Focusing on the past, present, and future of hepatology
Authors: Daniel Shouval, Scott L. Friedman
Journal: Journal of Hepatology (2014)

The past five years have borne witness to remarkable progress in almost all areas of hepatology, including: improved understanding of the molecular pathophysiology of developmental, infectious, inflammatory, metabolic and neoplastic liver diseases; the introduction of non-invasive diagnostic tools for fibrosis, and the discovery of direct acting anti-viral agents for hepatitis C, among many others [1Berlanga A. Guiu-Jurado E. Porras J.A. Auguet T. Molecular pathways in non-alcoholic fatty liver disease.Clin Exp Gastroenterol. 2014; 7: 221-239Crossref PubMed Scopus (289) Google Scholar, 2Charlton M.R. Improving long-term outcomes after liver transplantation.Clin Liver Dis. 2014; 18: 717-730Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 3Baffy G. The impact of network medicine in gastroenterology and hepatology.Clin Gastroenterol Hepatol. 2013; 11: 1240-1244Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 4Marcellin P. Asselah T. 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While a comprehensive description of progress in the science and practice of hepatology in these 5 years is beyond the scope of this commentary, we wish to use this final FOCUS piece to highlight some of the most meaningful advances in our field, and to glimpse into the future of our discipline. Basic and clinical research, focused primarily on the development of potent direct-acting anti-viral agents for HCV, has dominated the scene of viral hepatitis and promises to yield a profound public health benefit. Next-generation sequencing technologies have made genomic analysis extremely rapid, which is beginning to change the way liver diseases are discovered and diagnosed. For example, genome-wide association studies, which explore the relationship between molecular genotypes and clinical phenotypes identified an allelic polymorphism near the IL28B gene, predicting a favourable therapeutic response to interferon alpha and ribavirin in the CC genotype among genotype 1 patients [[12]Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google Scholar]. Improved understanding of the HCV life cycle led to the generation of genotype-specific cell lines that have been used in pre-clinical studies to select and validate novel targets for HCV. These have included the NS3-4A protease inhibitors, nucleot(s)ide analogue viral polymerase inhibitors, non-nucleoside inhibitors of the viral RNA polymerase, NS5A inhibitors, host targeted agents (HTA), cyclophilin inhibitors and a cellular miRNA antagonist [[13]Pawlotsky J.M. New hepatitis C virus (HCV) drugs and the hope for a cure: concepts in anti-HCV drug development.Semin Liver Dis. 2014; 34: 22-29Crossref PubMed Scopus (81) Google Scholar]. Over 30 new direct anti-viral agents (DAA) and HTAs are in clinical trials, and have already revolutionized the treatment of chronic HCV. The swift development of interferon-free protocols using DAA monotherapy or the combined administration of two or three DAAs or HTAs, administered for 8–12 and up to 24 weeks, is leading to SVR rates between 90% and 100% in genotypes 1′2′4-6, even in patients with cirrhosis, in those who failed previous anti-viral therapy, are co-infected with HIV or are re-infected with HCV post liver transplantation. Two of these agents, sofosbuvir and simeprevir, have already been licensed in the US and Western Europe, and others are expected to be approved during the next year. There has been remarkable progress in understanding the molecular pathophysiology of persistent HBV infection. This knowledge has been translated into highly efficient means for prevention and control of chronic HBV infection, primarily through vaccination [[14]Gerlich W.H. Medical virology of hepatitis B: how it began and where we are now.Virol J. 2013; 10: 239Crossref PubMed Scopus (212) Google Scholar]. Yet, complete eradication of overt and occult HBV infection, through targeting of intra-nuclear circular covalently closed (ccc) HBV-DNA, remains an elusive goal. A major breakthrough in this pursuit has been reported by Chinese investigators who identified the liver bile acid transporter sodium taurocholate co-transporting polypeptide (NTCP) as the putative HBV receptor, expressed on the basolateral membrane of hepatocytes [15Yan H. Peng B. Liu Y. Xu G. He W. Ren B. et al.Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide.J Virol. 2014; 88: 3273-3284Crossref PubMed Scopus (189) Google Scholar, 16Yan H. Zhong G. Xu G. He W. Jing Z. Gao Z. et al.Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.Elife (Cambridge). 2012; 1: e00049Crossref Scopus (1447) Google Scholar]. The NTCP receptor is thought to account for the specific hepatotropism of HBV, which has paved the way for the development of viral entry inhibitors against HBV and hepatitis delta virus (HDV). The first example of such an inhibitor, Myrcludex B, is a synthetic N-acylated pre-S1 derived polypeptide, developed in Germany, which efficiently inhibits HBV entry into hepatocytes in culture and in vivo [17Urban S. Bartenschlager R. Kubitz R. Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes.Gastroenterology. 2014; 147: 48-64Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 18Lempp F.A. Urban S. Inhibitors of hepatitis B virus attachment and entry.Intervirology. 