The second volume

The Journal of Hepatology Reports (JHEP Reports) has reached some important milestones. We are now in our second volume and just recently we were listed in PubMed Central. Our mandate was to publish quality articles with a high standard of peer review and to demonstrate that our journal is important in its own right, and not a poor cousin to EASL's other journal, the Journal of Hepatology (JHEP).

Since inception, the journal has accepted 37 reports of original work and rejected 66, i.e. two-thirds. In comparison, JHEP rejects about 90% of articles submitted to it. In part our rejection rate is not higher because some of the articles are sent to us from JHEP. These are articles worthy of publication, which have undergone external review, but which for various reasons are not published in JHEP. There were 50 of these, of which 12 were accepted, 15 rejected and the remainder are still in the review process or awaiting revision. In addition, we have published 23 reviews, mostly invited. These figures do not include manuscripts that are still in the review process. Currently, we receive about 11 original articles or short communications/month. I think these figures demonstrate our commitment to quality, and also show our independence from JHEP, in that we do not accept everything they pass our way. Now that JHEP Reports is listed in PubMed we expect the number of submissions to grow because articles that we publish will appear in PubMed searches and in citation analytics.

The articles in this the second issue of volume 2 reflect several current trends in liver disease. They deal with hepatocellular carcinoma (1 article), biliary cancer (2 articles), fatty liver disease (4 articles) and liver transplantation (1 article). Below is a commentary on some of the articles.

One of the holy grails of hepatology today is to improve the rates of and outcomes from liver transplantation. One approach to do this is to improve preservation rates so that fewer livers are rejected because of poor viability after longer than optimal preservation times.

Short term (2 hours) cold oxygenated perfusion of livers ex situ can enhance viability and decrease the risk of injury after preserving the liver in a cold solution without perfusion.¹ Using normothermic oxygenated perfusion and a discarded liver there is a report of extended preservation for >80 hours with evidence of viability,² and another report of a preservation time of 26 hours with successful transplantation.³ The transplant team in Groningen now document the successful studies of hypothermic oxygenated ex situ perfusion in pig livers over 24 hours with continued viability.⁴

The authors postulate that hypothermic oxygenated perfusion might enable prolonged preservation times, thus allowing for better scheduling of the surgery (during the day rather than at ungodly hours of the night) and potentially less expensive transport by commercial airlines rather than chartered jet. The hypothermic perfusion also requires less minute by minute attention. However, the problem of harvesting organs in distant non-transplant centers remains. These hospitals are unlikely to have the set up necessary to perform hypothermic oxygenated perfusion. Thus, the livers will still have to be brought in a reasonable amount of time to a center where the perfusion can be established. Finally, airlines might not be overjoyed at the idea of carrying a machine that dispenses a flammable gas (oxygen) on their planes.

Nonetheless if the viability of these preserved organs can be confirmed in a transplantation model using solutions that are used in human transplantation this does represent progress and will likely make more organs available for transplantation over time.

Drs. Patel and Sebastiani⁵ provide a skeptics' view of non-invasive tests of liver fibrosis. In their view too much emphasis has been placed on the use of these markers for purposes for which they were not designed. They highlight the fact that liver biopsy, to which all markers have been compared, is an imperfect gold standard. Liver biopsy may under call fibrosis in as many as 30% of cases as a result of sampling error.⁶ This is particularly the case in chronic viral hepatitis where macronodular cirrhosis (to use the older term) may result in the biopsy sampling from the interior of a large nodule, and although there may be subtle histological changes suggesting that some degree of regression of fibrosis may have occurred, these are often overlooked. Furthermore, disagreement in fibrosis level between different tests is not uncommon. Given this uncertainty around fibrosis scores a 1- or 2-point change in score, whether by Fibroscan or Fibrotest or another method does not necessarily mean improvement or deterioration.

This review serves as a reminder not to use non-invasive tests in situations where it is not appropriate and to be cautious in the interpretation of what a change in scores actually means.

Biliary tract cancer has been addressed in 2 studies in this issue. In one, the value of serum concentration of the soluble urokinase plasminogen activator receptor was evaluated in patients who had undergone resection for biliary cancer (the authors did not specify whether the cancers were intra- or extrahepatic cholangiocarcinoma or gall bladder cancer).⁷ They found that high expression of this receptor was associated with a poor prognosis.

There are many studies, mainly in hepatocellular carcinoma (HCC), looking at factors that predict outcome of liver cancers. Some models evaluate patients prior to treatment and some after different types of treatment. The aim of these studies ostensibly is to be able to decide on appropriate therapy (or no therapy) for specific patients meeting the specified criteria. However, few investigators go beyond identifying predictive factors to testing whether the predictions from the model should influence treatment. In this particular study it is not clear that knowing that the soluble urokinase plasminogen activator receptor levels are high means that the patient should not be treated. Indeed, to my knowledge there are no studies that investigate whether patients with poor predictive markers should not be treated or treated any differently than if the biomarker test had not been done. Obviously, predictive biomarkers have to be identified, but this is a plea to investigators to determine which, if any, of these biomarkers are clinically useful.

The second study on biliary tract cancer is a laboratory-based study in which excess tumour tissue from a mixed bag of biliary cancers (intra- and extrahepatic cholangiocarcinoma and gall bladder cancer) was used to develop xenografts.⁸ The success rate of establishing these xenografts was low (47 xenografts established from 87 individuals). Interestingly those cancers which resulted in successful xenografts were also those from patients with a more adverse prognosis. This might be expected from older work which showed the closer a cell's phenotype was to the original tissue the lower the likelihood of establishing a cell line. It may be that one of the requirements for engraftment is a cell with enhanced growth characteristics. The hope is that these xenografts can be used to evaluate drugs to treat this cancer.

Dr Wan and her colleagues explored the role of miR-22 in control of fat accumulation in the liver.⁹ From this work it is clear that miR-22 is a major regulator of fat accumulation, by interacting with several other important molecules, such as FGF21 and its receptor FGFR1. Inhibition of the effects of miR-22 decreases fat accumulation. Interestingly, the effects seemed to be similar whether the fat accumulation was dietary or alcohol induced, suggesting a common pathway. In their series of experiments, they introduced an miR-22 inhibitor using a viral vector and showed that this resulted in a decrease in the amount of fat in the livers of rats. The addition of obeticholic acid further decreased fat accumulation. Currently, inhibition of miR-22 is not a clinical reality, and though small molecule inhibitors of other steps in the pathways are available, none have been shown to effectively reduce fat accumulation clinically. Whether miR-22 has any role in the development of steatohepatitis rather than simple fat accumulation was not addressed. Nonetheless, by elucidating the importance of miR-22 and the pathways it interacts with this may result in a new direction of study to deal with hepatic steatosis.

It is well known that diets high in plant-derived food are associated with lower rates of non-alcoholic fatty liver disease (NAFLD). However, the compound(s) responsible have not been identified. Dr. Salomone and colleagues looked at the dietary history of a large cohort and calculated the content of phenols in their diets, using validated charts of food phenol content.¹⁰ After adjusting for other factors that might be associated with NAFLD they found that diets rich in phenols were indeed associated with a lower prevalence of NAFLD. Whether other factors present in phenol-rich diets might also be important was not explored. This is an association, but not necessarily a causal association. Nonetheless, this study supports the old adage “an apple a day keeps the doctor away.”

I believe that JHEP Reports will in future join other society on-line journals, such as Hepatology On-Line and Clinical Gastroenterology and Hepatology as prestigious journals, equal in stature to the society's primary journals. We are on our way!