Patrick S. Kamath

Embolization of spontaneous portosystemic shunts for management of severe persistent hepatic encephalopathy.

1. Arena U, Lupsor Platon M, Stasi C, Moscarella S, Assarat A, Bedogni G, et al. Liver stiffness is influenced by a standardized meal in patients with chronic hepatitis C virus hepatitis at different stages of fibrotic evolution. HEPATOLOGY 2013;58:65-72. 2. Berzigotti A, De Gottardi A, Vukotic R, Siramolpiwat S, Abraldes JG, Garcia-Pagan JC, et al. Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension. PLoS One 2013;8:e58742. 3. Mederacke I, Wursthorn K, Kirschner J, Rifai K, Manns MP, Wedemeyer H, et al. Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection. Liver Int 2009;29:15001506. 4. Popescu A, Bota S, Sporea I, Sirli R, Danila M, Racean S, et al. The influence of food intake on liver stiffness values assessed by acoustic radiation force impulse elastography-preliminary results. Ultrasound Med Biol 2013;39:579-584. 5. Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960-974. 6. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. HEPATOLOGY 2003;38:1449-1457. 7. Goodman ZD, Becker RL Jr, Pockros PJ, Afdhal NH. Progression of fibrosis in advanced chronic hepatitis C: evaluation by morphometric image analysis. HEPATOLOGY 2007;45:886-894. 8. Fontana RJ, Goodman ZD, Dienstag JL, Bonkovsky HL, Naishadham D, Sterling RK, et al. Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. HEPATOLOGY 2008;47:789-798. 9. Boursier J, Zarski JP, de Ledinghen V, Rousselet MC, Sturm N, Lebail B, et al. Determination of reliability criteria for liver stiffness evaluation by transient elastography. HEPATOLOGY 2013;57:1182-1191.

Use of nontraditional anticoagulants in portal vein thrombosis: A note of caution

Understanding hepatitis delta virus dynamics and antiviral efficacy of the prenylation inhibitor lonafarnib. HEPATOLOGY 2014;60(Suppl): 317A. 3. Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest 2003;112:407-414. 4. Murray JM, Kelleher AD, Cooper DA. Timing of the components of the HIV life cycle in productively infected CD4 T cells in a population of HIV-infected individuals. J Virol 2011;85:10798-10805. 5. Ishida Y, Chung TL, Imamura M, Higara N, Canini L, Uprichard SL, et al. HBV infection in humanized chimeric mice has multiphasic viral kinetics from inoculation to steady state and an HBV half-life of 1 hr. HEPATOLOGY 2014;60(Suppl):1023A-1024A. 6. Pugnale P, Pazienza V, Guilloux K, Negro F. Hepatitis delta virus inhibits alpha interferon signaling. HEPATOLOGY 2009;49:398-406. 7. Guedj J, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci U S A 2013;110:3991-3996.

Impact factor: Misused and overhyped?

