Risk Factors and Preventive Measures for Hepatocellular carcinoma (HCC) 울산의대울산대병원소화기내과박능화

Risk Factors and Preventive Measures for Hepatocellular carcinoma (HCC) 울산의대울산대병원소화기내과박능화

Risk factors for HCC development (I) Environmental factors Infectious HBV HCV HDV Alimentary Alcohol Diet High calory intake Toxic Aflatoxin B1 Steroids Anabolics Chronic inflammation HCC Liver cirrhosis Host/genetic factors General Gender Ethnlclty Metabolic defect Hemochromatosis NAFLD Obesity Alpha-1-antitrypsin deficiency Autoimmune hepatitis Cryptogenic cirrhosis Dig Dis 2009;27:80 92

Natural history of chronic liver disease * Incidence per 100 person years

Risk factors for HCC development (II) Dig Dis 2009;27:80 92

The etiology of HCC in Korea HBV HCV Alcohol Autoimmune PBC Wilson Cryptogenic Miscellaneous 14.5% 0.4% 66.6% 9.4% 0.2% 0.2% 4.2% 4.5% ; > 80% NAFLD 환자 20,964 명 5 10 15 60 (%) Lee CH, 2001

Annual incidence rates of HCC according to underlying disease Dig Dis 2009;27:80 92

Chronic hepatitis B EM Schematic structure The story began back in 1965... Genome and proteins when Baruch Blumberg discovered the Australia antigen in serum

Natural history of hepatitis B recovery perinatal infection childhood infection adult infection recovery 10~90% 30% < 5% Chronic infection Mild/moderate/severe Chronic hepatitis ~ 1 * Inactive carrier state 2~10* ~ 4 * Cirrhosis 2~8* ~ 0.1 * ~ 3 * decompensation Death/transplantation HCC * Incidence per 100 person years

Current concepts of HBV-associated hepatocarcinognesis

Association of HBV with HCC (I) High prevalence of chronic HBV infection = high incidence and mortality of HCC

Risk factors associated with HCC Association of HBV with HCC (II) In an 8-year follow-up of the 90,000-Person prospective cohort study in Haimen City, China Cancer Epidemiol Biomarkers Prev 2002;11:369-376

Factors in increasing risk of HBV-HCC Viral factors: HBV replication, genotype, longer duration of infection, co-infection with HCV, HIV or HDV Clinical factor: cirrhosis Host factors: male, older age, Asian, family Hx of HCC Environmental factors: aflatoxin B1, alcohol, smoking

The incidence rates of HCC in subjects with chronic HBV infection Journal of Hepatology 48 (2008) 335 352

Virus factors for progression of HBV-HCC HBeAg positivity and the risk of HCC NEJM 2002;347:168-74

Association between viral replication and HBV-HCC REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer): prospective, multicenter, observational cohort study 1991-1992: 7 Taiwanese townships Individuals aged 30-65 years eligible (N = 89,293) HCC-free individuals enrolled (n = 23,820) Excluded if cirrhotic within 6 months Cirrhosis Analysis (n = 3774) 2004: 42,115 PYs follow-up 395 cirrhotic patients (10.5%) Gastroenterology 2006;130:678-686 HCC Analysis HBsAg+ with BL HBV DNA (n = 3851) 2004: 43,993 PYs follow-up 176 HCC patients (4.5%) JAMA 2006;295:65-73

REVEAL: Baseline HBV DNA and Liver Disease Progression at natural history cohort REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer): prospective, multicenter, observational cohort study 1991 2004 HBV DNA HCC : LC: JAMA 2006;295:65-73 Gastroenterology 2006; 130:678-686 HCC: Gastroenterology 2011; 142:1240-1248 ALT

Risk factors associated with HCC JAMA 2006;295:65-73

간세포암종누적발생률 (%) Cumulative incidence of HCC by serum HBV DNA at entry 16 14 Multivariate-adjusted Relative Risk 환자수 = 3,653 (*HBeAg negative N=3,088) Baseline HBV DNA 10 6 (copies/ml) RR* 6.6 12 10 5 <10 6 6.1 10 8 6 p<0.001 4 10 4 <10 5 2.3 2 0 300 <10 4 <300 1.1 1.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 추적년수 *Multiple Cox Proportional Hazard Regression Analyses JAMA 2006;295:65-73

HCC by serum HBV DNA levels at entry and at last f/u JAMA 2006;295:65-73

Nine groups of long-term changes in HBV DNA over follow-up Gastroenterology 2011;142:1240-1248

Risk factors of HCC for group of long-term changes of HBV DNA, and ALT Gastroenterology 2011;142:1240-1248

REVEAL: Summary of Key Conclusions Higher HBV DNA levels at baseline associated with an increased risk of cirrhosis and HCC. Continued viremia associated with an increased risk for HCC. For participants with the same HBV DNA levels at enrollment, greater decreases in serum HBV DNA levels during follow-up were associated with lower risk of HCC.

Associations between HBV genotype and mutants and the risk of HCC J Natl Cancer Inst 2008;100: 1134 1143.

