| セッション情報 |
International Forum 2(Liver) 1.Pathogenesis and Epidemiology
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| タイトル |
IF2-1-III (Keynote lecture) Epidemiology of HCC
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| 演者 |
Stephen H.Caldwell（HepatologyUniversity of VirginiaCharlottesvilleUSA） |
| 共同演者 |
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| 抄録 |
The epidemiology of hepatocellular cancer can be viewed from a number of relevant perspectives fromthe overall public health impact to variatibn in underlying disease to variation in HCC biology which islikely to become increasingly important wnh the emergence of new therapeutics．Overoiew ： By annual incidencehepatocellutar cancer （HCC） is the 5th most common cancer worldwideand the 3’d leading cause of cancer death． L2’3 From cancer registriesit is estimated that there were564000 new cases of HCC in the year 2000 accounting for 7．5% of cancer in men and 3．5% of cancer inwomen．‘ Among the common threads emerging from these studies are that men are usually twice ascommonly af且icted aS females and that viral hepatitis plays a role in many cases．耳oweverthere is widegeographic variation such that certain regions in Asia and Africa have 40 fold more cases based on theage-adjusted incidence rate than other regions of the world． On the other handthe incidence of HCC hasbeen rising worldwide with particularly steep increases in Japan and many western countries includingthe US．5’6 ln Japanage-adjusted death rates attributed to Primary Liver Cancer began to increase in 1975and have been attributed mostly to increased hepatitis C． ln the USthe sharp increase in incidence overthe past 25 years has been associated with an increasing associated mortality from 1．54 to 2．58 per 100000between 1980 and 1990．7’8 Alsoin the USsubstantial variation has been noted among different ethnicgroups with the highest rates among AsiansHispanics and African Americans compared to Euro-Ameri-cans．9’iO Consistent with these overall epidemiological trendswe have seen a 200% increase in annualcases of HCC over the past 5 years at UVA．Li-獅求@to Viral Hepatitis ： Bosch et al have estimated that viral hepatitis plays a role in up to 80% of allHCC with roughly 2／3 related to HBV and 1／3 to HCV．4 To a large extentthe greater impact of且BV re-flect populations in which vertical transmission is common resulting in early age exposure and endemicHBV and subsequently of HCC． Past exposure （positive anti-HBV markers） increases the risk of HCC withor without surface antigen and in the presence or absence of cirrhosis．ii Howeverthe recent explosive in-crease in HCC in various regions of the world is more likely attributable to actively replicating HCV andassociated cirrhosis and possibly to the increasing prevalence of NAFLD as discussed below． As pointedout by LB Seeff in a summary statement on the impact of HCCthe natural history of HCV indicates thatthe worse is yet to come．i2 Fattovich dembnstrated that 1-4% of HCV-related cirrhosis will develop HCCper year in an extended natural history study．i3 Given the high prevalence of HCV and the fact that 20-30% of infected patients will develop cirrhosisit is likely that the peak incidence of HCC is indeed yet tocome．Link to Cirrhosis ： Cirrhosis is present in about 80-90% of HCC patients and constitutes the largest sin-gle risk factor．141ts presence impacts survival and strongly in且uences treatment decisions and clearly ne-cessitates the increasingly common multidisciplinary approach to HCC management．i5 The risk of devel-oping HCC among cirrhosis patients varies with the underlying disease and regionally among dis6ase sub-sets． The highest 5 year cumulative risk is seen with且Cv cirrhosis（30％in Japan versus 17％in theWest） followed by hemochromatosis （21%）HBV cirrhosis （15% in Asia and 10% in the West）alcoholiccirrhosis （8%）and biliary cirrhosis （4%）．i6 ln additional to regional variationsfactors which influence therisk include older agemale sexthe severity of cirrhosisco-infectionconcomitant alcohol use andinsome regionsaflatoxin exposureUnderstanding of the relationship to steatosis is emerging and is dis-cussed further below．Link to NAFLD ： Obesity is now widely recognized as a significant risk of cancer mortality in general andconstitutes a significant risk factor for hepatocellular cancer in particular．iZ’8’igpa Although ethnic variationexistsabout 90% of people with obesity （BMI 〉 30） in Western countries have fatty liver ranging fromsimple steatosis to more severe forms of NASH including cirrhosis．2i Similar epidemiological data supportsan increased risk of hepatocellular carcinoma among diabetic patients．22232‘ ThusHCC shares in commonthe two maj or risk factors found in NAFLD-obesity and diabetes．za260r The relationship likely reflects theeffects of concomitant steatosisThis has been most studied in Western countries but a link is also sus-pected in Asian countries．28 A number of detailed case studies （including several from Japan and nicelysummarized in the review paper of Bugianesi） have now documented the development of HCC in NASHusually but not invariably associated with antecedent progression to cirrhosis． lndeedin some of thesecase studiesthe development of HCC is noted only after progression of NASH to the late stage of crypto-genic cirrhosis．29 This association is also supported by epidemiological data． ln one series of 105 consecu-tive HCC patients51% had underlying cirrhosis due to hepatitis C and 29% had cryptogenic cirrhosisamong which 50% had either histological or epidemiological factors to suggest antecedent NASH．so Thusat a minimum NAFLD appears to account for 13% of HCC． Howeverbecause NASH and hepatitis C fre-quently co-exist and because steatosis is a risk factor for the development of HCC in patients with chronicHCV infectionthe overall effect of underlying fatty liver disease in the development of HCC may be evengreater still．3L32’33 ln a recent study from Yamaguchisteatosis was found to be an independent predictor ofpost-operative HCC recurrence in HCV-associated HCC （RR ＝ 3．31CI ＝ 1．49-7．41p＝0.003）．3‘ Amongpatients with Grade 2 steatosisthe 5 year recurrence was 100% versus 60% in those with grade O． Themechanisms remain to be resolved but the pathophysiological components of NASH include oval cell pro-liferationlipid peroxidation and increased growth factors （such as insulin and TGF） which recapitulate thecomponents of cancer development （initiationpromotion and progression）． 35’se’3’38’39 Moreoverchanges infat metabolism including expression of adipocyte-like gene pathways appears to play a role in both he-patic regeneration and neoplastic transformation．oo’‘’Epidemiology of Cancer Biological Variables ： With the recent emergence of new biologicals such as themulti-kinase inhibitor sorafenibthe importance of understanding cancer biology is taking on greater em-phasis because tumor biology is highly likely to influence the response or non-response to various inter-ventions． Thusgenetic and associated phenotypic variation in HCC is likely to emerge as important deci-sion points in determining optimal therapy．‘2 For exampleit is estimated that about 28-50 % of HCC carrymarkers（anti-CK 19）for origin in the hepatic stem cells．43 Moreoverthis variety appears to behave differ-ently （more aggressively） after surgical intervention．“ ln additionthe epidemiology of host genetic fac-torswhich are also likely to influence HCC behavioris emerging． For exampleepidermal growth factor（EGF） polymorphisms have recently been linked to the risk of developing HCC in patients with cirrhosis．‘5Much work is needed to define the prevalence of these variablesthe best means to detect them （pheno-typic correlates） and their influence on anti-cancer therapy． |
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