Editors of many scientific journals look upon the arrival of summer with a fair bit of trepidation for it is in summer that the impact factor (IF) for journals is released. This term was first coined by Eugene Garfield in 1955. The idea matured and resulted in the publication in 1961 of the Science Citation Index (SCI). The aim of the SCI was and continues to be to identify journals that are highly cited. That is, the IF is a benchmark for the journal and not for the research work. The calculation of the IF is based on two variables: the numerator is the number of citations in the current year of any article published in the journal in the previous two years, and the denominator is the number of articles published within the 2-year period. According to this formula, CA: A Cancer Journal for Clinicians has the highest IF of all medical journals in 2007 at 69 (see Table 1 for the calculation of IF); it is followed by the New England Journal of Medicine at 52.6 and the Annual Review of Immunology at 48. Contrary to what might be expected, the most cited journal up to 2006 and the second most cited journal in 2007, the Journal of Biological Chemistry, has an IF of just 5.6. The 2008 report on the IF will be published in June 2009. The IF is used (and misused) by various sources for different purposes. Publishers use the report on the IF to determine the journal’s influence in the field and also to review strategies to increase the IF. Librarians evaluate and document the value of their journal purchases on the basis of the IF. Editors use the IF to identify how influential their journal is; publication committees of different societies use the IF to determine how effective an editorial team has been. Several institutions tabulate the IF of journals in which their staff has published to decide the amount of research funding that departments should receive. In addition, publications in journals with a high IF may be important for promotion in academic rank. With the increasing number of journals being published, researchers use the IF to identify journals in which they believe their research is likely to be most recognized. Researchers and institutions thus imply that the publication of any research in a journal with a high IF is recognition that the research is good. It is important to understand that fewer than 20% of all articles account for 80% of all scientific citations. Over 90% of the IF for Nature is based on less than a quarter of its publications. Even when a paper is published in a high-impact journal, the paper may not be cited. A study of all citations from 1900 to 2005 shows that only 0.02% of all papers published over this period were cited more than 1000 times. Only 2.44% of papers published were cited more than 100 times, and 60% of papers received fewer than 10 citations in their lifetime. Therefore, researchers should come to terms with the fact that, unfortunately, most papers they publish are not likely to be cited often! On the other hand, there are a few papers like the paper by O. H. Lowry on protein measurement with the Folin phenol reagent, which was published in 1951 in the Journal of Biological Chemistry (IF of only 5.6) and has been cited no less than 293,328 times, or the paper by U. K. Laemmli on the cleavage of structural proteins during assembly of the head of bacteriophage T4, which was published in Nature in 1970 and has been cited 192,022 times. Thus, the total number of times that a paper is cited in its lifetime is likely to be a better representation of the quality of the research work carried out than the IF of the journal in which the paper is published. The important distinction here is that the IF relates only to the journal, but the number of times that a particular paper is cited reflects the quality of the research work. If institutions so desire, they can use the h index to determine the impact of a researcher’s publications. For example, an h index of 25 indicates that the researcher has 25 papers that have been cited at least 25 times, and an h index of 50 indicates that 50 of the researcher’s papers have been cited at least 50 times. The higher the h index is, the higher the impact is that a researcher has had on the literature. The h index for individual researchers is obtained from the ISI Web of Science, a publication of Thomson Reuters. There are numerous ways by which the IF can be manipulated. One can elevate the factor by increasing the numerator (the number of citations) while decreasing the denominator. The easiest way of decreasing the denominator is to decrease the number of articles published. Nature and Science each publish more than 900 articles per year, and Hepatology now publishes approximately 350 articles per year. CA: A Cancer Journal for Clinicians, the journal with the highest IF, publishes only reviews and, moreover, only approximately 20 per year (Table 1). ReAbbreviations: IF, impact factor; SCI, Science Citation Index. Address reprint requests to: Patrick S. Kamath, M.D., Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail: kamath.patrick@mayo.edu; fax: 507-284-0538. Copyright

Publications in Hepatology: Is there a pro-United States bias?

