Focus

Abstract

Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary teamJournal of HepatologyVol. 60Issue 1PreviewHepatocellular cancer (HCC) commonly complicates chronic liver disease and increases in incidence have been reported despite falling prevalences of viral hepatitis. Full-Text PDF We’ve hit the Iceberg – The threat of NASH-related HCC arrivesDuring the ∼12 years since the risk of hepatocellular carcinoma (HCC) first surfaced in patients with fatty liver disease and ‘cryptogenic’ cirrhosis, we have likened this rising incidence to ‘the tip of an iceberg’. A rigorous epidemiologic study from Newcastle in the United Kingdom by Dyson et al. in this month’s issue of the Journal convincingly demonstrates that we have now struck the iceberg itself – non-alcoholic steatohepatitis (NASH) is a dominant cause of HCC.Reports linking NASH to HCC first began to appear in 2001 in Japan, the US and Europe [1Bugianesi E. Leone N. Vanni E. Marchesini G. Brunello F. Carucci P. et al.Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1249) Google Scholar, 2Shimada M. Hashimoto E. Taniai M. Hasegawa K. Okuda H. Hayashi N. et al.Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.J Hepatol. 2002; 37: 154-160Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 3El-Serag H.B. Hepatocellular carcinoma: recent trends in the United States.Gastroenterology. 2004; 127: S27-S34Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar]. Concurrently, studies highlighted the generalized risk of cancer – including HCC – among patients who are overweight or obese [[4]Calle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5838) Google Scholar]. Many of the HCCs in these initial reports arose in patients with ‘cryptogenic’ cirrhosis, who bore historical or metabolic vestiges of metabolic syndrome but no longer had classic biopsy features of NASH, leading to the moniker of ‘burnt-out NASH’ for such individuals. More worrisome has been the recent increase of HCC in patients with NASH who do not yet have cirrhosis [5Paradis V. Zalinski S. Chelbi E. Guedj N. Degos F. Vilgrain V. et al.Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.Hepatology. 2009; 49: 851-859Crossref PubMed Scopus (426) Google Scholar, 6Ertle J. Dechene A. Sowa J.P. Penndorf V. Herzer K. Kaiser G. et al.Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.Int J Cancer. 2011; 128: 2436-2443Crossref PubMed Scopus (369) Google Scholar], raising uncertainty about the optimal screening strategy for early detection of HCC, which is essential to preserve the hope of curative therapies that include ablation, resection or transplantation.The Dyson study carefully characterizes the demographics of HCC from 2000 to 2010 in the region surrounding Newcastle-upon-Tyne in North East England. The effort benefited from a well-maintained regional cancer registry created by the National Health Service, and the formation of regional specialist ‘multidisciplinary meetings’ (MDM) to centralize care of complex diseases at centers of excellence, thereby ensuring that most patients (>75%) within the region were captured and received specialized care. During this interval, the regional mortality, which reflected the overall incidence of HCC rose 1.8 fold, mirroring trends in other epidemiologic studies of HCC. Not surprisingly, this rising incidence of HCC has been associated with a staggering prevalence in England of overweight, obesity or morbid obesity rising from 61% in 2000 of 65.5% in 2010.Most striking in the Dyson data was a >10 fold increase in HCC associated with NAFLD, accounting for 34.8% of all the cases in 2010, and making it the single most common underlying etiology. Case definitions for NAFLD were quite stringent, and required absence of other etiologies including alcohol, combined with evidence of fatty liver disease on biopsy or imaging. As in previous reports, HCC was detected in the absence of cirrhosis in some cases, but these patients now comprised 30% of the HCCs diagnosed, which reflects a very worrisome trend. Patients with NAFLD-associated HCC (with or without cirrhosis) were older than those with other etiologies and less likely to be detected by surveillance, yet their overall survival was the same, which was attributed in part to the lower prevalence of cirrhosis and advanced liver disease and a higher likelihood of incidental detection.The rising incidence of HCC in the absence of cirrhosis in NAFLD obligates us to seek mechanisms of carcinogenesis that are related to the pathogenesis of the underlying disease rather than to fibrosis alone. Initial reports further indicate that at least some HCCs arising in non-cirrhotic NASH have distinct histologic features [7Salomao M. Yu W.M. Brown Jr., R.S. Emond J.C. Lefkowitch J.H. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH.Am J Surg Pathol. 2010; 34: 1630-1636PubMed Google Scholar, 8Alexander J. Torbenson M. Wu T.T. Non-alcoholic fatty liver disease contributes to hepatocellular carcinoma in non-cirrhotic liver: A clinical and pathological study.J Gastroenterol Hepatol. 2013; 28: 848-854Crossref PubMed Scopus (84) Google Scholar]. While the picture is far from complete, animal models and other preclinical studies have borne remarkable progress in uncovering potential carcinogenic pathways directly related to NASH. Several candidate mechanisms have emerged, including altered nuclear receptor signaling (FXR, PPARα, and vitamin D receptor), dysbiosis from a perturbed microbiome and gut-liver axis, disturbed bile salt homeostasis, an altered microenvironment due to interactions between activated stellate cells and liver macrophages, and increased progenitor cell responses that could underlie stem cell-driven cancers.An altered intestinal microbiome is now implicated in the development of obesity, insulin resistance and NAFLD by enhancing caloric extraction from the diet and altering the bioavailability of essential nutrients such as choline [[9]Dumas M.E. Barton R.H. Toye A. Cloarec O. Blancher C. Rothwell A. et al.Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice.Proc Natl Acad Sci U S A. 2006; 103: 12511-12516Crossref PubMed Scopus (865) Google Scholar]. At the same time bacterial overgrowth may compromise gut barrier integrity and lead to activation of the inflammasome in hepatocytes, an intracellular protein scaffold, to enhance cellular injury and chronic inflammation driven by the innate immune response. Two elegant studies have now drawn stellate cells into this microbiome-driven inflammatory axis, by focusing on the contribution of the senescence associated secretory phenotype (SASP) in these cells. An altered gut microbiome associated with a high fat diet in mice leads to increased levels of deoxycholic acid, which accelerates SASP in stellate cells via the enterohepatic circulation; these findings have been identified in human NASH as well [[10]Yoshimoto S. Loo T.M. Atarashi K. Kanda H. Sato S. Oyadomari S. et al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.Nature. 2013; 499: 97-101Crossref PubMed Scopus (1319) Google Scholar]. In a separate study, loss of p53-dependent SASP leads to altered macrophage polarization in the liver’s microenvironment, favoring the predominance of M1 macrophages, which are generally tumor promoting [[11]Lujambio A. Akkari L. Simon J. Grace D. Tschaharganeh D.F. Bolden J.E. et al.Non-cell-autonomous tumor suppression by p53.Cell. 2013; 153: 449-460Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar]. Loss of p53 in stellate cells, while not yet documented in human liver, could therefore amplify a tumor-permissive microenvironment [[11]Lujambio A. Akkari L. Simon J. Grace D. Tschaharganeh D.F. Bolden J.E. et al.Non-cell-autonomous tumor suppression by p53.Cell. 2013; 153: 449-460Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar].Three nuclear receptors FXR, PPARα, and vitamin D receptor, and their cognate ligands are protective against HCC and may be suppressed as fatty liver disease progresses (reviewed in [[12]Lade A. Noon L.A. Friedman S.L. Contributions of metabolic dysregulation and inflammation to non-Alcoholic steatohepatitis, hepatic fibrosis, and cancer.Curr Opin Oncol. 2013; (in press)Google Scholar]). Other receptors also implicated in protection from HCC include PXR, CAR and the G protein coupled receptor Tgr5.NAFLD and NASH have been associated with a brisk progenitor cell response, which has been attributed in part to enhanced hedgehog signaling in regions of injury [[13]Bohinc B.N. Diehl A.M. Mechanisms of disease progression in NASH: new paradigms.Clin Liver Dis. 2012; 16: 549-565Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Hedgehog (Hh) activation has been implicated in tumor stroma crosstalk in other tumor models [[14]Yauch R.L. Gould S.E. Scales S.J. Tang T. Tian H. Ahn C.P. et al.A paracrine requirement for hedgehog signalling in cancer.Nature. 