111-1121) In order to determine geographical and temporal trends in the contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to HCC, de Martel et al. performed a systematic review of case series published up to 2014. They included 260 studies from 50 countries totaling 119,000 cases. In the United States, HBV contributes to less than 20% of HCCs, whereas HCV contributes to nearly half of cases, with an increase after 2000. As expected, HBV is the preponderant contributor in China, whereas in Japan it is HCV. In Europe, HBV, HCV, and nonviral causes are more balanced, with nearly two thirds of cases linked to viral hepatitis. These data emphasize the impact that systematic HBV vaccination and viral hepatitis therapies could have on HCC incidence. (Hepatology 2015;62:1190-1200) Carbohydrate-responsive element-binding protein (ChREBP) is a transcription factor that regulates de novo hepatic lipogenesis. In a very elegant series of experiments, Marmier et al. investigated the role of ChREBP in an experimental mouse model of binge drinking. They report that ethanol metabolism leads to acetylation of ChREBP and its subsequent activation. This explains the steatosis after binge drinking. ChREBP silencing prevented binge-drinking–induced steatosis, but was associated with increased blood concentrations of ethanol and acetaldehyde, as well as higher postbinging mortality. This further highlights the link between protective mechanisms and steatosis. (Hepatology 2015;62:1086-1100) Obesity and alcohol get along well to pick on the liver. How worse is binge drinking when it occurs in an already fatty liver? Chang et al. subjected mice fed on a high-fat diet to a protocol of binge drinking. Only 3 days of a high-fat diet was enough to worsen the hepatic lesions and, in particular, neutrophil infiltration. Hepatic production of chemokine (C-X-C motif) ligand 1 (CXCL1) was massively induced by this protocol. The investigators were able to show that genetic depletion as well as pharmacological blockage of CXCL1 reduced neutrophilic infiltration and hepatic lesions induced by the dual stress, whereas CXCL1 overexpression exacerbated them. This is an interesting finding with possible clinical implications. (Hepatology 2015;62:1070-1085) Saliva is easy to collect. Nevertheless, this fluid has been neglected in hepatology even though it may reflect pathogenic and prognostic changes. Bajaj et al. hypothesized that the saliva microbiota is modified in patients with cirrhosis with encephalopathy. They analyzed the gut and the saliva microbiome of 102 patients with cirrhosis, of whom 43 had previous episodes of encephalopathy, and compared them with those of 32 healthy controls. Both microbiotas showed a decrease in the relative abundance of autochthonous families of bacteria in cases of previous encephalopathy episodes. Interestingly, the investigators report that salivary dysbiosis was predictive of 90-day hospitalization independent of cirrhosis severity. Moreover, the saliva of patients with cirrhosis was characterized by low levels of antimicrobial histatins and lysozyme and high levels of inflammatory cytokines. This work highlights that gastrointestinal troubles of patients with cirrhosis begin in the mouth. (Hepatology 2015;62:1260-1271) Primary biliary cholangiopathy (PBC) and primary sclerosing cholangitis (PSC) are diseases of the biliary epithelium with a pathogenic immune component that is still poorly understood. Biliary epithelial cells can be part of this immune response as targets, but also, interestingly, as initiators. Schrumpf et al. investigated the ability of cholangiocytes to present antigens and activate T cells. They showed that murine and human cholangiocytes express the major histocompatibility complex class I–like molecule, CD1d, to present lipid antigens to natural killer T cells, thereby activating them. It seems that the biliary epithelium loses this function in PBC and PSC owing to the fact that biliary expression of CD1d is down-regulated in these diseases. It will be fascinating to identify the lipids that are presented as antigens by this mechanism. (Hepatology 2015;62:1249-1259) It has been repeatedly shown that mitochondrial defects, such as impaired respiration, favor cancer progression. In fact, altered mitochondrial metabolism affects the nuclear expression of genes. Lee et al. undertook to identify the most frequent genes whose expression is affected by mitochondrial defects in liver cancer cells. The investigators performed gene expression profiling in cell lines with different mitochondrial defects. They identify a common set of 10 affected genes whose concomitant expression in HCC was associated with poor outcome. The investigators focused their attention on one of these genes, NUPR1, a transcription factor that, they found, regulates expression of granulin, a secreted glycopeptide, which functions as a growth factor. The importance of this new pathway should be confirmed. (Hepatology 2015;62:1174-1189) Hepatic fibrosis is becoming a real target for clinical trials. Long-term successful treatment of chronic liver disease leads to its spontaneous regression, but the process is slow and can be pharmacologically hastened. Jiménez Calvente et al. are tackling the problem at its roots by using small interfering RNA (siRNA) to silence the expression of procollagen a1(I), the main collagen that accumulates in hepatic fibrosis. The tricky part is how to deliver this siRNA effectively. The investigators solved this difficulty by encapsulating the siRNA in cationic lipid nanoparticles. They showed that these nanoparticles are taken up by hepatic cells, even in cases of fibrosis. This results in a potent suppression of procollagen 1a(I) expression in vivo and a significant reduction of fibrosis in two different experimental models. Finally, the researchers report no side effect and no activation of innate immunity. A quite promising approach to deliver siRNA into liver cells. (Hepatology 2015;62:1285-1297) The combination of the second-generation NS3/4 protease inhibitor, simeprevir (SMV), with the nucleotide analog polymerase inhibitor, sofosbuvir (SOF), has been approved by the U.S. Food and Drug Administration with a 24-week duration of treatment in patients with cirrhosis. Aqel et al. report on their experience with this combination given for 12 weeks with or without ribavirin (RBV) in 119 patients with cirrhosis Child A or B (30%). The sustained virological response (SVR) at 12 weeks was 78%: In light of the results of the COSMOS study, this relatively low SVR can be attributed to the short treatment duration. Neither the addition of RBV nor previous treatment had an impact on the SVR. In contrast, pretreatment Model for End-Stage Liver Disease (MELD) score was inversely related to SVR. Approximateloy one third of patients demonstrated an amelioration of their MELD score at 12 weeks after completion of the treatment. This work adds to the growing evidence for the positive effects of the new anti-HCV treatments in decompensated patients with cirrhosis. (Hepatology 2015;62:1004-1012) Alisporivir, a nonimmunosuppressive derivate of cyclosporine, inhibits cyclophilin A, a host protein used by HCV for replication. Consequently, alisporivir has pangenotypic anti-HCV activity and a high barrier to resistance. Unfortunately, the clinical development of this drug was put on hold in order to investigate possible drug-related cases of pancreatitis. Pawlotsky et al. report the result of the VITAL-1 trial: a phase IIb, international, open-label study involving treatment-naïve patients without cirrhosis chronically infected with HCV genotype 2 or 3. Patients were randomized to five treatment arms: Four arms included alisporivir with/without RBV and/or pegylated interferon (Peg_IFN), depending on the virological response at week 4; and one arm included Peg-IFN with RBV. Treatments lasted 24 weeks. Even if it is rather difficult to get a clear message from this complicated design, it appears that those in the alisporivir treatment arms achieved an SVR at week 24 (SVR24) ≥80%, whereas the group receiving Peg-IFN/RBV achieved an SVR24 of 58%. Interestingly, in each group, the response rate of patients with genotype 3 was higher than those with genotype 2. Serious adverse events occurred in 6% of patients, none of which were cases of pancreatitis. Hopefully, it will not remain wishful thinking to test alisporivir in combination with other direct antiviral agents. (Hepatology 2015;62:1013-1023)