I nternational meetings have provided me with many opportunities to interact socially with investigators from different countries. The evening often follows the same script. Toward the end of the dinner, when tongues have been sufficiently loosened, the topic of conversation focuses on my role as an Associate Editor (AE) in HEPATOLOGY. The pointed question I am usually asked, depending on whom I am with, is ‘‘Why is HEPATOLOGY biased against Europeans, or against Asians?’’ To be fair, I too had some of these reservations about American journals, albeit not evidence-based, before I moved to the United States. Moreover, there have also been American authors who have indicated to me that they believe there is a pro-European bias in the decision-making process! In this Editorial, I hope to dispel any notion that there is a systematic bias in HEPATOLOGY either in favor of or against specific geographic regions of the world. It is a well-known fact that manuscripts from developed countries are more likely to be published in international journals than manuscripts from developing countries. Other interesting suggestions are that there might be a gender bias in the refereeing process, and that submissions with more than four authors more likely to be published than papers with fewer authors. If the corresponding author is from the same country as that of the publishing journal, the acceptance rate is higher. However, the most common perception is that there is a bias in publication in favor of the United States. This perception exists despite the fact that there has been an increase in recent years in the number of articles published from non–United States (US) sources among medical journals published from the United States. Currently, approximately 25% of all manuscripts published in US journals originate from outside the United States. Being a native English speaker is associated with a higher acceptance rate of a manuscript in US journals. Among internal medicine journals, there is no difference in publication rates for manuscripts submitted from the United States or Canada, and these rates are slightly higher than those for Europe. The acceptance rates from other parts of the world are smaller. In fact, acceptance rates for English-speaking countries are more than twice the acceptance rates of non–English-speaking countries, emphasizing the importance of communicating easily in the English language. Potential reasons for lower publication rates from developing countries include difficulty writing in English and submission of best manuscripts to national rather than US journals, although there is no evidence that this is the case. Some studies have been conducted to identify quality characteristics associated with manuscripts accepted for publication. Such studies have confirmed that manuscripts are most likely to be published if they have high methodological quality. Randomized control studies are the most likely to be published, especially with descriptive or qualitative analytical methods and disclosure of any funding sources. Larger sample size also increases the chance of acceptance of publication. Spectacular results (large treatment effects, strong associations, and unusually novel or exciting findings) are preferentially published. Although difficult to ascertain, we do accept that there may be biases, in general, in favor of well-known researchers in the field who are more likely to get a pass than the less-recognized researcher. However, this bias is not based on country of origin, but rather reputation within the field. The American Association for the Study of Liver Diseases performed a survey of submitting authors to provide more insight into its academic journals. One important aspect of the report was this: Corresponding authors from Europe and Asia were more likely to believe the review process was biased, and there were a few suggestions that the process is discriminatory and/or that there is preferential treatment toward US manuscripts. Given concerns from submitting authors that HEPATOLOGY may be biased against non-US authors, rather than take umbrage, we performed an in-depth analysis of acceptance rates. But first, some details of how we at HEPATOLOGY have attempted to avoid bias. The first step is the assignment of the AE who will handle the manuscript. The AE not only has expertise and is familiar with the investigators and Abbreviations: AE, Associate Editor; SCI, Science Citation Index; US, United States. Address reprint requests to: Patrick S. Kamath, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. E-mail: kamath.patrick@mayo.edu. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24497 Potential conflict of interest: Nothing to report.

The brain gets its say: Hepatic encephalopathy and its evolving role in transplant priority

Hepatic encephalopathy (HE), overt and even covert, has a major impact on patient morbidity and survival. In recent years, the rapidly changing impact of HE on transplant priority and survival on the waiting list has been studied extensively using the United Network for Organ Sharing (UNOS) database and through well-characterized cohorts. The subjective nature of clinical assessment of HE makes including it in organ allocation a divisive issue. Lucidi et al. in 2 large cohorts from Italy and Canada defined 1 approach toward solving this issue. Specifically, the authors used HE-related hospitalizations with grade 2 or higher, that is, overt HE defined by the European Association for the Study of the Liver/American Association for the Study of Liver Diseases guidelines using asterixis and disorientation as diagnostic of HE. Stages lower than grade 2 were bundled into a user-friendly pragmatic no-HE group that included covert HE. A key strength of the study was validation across 2 separate continents with diverse populations and varying transplant organ allocation systems. The authors demonstrated that the contribution of HE to mortality was equivalent to 7 points of Model for End-Stage Liver Disease (MELD) score. Interestingly, the impact on mortality was independent of the maximum grade of HE achieved beyond grade II, the proximity of the HE episode to enrollment, and the number of recent HE episodes. These findings point toward a biological “crossing of the Rubicon” that occurs when a patient reaches grade 2 HE in cirrhosis. The consequences of an overt HE (grade 2 or higher) episode requiring hospitalization are important from a psychosocial and clinical perspective. The incorporation of these findings by Lucidi et al. into organ allocation remains difficult. The advantages of the MELD score include its objectivity. In contrast, when the Child-Pugh score was the basis of organ allocation assessment of HE, in the listing the clinician’s word was paramount and could not be challenged due to the waxing and waning nature of HE. Interestingly, when HE lost its role in organ allocation after the introduction of the MELD score, the proportion of listed patients coded as grade 3/4 HE in the UNOS database dropped precipitously at a rate far higher than that expected biologically. These findings indicate that a portion of the HE patients in the Child-Pugh era were likely overcoded. Ultimately, regardless of which definition of HE is used, it will remain difficult to clinically justify its use. Therefore, as prior studies have demonstrated, corroboration with cognitive, neuropsychological, and neurophysiological techniques may be important objective techniques that could help in the appeal to regional review boards regarding potential listing priority changes in affected patients. Moreover, with the introduction of MELD score with sodium for organ allocation, the numeric value to be assigned to HE> grade 2 needs to be recalculated. An increase in priority listing for patients with advanced HE is also relevant from a posttransplant recovery standpoint because pretransplant cognitive impairment with HE is consistently associated with a relatively lower recovery after transplant compared with those without these issues. Posttransplant liver recovery may not necessarily translate into return to the workforce and independence if cognitive Abbreviations: HE, hepatic encephalopathy; MELD, Model for End-Stage Liver Disease; UNOS, United Network for Organ Sharing.