2008; 455: 406-410Crossref PubMed Scopus (808) Google Scholar] and could represent a potential therapeutic target because a Hh antagonist is already in use to treat basal cell carcinoma.In returning the clinical implications of the Dyson study, it remains to be determined whether the risk of HCC will parallel the rising incidence of NAFLD to the same extent in all ethnicities, since this study population was 97% Caucasian. Specifically, will genetic determinants of NAFLD that are more common in other ethnicities, for example a PNPLA3 polymorphism in Latinos [[15]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2139) Google Scholar], independently increase HCC risk, and will this necessitate targeted screening strategies for patients at high risk? Moreover, should the presence of significant steatosis in chronic liver disease from other etiologies also heighten screening since it still increases the risk of HCC? Regardless of the answers to these questions, with 30% of the HCCs arising in non-cirrhotic livers of patients with NAFLD in the Dyson study, a thorough reassessment of current screening strategies is warranted, because if we wait until cirrhosis is present to begin screening in NAFLD it will be too late for many patients.Both the authors of the Dyson study and the National Health Service should be commended for implementing and executing a disciplined system of disease tracking and centralization of care. In addition to facilitating the detection of an important epidemiologic trend, their efforts have reinforced the value of focusing expertise in regional centers to ensure that care and outcomes are optimized. This strategy is not only rational, but is likely to reduce costs and improve efficiencies [[16]Porter M.E. Lee T.H. The strategy that will fix health care.Harv Bus Rev. 2013; (<[http://hbr.org/2013/10/the-strategy-that-will-fix-health-care/ar/1]>)Google Scholar].To use a trite metaphor, just as the Titanic sailed from the United Kingdom only to encounter an iceberg, Dyson and colleagues from Newcastle have come upon an iceberg that is far more pervasive, and threatens even greater hardship than the cold North Atlantic did in 1912.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We’ve hit the Iceberg – The threat of NASH-related HCC arrivesDuring the ∼12 years since the risk of hepatocellular carcinoma (HCC) first surfaced in patients with fatty liver disease and ‘cryptogenic’ cirrhosis, we have likened this rising incidence to ‘the tip of an iceberg’. A rigorous epidemiologic study from Newcastle in the United Kingdom by Dyson et al. in this month’s issue of the Journal convincingly demonstrates that we have now struck the iceberg itself – non-alcoholic steatohepatitis (NASH) is a dominant cause of HCC.Reports linking NASH to HCC first began to appear in 2001 in Japan, the US and Europe [1Bugianesi E. Leone N. Vanni E. Marchesini G. Brunello F. Carucci P. et al.Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1249) Google Scholar, 2Shimada M. Hashimoto E. Taniai M. Hasegawa K. Okuda H. Hayashi N. et al.Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.J Hepatol. 2002; 37: 154-160Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 3El-Serag H.B. Hepatocellular carcinoma: recent trends in the United States.Gastroenterology. 2004; 127: S27-S34Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar]. Concurrently, studies highlighted the generalized risk of cancer – including HCC – among patients who are overweight or obese [[4]Calle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5838) Google Scholar]. Many of the HCCs in these initial reports arose in patients with ‘cryptogenic’ cirrhosis, who bore historical or metabolic vestiges of metabolic syndrome but no longer had classic biopsy features of NASH, leading to the moniker of ‘burnt-out NASH’ for such individuals. More worrisome has been the recent increase of HCC in patients with NASH who do not yet have cirrhosis [5Paradis V. Zalinski S. Chelbi E. Guedj N. Degos F. Vilgrain V. et al.Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.Hepatology. 2009; 49: 851-859Crossref PubMed Scopus (426) Google Scholar, 6Ertle J. Dechene A. Sowa J.P. Penndorf V. Herzer K. Kaiser G. et al.Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.Int J Cancer. 2011; 128: 2436-2443Crossref PubMed Scopus (369) Google Scholar], raising uncertainty about the optimal screening strategy for early detection of HCC, which is essential to preserve the hope of curative therapies that include ablation, resection or transplantation.The Dyson study carefully characterizes the demographics of HCC from 2000 to 2010 in the region surrounding Newcastle-upon-Tyne in North East England. The effort benefited from a well-maintained regional cancer registry created by the National Health Service, and the formation of regional specialist ‘multidisciplinary meetings’ (MDM) to centralize care of complex diseases at centers of excellence, thereby ensuring that most patients (>75%) within the region were captured and received specialized care. During this interval, the regional mortality, which reflected the overall incidence