2014; 57: 151-157Crossref PubMed Scopus (49) Google Scholar, 19Ni Y. Lempp F.A. Mehrle S. Nkongolo S. Kaufman C. Falth M. et al.Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes.Gastroenterology. 2014; 146: 1070-1083Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar]. Direct targeting and silencing of ccc HBV-DNA is only at an early developmental stage. However, blocking the NTCP receptor and HBV entry into hepatocytes, in combination with a potent nucleot(s)ide analogue, are expected to prevent HBV infection of naïve liver cells. Efforts have continued to define and improve new strategies for the immunologic control of persistent HBV infection. These include restoration of defective T-cell functions through inhibition of viral replication by nucleot(s)ide analogues or blocking of negative regulatory pathways, development of anti-apoptotic agents, targeted delivery of cytokines towards infected hepatocytes through TCR-like antibodies and the development of TLR antagonists [20Boni C. Laccabue D. Lampertico P. Giuberti T. Vigano M. Schivazappa S. et al.Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues.Gastroenterology. 2012; 143: e969Abstract Full Text Full Text PDF Scopus (279) Google Scholar, 21Rehermann B. Bertoletti A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections.Hepatology. 2014; PubMed Google Scholar, 22Bertoletti A. Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection.Postgrad Med J. 2013; 89: 294-304Crossref PubMed Scopus (34) Google Scholar]. The emerging world-wide epidemics of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are attracting significant attention from basic scientists, epidemiologists, nutritionists, clinicians, the pharmaceutical industry and the public alike [[8]Loomba R. Sanyal A.J. The global NAFLD epidemic.Nat Rev Gastroenterol Hepatol. 2013; 10: 686-690Crossref PubMed Scopus (1229) Google Scholar]. While no specific treatments are available yet, recent AASLD guidelines recommend weight loss, change in life-style to incorporate more physical activity, control of hyperglycemia and treatment of hyperlipidemia with statins [[23]Chalasani N. Younossi Z. Lavine J.E. Diehl A.M. Brunt E.M. Cusi K. et al.The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.Hepatology. 2012; 55: 2005-2023Crossref PubMed Scopus (2597) Google Scholar]. There has also been meaningful progress in developing more specific strategies to control the manifestations of NASH, including the metabolic syndrome and hyperlipidemia, as well as associated insulin resistance and diabetes mellitus. At the same time, clinical trials of specific agents to treat NASH have begun to show promise. For example, administration of vitamin E is reportedly superior to placebo for the treatment of NASH in adults without diabetes, whereas pioglitazone has no benefit over placebo [[24]Sanyal A.J. Chalasani N. Kowdley K.V. McCullough A. Diehl A.M. Bass N.M. et al.Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.N Engl J Med. 2010; 362: 1-5Crossref PubMed Scopus (2328) Google Scholar]. At present, there is partial consensus that vitamin E can be recommended in adults with advanced NASH (albeit not in children [[25]Lavine J.E. Schwimmer J.B. Van Natta M.L. Molleston J.P. Murray K.F. Rosenthal P. et al.Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.JAMA. 2011; 305: 1659-1668Crossref PubMed Scopus (827) Google Scholar]) who do not have diabetes or cirrhosis, although long-term follow-up data are still lacking. Several agents in preclinical studies and early clinical trials may offer new tools in the management of this clinical challenge. These include pentoxifylline, obeticholic acid (INT-747), a dual peroxisome proliferator-activated receptor agonist GFT505, S-adenosylmethionine and anti-lysyl oxidase monoclonal antibodies, among others [26Zein C.O. Yerian L.M. Gogate P. Lopez R. Kirwan J.P. Feldstein A.E. et al.Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial.Hepatology. 2011; 54: 1610-1619Crossref PubMed Scopus (278) Google Scholar, 27Pellicciari R. Gioiello A. Macchiarulo A. Thomas C. Rosatelli E. 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Hsu C.C. et al.Deactivation of hepatic stellate cells during liver fibrosis resolution in mice.Gastroenterology. 2012; 143: e1022Abstract Full Text Full Text PDF Scopus (360) Google Scholar, 30Kisseleva T. Brenner D.A. Inactivation of myofibroblasts during regression of liver fibrosis.Cell Cycle. 2013; 12: 381-382Crossref PubMed Scopus (34) Google Scholar], the control of stellate cell activation by epigenetic modulations that are transmissible from parent to offspring [[31]Zeybel M. Hardy T. Wong Y.K. Mathers J.C. Fox C.R. Gackowska A. et al.Multigenerational epigenetic adaptation of the hepatic wound-healing response.Nat Med. 2012; 18: 1592Crossref Scopus (6) Google Scholar], and the roles of adipokines, hormones and cytokines in driving stellate cell responses [32Ebrahimkhani M.R. Oakley F. Murphy L.B. Mann J. Moles A. 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Natural killer and natural killer T cells in liver fibrosis.Biochim Biophys Acta. 2013; 1832: 1061-1069Crossref PubMed Scopus (103) Google Scholar], and the importance of matrix cross-linking [[37]Barry-Hamilton V. Spangler R. Marshall D. McCauley S. Rodriguez H.M. Oyasu M. et al.Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.Nat Med. 2010; 16: 1009-1017Crossref PubMed Scopus (654) Google Scholar]. The effective treatment of HBV and HCV has unveiled the latent regenerative capacity of the liver, yielding unequivocal evidence that even cirrhosis may be reversible in many patients with these infections [38Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1284) Google Scholar, 39D'Ambrosio R. Aghemo A. Rumi M.G. Ronchi G. Donato M.F. Paradis V. et al.A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.Hepatology. 2012; 56: 532-543Crossref PubMed Scopus (321) Google Scholar]. Efforts to validate clinical tests that non-invasively monitor fibrosis have been spearheaded by the widespread acceptance of transient elastography as a primary screening tool for cirrhosis [[40]Roulot D. Costes J.L. Buyck J.F. Warzocha U. Gambier N. Czernichow S. et al.Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years.Gut. 2011; 60: 977-984Crossref PubMed Scopus (242) Google Scholar], while many newer technologies to quantify fibrosis non-invasively are actively being developed. With the rising tide of HCC, worldwide progress is desperately needed in preventing, detecting and curing this neoplasm, and our current state of treatment lags far behind that of many other solid tumours. Nonetheless, the approval of sorafenib as the first molecularly targeted therapy for HCC [[41]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (9271) Google Scholar] heralded a new era in managing HCC, but progress after sorafenib's success has been slow, with many failed trials of other agents left in its wake. Meanwhile, efforts continue to identify molecular tissue and circulating biomarkers for HCC. Such marker(s) are intended to identify subpopulations of patients with chronic liver disease at increased risk to develop HCC as well as to assess prognosis, predict recurrence and response to treatment in patients with already established tumours [42Pinato D.J. Pirisi M. Maslen L. Sharma R. Tissue biomarkers of prognostic significance in hepatocellular carcinoma.Adv Anat Pathol. 2014; 21: 270-284Crossref PubMed Scopus (15) Google Scholar, 43Lee S.C. Tan H.T. Chung M.C. Prognostic biomarkers for prediction of recurrence of hepatocellular carcinoma: current status and future prospects.World J Gastroenterol. 2014; 20: 3112-3124Crossref PubMed Scopus (77) Google Scholar]. Yet, while improvement in the imaging of early HCC has been steady, so far there have been no new validated circulating biomarkers approved for the detection of HCC. The American baseball player Yogi Berra euphemistically remarked, "It's tough to make predictions, especially about the future". Nonetheless, we predict a hopeful outlook for a future that promises an improved prognosis for patients with liver disease. With effective therapies for controlling or curing HBV and HCV, we will focus increasingly on public health measures to reduce the prevalence of advanced liver disease through widespread screening and early treatment, but huge pockets of the earth's population will be slow to benefit from these advances, leading to a continued increase in HCC incidence. However, appreciation for the marked heterogeneity of HCC foreshadows an era when treatment of this cancer will be personalized and more effective. Genetic liver diseases will eventually benefit from progress in induced pluripotent stem cell technologies that permit correction of single gene defects and liver cell repopulation, or population of liver support devices with patient-derived cells. For those with fulminant or alcoholic liver injury, hepato-protective and regenerative agents may reduce the reliance on liver transplantation by sustaining liver function through the critical early period when these illnesses are most life-threatening. Likewise, anti-fibrotic therapies are just around the corner, built upon a solid foundation of progress in basic and translational research in fibrosis. In contrast, developmental diseases and immune disorders, especially primary sclerosing cholangitis, have seen almost no progress in the clinical setting, but insights in understanding their molecular pathogenesis portend eventual success in their treatment, albeit not in the immediate future. With all these exciting prospects, there is little doubt that hepatology will remain vibrant in the coming years, and the Journal of Hepatology is certain to have plenty of exciting new advances on which to focus. Five years ago the newly appointed Editor of the Journal of Hepatology, Professor Didier Samuel approached us with an "offer we could not refuse". Specifically, we were asked to read all accepted papers for the Journal of Hepatology each month to identify a report(s) of special interest that merited the readers' attention, by writing a commentary for the new FOCUS section in each issue. Not realizing the magnitude of the task, we agreed enthusiastically. Although this enthusiasm has occasionally waned (most acutely when the monthly deadline approached), we consider ourselves privileged to have gained an early peek at many exciting developments in hepatology. What we had not anticipated is the rich educational experience this task has been, positioning us at the forefront of a discipline that is enjoying a golden era of progress. We thank Professor Samuel for his leadership and the Editorial Board members and readers for their trust in our perspectives. We are confident that the Journal of Hepatology will continue to thrive under the new Editor, Professor Rajiv Jalan and his leadership team, and we wish them every success. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.