Alcoholic hepatitis: Can we outwit the Grim Reaper?

Whether you are an avid reader of the Book Thief or a fan of the Blue Oyster Cult, you know that messing with me is serious business. Be warned, that if you want to outwit me, you better come armed with the ability to predict your future.

Diagnostic and therapeutic advances in hepatology: A new feature in the journal

The recent explosion of diagnostic and therapeutic modalities has provided much hope for our patients with liver disease and the treating hepatologist alike. However, it has also posed a challenge as many of the newer advances were not even on the drawing board during the training of the hepatologist looking after these patients. Moreover, even when the hepatologist receives information regarding the newer drugs or devices, it has often been through pharmaceutical-sponsored dinner meetings or symposia where a somewhat biased presentation may be made. As recently as the late 1970s, therapy was restricted to the three L’s — lactulose, lactone (spironolactone), and Lasix for patients with cirrhosis. Steroids and azathioprine were used only by the few hepatologists who were familiar with treatment of autoimmune hepatitis. Physicians looking after patients with liver disease required only a limited knowledge of pharmacology to manage their patients with liver disease. In the early 1980s, beta blockers were more widely used for prophylaxis against variceal bleeding, and vasopressin was increasingly used in the control of acute esophageal variceal hemorrhage. Chenodeoxycholic acid and ursodeoxycholic acid were subsequently introduced for dissolution of gallstones, but ursodeoxycholic acid is now mainly used for primary biliary cirrhosis. Technology for imaging of the liver was also limited, with gray scale ultrasound, poor quality nuclear scans, and invasive procedures such as spleno-porto-venograms being utilized to visualize the liver and its vasculature. Subsequently, agents were introduced for immunosuppression following liver transplantation, and there was an explosion of imaging technology including ultrasound, Doppler sonography, computer tomography and positron emission tomography (PET) scans, and magnetic resonance imaging. In the last decade several agents have been introduced for treatment of hepatitis B and hepatitis C and, more recently, for palliative therapy of hepatocellular carcinoma. The current unmet need is finding a simple modality for educating the hepatologist in the proper use of newer drugs, devices or techniques. Beginning in this issue of HEPATOLOGY, we have introduced a new section termed “Diagnostic and Therapeutic Advances in Hepatology”. This section will feature on an intermittent basis and deal mainly with agents that have been recently added to the therapeutic and diagnostic armamentarium of the hepatologist. The section will typically be authored by an expert in the field who has had only limited ties with the particular drug or device company. The format to be followed will be standardized, very practical, and patientbased. For new drugs, the discussant will cover the pharmacology of the drug, including its mechanism of action, the adverse effect profile and, most important of all, how the drug is to be used, including monitoring and dose adjustments. Since it is anticipated that there will be not only several new drugs introduced for treatment of liver disease in the future, but also newer devices (artificial and bioartificial liver support systems), as well as newer imaging modalities (such as ultrasound and MR Elastography), new devices will also be discussed. We are confident that this section will be a step in the right direction in providing the practicing hepatologist with expert and unbiased advice regarding newer advances in the field.

Predictors of outcomes in patients with ascites, hyponatremia, and renal failure

Watch a video presentation of this article