of HCC rose 1.8 fold, mirroring trends in other epidemiologic studies of HCC. Not surprisingly, this rising incidence of HCC has been associated with a staggering prevalence in England of overweight, obesity or morbid obesity rising from 61% in 2000 of 65.5% in 2010.Most striking in the Dyson data was a >10 fold increase in HCC associated with NAFLD, accounting for 34.8% of all the cases in 2010, and making it the single most common underlying etiology. Case definitions for NAFLD were quite stringent, and required absence of other etiologies including alcohol, combined with evidence of fatty liver disease on biopsy or imaging. As in previous reports, HCC was detected in the absence of cirrhosis in some cases, but these patients now comprised 30% of the HCCs diagnosed, which reflects a very worrisome trend. Patients with NAFLD-associated HCC (with or without cirrhosis) were older than those with other etiologies and less likely to be detected by surveillance, yet their overall survival was the same, which was attributed in part to the lower prevalence of cirrhosis and advanced liver disease and a higher likelihood of incidental detection.The rising incidence of HCC in the absence of cirrhosis in NAFLD obligates us to seek mechanisms of carcinogenesis that are related to the pathogenesis of the underlying disease rather than to fibrosis alone. Initial reports further indicate that at least some HCCs arising in non-cirrhotic NASH have distinct histologic features [7Salomao M. Yu W.M. Brown Jr., R.S. Emond J.C. Lefkowitch J.H. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH.Am J Surg Pathol. 2010; 34: 1630-1636PubMed Google Scholar, 8Alexander J. Torbenson M. Wu T.T. Non-alcoholic fatty liver disease contributes to hepatocellular carcinoma in non-cirrhotic liver: A clinical and pathological study.J Gastroenterol Hepatol. 2013; 28: 848-854Crossref PubMed Scopus (84) Google Scholar]. While the picture is far from complete, animal models and other preclinical studies have borne remarkable progress in uncovering potential carcinogenic pathways directly related to NASH. Several candidate mechanisms have emerged, including altered nuclear receptor signaling (FXR, PPARα, and vitamin D receptor), dysbiosis from a perturbed microbiome and gut-liver axis, disturbed bile salt homeostasis, an altered microenvironment due to interactions between activated stellate cells and liver macrophages, and increased progenitor cell responses that could underlie stem cell-driven cancers.An altered intestinal microbiome is now implicated in the development of obesity, insulin resistance and NAFLD by enhancing caloric extraction from the diet and altering the bioavailability of essential nutrients such as choline [[9]Dumas M.E. Barton R.H. Toye A. Cloarec O. Blancher C. Rothwell A. et al.Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice.Proc Natl Acad Sci U S A. 2006; 103: 12511-12516Crossref PubMed Scopus (865) Google Scholar]. At the same time bacterial overgrowth may compromise gut barrier integrity and lead to activation of the inflammasome in hepatocytes, an intracellular protein scaffold, to enhance cellular injury and chronic inflammation driven by the innate immune response. Two elegant studies have now drawn stellate cells into this microbiome-driven inflammatory axis, by focusing on the contribution of the senescence associated secretory phenotype (SASP) in these cells. An altered gut microbiome associated with a high fat diet in mice leads to increased levels of deoxycholic acid, which accelerates SASP in stellate cells via the enterohepatic circulation; these findings have been identified in human NASH as well [[10]Yoshimoto S. Loo T.M. Atarashi K. Kanda H. Sato S. Oyadomari S. et al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.Nature. 2013; 499: 97-101Crossref PubMed Scopus (1319) Google Scholar]. In a separate study, loss of p53-dependent SASP leads to altered macrophage polarization in the liver’s microenvironment, favoring the predominance of M1 macrophages, which are generally tumor promoting [[11]Lujambio A. Akkari L. Simon J. Grace D. Tschaharganeh D.F. Bolden J.E. et al.Non-cell-autonomous tumor suppression by p53.Cell. 2013; 153: 449-460Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar]. Loss of p53 in stellate cells, while not yet documented in human liver, could therefore amplify a tumor-permissive microenvironment [[11]Lujambio A. Akkari L. Simon J. Grace D. Tschaharganeh D.F. Bolden J.E. et al.Non-cell-autonomous tumor suppression by p53.Cell. 2013; 153: 449-460Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar].Three nuclear receptors FXR, PPARα, and vitamin D receptor, and their cognate ligands are protective against HCC and may be suppressed as fatty liver disease progresses (reviewed in [[12]Lade A. Noon L.A. Friedman S.L. Contributions of metabolic dysregulation and inflammation to non-Alcoholic steatohepatitis, hepatic fibrosis, and cancer.Curr Opin Oncol. 2013; (in press)Google Scholar]). Other receptors also implicated in protection from HCC include PXR, CAR and the G protein coupled receptor Tgr5.NAFLD and NASH have been associated with a brisk progenitor cell response, which has been attributed in part to enhanced hedgehog signaling in regions of injury [[13]Bohinc B.N. Diehl A.M. Mechanisms of disease progression in NASH: new paradigms.Clin Liver Dis. 2012; 16: 549-565Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Hedgehog (Hh) activation has been implicated in tumor stroma crosstalk in other tumor models [[14]Yauch R.L. Gould S.E. Scales S.J. Tang T. Tian H. Ahn C.P. et al.A paracrine requirement for hedgehog signalling in cancer.Nature. 2008; 455: 406-410Crossref PubMed Scopus (808) Google Scholar] and could represent a potential therapeutic target because a Hh antagonist is already in use to treat basal cell carcinoma.In returning the clinical implications of the Dyson study, it remains to be determined whether the risk of HCC will parallel the rising incidence of NAFLD to the same extent in all ethnicities, since this study population was 97% Caucasian. Specifically, will genetic determinants of NAFLD that are more common in other ethnicities, for example a PNPLA3 polymorphism in Latinos [[15]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2139) Google Scholar], independently increase HCC risk, and will this necessitate targeted screening strategies for patients at high risk? Moreover, should the presence of significant steatosis in chronic liver disease from other etiologies also heighten screening since it still increases the risk of HCC? Regardless of the answers to these questions, with 30% of the HCCs arising in non-cirrhotic livers of patients with NAFLD in the Dyson study, a thorough reassessment of current screening strategies is warranted, because if we wait until cirrhosis is present to begin screening in NAFLD it will be too late for many patients.Both the authors of the Dyson study and the National Health Service should be commended for implementing and executing a disciplined system of disease tracking and centralization of care. In addition to facilitating the detection of an important epidemiologic trend, their efforts have reinforced the value of focusing expertise in regional centers to ensure that care and outcomes are optimized. This strategy is not only rational, but is likely to reduce costs and improve efficiencies [[16]Porter M.E. Lee T.H. The strategy that will fix health care.Harv Bus Rev. 2013; (<[http://hbr.org/2013/10/the-strategy-that-will-fix-health-care/ar/1]>)Google Scholar].To use a trite metaphor, just as the Titanic sailed from the United Kingdom only to encounter an iceberg, Dyson and colleagues from Newcastle have come upon an iceberg that is far more pervasive, and threatens even greater hardship than the cold North Atlantic did in 1912. During the ∼12 years since the risk of hepatocellular carcinoma (HCC) first surfaced in patients with fatty liver disease and ‘cryptogenic’ cirrhosis, we have likened this rising incidence to ‘the tip of an iceberg’. A rigorous epidemiologic study from Newcastle in the United Kingdom by Dyson et al. in this month’s issue of the Journal convincingly demonstrates that we have now struck the iceberg itself – non-alcoholic steatohepatitis (NASH) is a dominant cause of HCC. Reports linking NASH to HCC first began to appear in 2001 in Japan, the US and Europe [1Bugianesi E. Leone N. Vanni E. Marchesini G. Brunello F. Carucci P. et al.Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.Gastroenterology. 2002; 123: 134-140Abstract Full Text Full Text PDF PubMed Scopus (1249) Google Scholar, 2Shimada M. Hashimoto E. Taniai M. Hasegawa K. Okuda H. Hayashi N. et al.Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.J Hepatol. 2002; 37: 154-160Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 3El-Serag H.B. Hepatocellular carcinoma: recent trends in the United States.Gastroenterology. 2004; 127: S27-S34Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar]. Concurrently, studies highlighted the generalized risk of cancer – including HCC – among patients who are overweight or obese [[4]Calle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5838) Google Scholar]. Many of the HCCs in these initial reports arose in patients with ‘cryptogenic’ cirrhosis, who bore historical or metabolic vestiges of metabolic syndrome but no longer had classic biopsy features of NASH, leading to the moniker of ‘burnt-out NASH’ for such individuals. More worrisome has been the recent increase of HCC in patients with NASH who do not yet have cirrhosis [5Paradis V. Zalinski S. Chelbi E. Guedj N. Degos F. Vilgrain V. et al.Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.Hepatology. 2009; 49: 851-859Crossref PubMed Scopus (426) Google Scholar, 6Ertle J. Dechene A. Sowa J.P. Penndorf V. Herzer K. Kaiser G. et al.Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.Int J Cancer. 2011; 128: 2436-2443Crossref PubMed Scopus (369) Google Scholar], raising uncertainty about the optimal screening strategy for early detection of HCC, which is essential to preserve the hope of curative therapies that include ablation, resection or transplantation. The Dyson study carefully characterizes the demographics of HCC from 2000 to 2010 in the region surrounding Newcastle-upon-Tyne in North East England. The effort benefited from a well-maintained regional cancer registry created by the National Health Service, and the formation of regional specialist ‘multidisciplinary meetings’ (MDM) to centralize care of complex diseases at centers of excellence, thereby ensuring that most patients (>75%) within the region were captured and received specialized care. During this interval, the regional mortality, which reflected the overall incidence of HCC rose 1.8 fold, mirroring trends in other epidemiologic studies of HCC. Not surprisingly, this rising incidence of HCC has been associated with a staggering prevalence in England of overweight, obesity or morbid obesity rising from 61% in 2000 of 65.5% in 2010. Most striking in the Dyson data was a >10 fold increase in HCC associated with NAFLD, accounting for 34.8% of all the cases in 2010, and making it the single most common underlying etiology. Case definitions for NAFLD were quite stringent, and required absence of other etiologies including alcohol, combined with evidence of fatty liver disease on biopsy or imaging. As in previous reports, HCC was detected in the absence of cirrhosis in some cases, but these patients now comprised 30% of the HCCs diagnosed, which reflects a very worrisome trend. Patients with NAFLD-associated HCC (with or without cirrhosis) were older than those with other etiologies and less likely to be detected by surveillance, yet their overall survival was the same, which was attributed in part to the lower prevalence of cirrhosis and advanced liver disease and a higher likelihood of incidental detection. The rising incidence of HCC in the absence of cirrhosis in NAFLD obligates us to seek mechanisms of carcinogenesis that are related to the pathogenesis of the underlying disease rather than to fibrosis alone. Initial reports further indicate that at least some HCCs arising in non-cirrhotic NASH have distinct histologic features [7Salomao M. Yu W.M. Brown Jr., R.S. Emond J.C. Lefkowitch J.H. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH.Am J Surg Pathol. 2010; 34: 1630-1636PubMed Google Scholar, 8Alexander J. Torbenson M. Wu T.T. Non-alcoholic fatty liver disease contributes to hepatocellular carcinoma in non-cirrhotic liver: A clinical and pathological study.J Gastroenterol Hepatol. 2013; 28: 848-854Crossref PubMed Scopus (84) Google Scholar]. While the picture is far from complete, animal models and other preclinical studies have borne remarkable progress in uncovering potential carcinogenic pathways directly related to NASH. Several candidate mechanisms have emerged, including altered nuclear receptor signaling (FXR, PPARα, and vitamin D receptor), dysbiosis from a perturbed microbiome and gut-liver axis, disturbed bile salt homeostasis, an altered microenvironment due to interactions between activated stellate cells and liver macrophages, and increased progenitor cell responses that could underlie stem cell-driven cancers. An altered intestinal microbiome is now implicated in the development of obesity, insulin resistance and NAFLD by enhancing caloric extraction from the diet and altering the bioavailability of essential nutrients such as choline [[9]Dumas M.E. Barton R.H. Toye A. Cloarec O. Blancher C. Rothwell A. et al.Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice.Proc Natl Acad Sci U S A. 2006; 103: 12511-12516Crossref PubMed Scopus (865) Google Scholar]. At the same time bacterial overgrowth may compromise gut barrier integrity and lead to activation of the inflammasome in hepatocytes, an intracellular protein scaffold, to enhance cellular injury and chronic inflammation driven by the innate immune response. Two elegant studies have now drawn stellate cells into this microbiome-driven inflammatory axis, by focusing on the contribution of the senescence associated secretory phenotype (SASP) in these cells. An altered gut microbiome associated with a high fat diet in mice leads to increased levels of deoxycholic acid, which accelerates SASP in stellate cells via the enterohepatic circulation; these findings have been identified in human NASH as well [[10]Yoshimoto S. Loo T.M. Atarashi K. Kanda H. Sato S. Oyadomari S. et al.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.Nature. 2013; 499: 97-101Crossref PubMed Scopus (1319) Google Scholar]. In a separate study, loss of p53-dependent SASP leads to altered macrophage polarization in the liver’s microenvironment, favoring the predominance of M1 macrophages, which are generally tumor promoting [[11]Lujambio A. Akkari L. Simon J. Grace D. Tschaharganeh D.F. Bolden J.E. et al.Non-cell-autonomous tumor suppression by p53.Cell. 2013; 153: 449-460Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar]. Loss of p53 in stellate cells, while not yet documented in human liver, could therefore amplify a tumor-permissive microenvironment [[11]Lujambio A. Akkari L. Simon J. Grace D. Tschaharganeh D.F. Bolden J.E. et al.Non-cell-autonomous tumor suppression by p53.Cell. 2013; 153: 449-460Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar]. Three nuclear receptors FXR, PPARα, and vitamin D receptor, and their cognate ligands are protective against HCC and may be suppressed as fatty liver disease progresses (reviewed in [[12]Lade A. Noon L.A. Friedman S.L. Contributions of metabolic dysregulation and inflammation to non-Alcoholic steatohepatitis, hepatic fibrosis, and cancer.Curr Opin Oncol. 2013; (in press)Google Scholar]). Other receptors also implicated in protection from HCC include PXR, CAR and the G protein coupled receptor Tgr5. NAFLD and NASH have been associated with a brisk progenitor cell response, which has been attributed in part to enhanced hedgehog signaling in regions of injury [[13]Bohinc B.N. Diehl A.M. Mechanisms of disease progression in NASH: new paradigms.Clin Liver Dis. 2012; 16: 549-565Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Hedgehog (Hh) activation has been implicated in tumor stroma crosstalk in other tumor models [[14]Yauch R.L. Gould S.E. Scales S.J. Tang T. Tian H. Ahn C.P. et al.A paracrine requirement for hedgehog signalling in cancer.Nature. 2008; 455: 406-410Crossref PubMed Scopus (808) Google Scholar] and could represent a potential therapeutic target because a Hh antagonist is already in use to treat basal cell carcinoma. In returning the clinical implications of the Dyson study, it remains to be determined whether the risk of HCC will parallel the rising incidence of NAFLD to the same extent in all ethnicities, since this study population was 97% Caucasian. Specifically, will genetic determinants of NAFLD that are more common in other ethnicities, for example a PNPLA3 polymorphism in Latinos [[15]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2139) Google Scholar], independently increase HCC risk, and will this necessitate targeted screening strategies for patients at high risk? Moreover, should the presence of significant steatosis in chronic liver disease from other etiologies also heighten screening since it still increases the risk of HCC? Regardless of the answers to these questions, with 30% of the HCCs arising in non-cirrhotic livers of patients with NAFLD in the Dyson study, a thorough reassessment of current screening strategies is warranted, because if we wait until cirrhosis is present to begin screening in NAFLD it will be too late for many patients. Both the authors of the Dyson study and the National Health Service should be commended for implementing and executing a disciplined system of disease tracking and centralization of care. In addition to facilitating the detection of an important epidemiologic trend, their efforts have reinforced the value of focusing expertise in regional centers to ensure that care and outcomes are optimized. This strategy is not only rational, but is likely to reduce costs and improve efficiencies [[16]Porter M.E. Lee T.H. The strategy that will fix health care.Harv Bus Rev. 2013; (<[http://hbr.org/2013/10/the-strategy-that-will-fix-health-care/ar/1]>)Google Scholar]. To use a trite metaphor, just as the Titanic sailed from the United Kingdom only to encounter an iceberg, Dyson and colleagues from Newcastle have come upon an iceberg that is far more pervasive, and threatens even greater hardship than the cold North Atlantic did in 1912. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.