Carriers of inactive HBV are still at risk for HCC GASTROENTEROLOGY 2010;138:1747 1754

Association between occult HBV infection and the risk of HCC: a meta-analysis (II) Comparing HCC risk in occult HBV and HCV-co-infected cases with that in those with HCV mono-infection Liver Int 2012; 32:231-240

Association between occult HBV infection and the risk of HCC (I) The risk of HCC risk individuals with occult HBV infection with that in those without infection Liver Int 2012; 32:231-240

Family History of Liver Cancer and HCC HEPATOLOGY 2012;55:1416-1425

The combined effect of HBV and HCV infections in causing HCC British Journal of Cancer 2005; 92: 607 612

Cigarette smoking, alcohol drinking, Hepatitis B, and risk for HCC in Korea J Natl Cancer Inst 2004;96:1851 5]

Prevention of HCC in patients with HBV infection Primary Prevention of HCC: vaccination, including passive immunization, particularly of infants whose mothers have HBeAg Secondary Prevention of HCC: 1) control of viral replication with appropriate antiviral therapy 2) detect HCC at an early stage : periodic surveillance using ultrasonography and serum AFP Tertiary Prevention of HCC : to prevent tumor recurrence after resection J Natl Cancer Inst 2004;96:1851 5]

Hepatitis B vaccination program: historic overview in Korea 1982 First home-made plasma-derived hepatitis B vaccine in Korea 1983 HBV vaccine launched in Korea 1985 Newborn infants whose mothers were HBsAg carriers in Korea 1988 HBV vaccination for school age children in Korea 1991 Listed on vaccination guideline for children in Korea 1995 Universal HBV vaccination for infants in Korea 2002 HBV vertical transmission prevention program

Changes in HBsAg positivity among children for 25 years HBsAg positivity (%) % 10 9 Primary prevention (I) 8 8.0 7 6 5 6.21 5.27 4 3.9 3 1983 2 1 0 1983 0.9 1985 0.2 2007 1990 1996 1.3 1999 0.44 2006 <10 10~19 Age(years)

Changes in HBsAg positivity by age group for 25 years HBsAg positivity (%) Primary prevention (I) % Kor J Gastroenterol 1999;33:642 652 A National Health and Nutrition Survey (NHNS)

Changes in HBsAg positivity by age group for 25 years Primary prevention (I)

Universal HBV vaccination in Taiwan and the incidence of HCC in children Primary prevention (II) N Engl J Med 1997;336:1855-9

Hepatitis B vaccination and risk of HCC among male adults Primary prevention (I) Serologlcal profiles and vacclnation status HBsAg(-) and Anti-HBs(-) Incidence rate of HCC Relative risk of HCC (95% CI) Non-vaccinee 13.7 1.0 (The unvaccinated and uninfected group) Vaccinee 8.0 0.58 (The vaccinated group) (0.31-1.09) HBsAg(-) and Anti-HBs(+) 4.4 0.34 (The unvaccinated and infected group) (0.19-0.60) HBsAg(+) and Anti-HBs(-) 215.9 18.1 (The chronically infected group) (14.2-22.9) International Journal of Epidemiology 1998:27:315-319

Decreased Incidence of HCC in Hepatitis B Vaccinees: A 20-Year Follow-up Study Primary prevention (II) J Natl Cancer Inst 2009;101:1348 1355

Management of HBV related liver disease Secondary Prevention of HCC (I) 30.8% 19.6% 17.0% 13.3% 4.5% 7.0% 3 Cumulative appearance rates of hepatocellular carcinoma (HCC) in the interferon (IFN) therapy group and the untreated group (product-limit method). Cancer 1998;82:827-835

Effects of IFN on development of HCC groups: a meta-analysis of randomized controlled trials (I) In HBV-infected patients Aliment Pharmacol Ther 2008;28: 1067 1077

Effects of IFN on development of HCC groups: a meta-analysis of randomized controlled trials (II) In HBV-infected patients Journal of Viral Hepatitis 2009; 16: 265 271

Effects of Lamivudine on development of HCC The Cirrhosis and Lamivudine Monotherapy (CALM) study 16(7.8%) 17(3.4%) NEJM 2004;351:1521-1531

Cumulative incidence of HCC during Lamivudine Therapy 656 HBe Ag(-) (MVR, maintained virological response ; VBT, virological breakthrough) Hepatology 2004;40:883-891

Cumulative rates of development of cirrhosis or HCC 142 HBe Ag(+) for long-term LAM (mean 89.9 months) 124 HBe Ag(+) control Antivir Ther 2007;12:1295-1303

CHB related HCC with Lamivudine J Hepatology 2010;53:118-125

HBe Ag(-) liver cirrhosis with Lamivudine in Greece Gut 2011;60:1109-1116

The incidence of LTCs in patients without drugresistance between NA treatment and no treatment: a meta-analysis Virology J 2011;8:72-83

The incidence of LTCs in patients with drugresistance between NA treatment and no treatment: a meta-analysis Virology J 2011;8:72-83

The incidence of LTCs between patients with and without drug-resistance among the NA treatment groups: a meta-analysis Virology J 2011;8:72-83

The incidence of LTCs in HBeAg-negative patients between NA treatment and no treatment: a metaanalysis Virology J 2011;8:72-83

The incidence of LTCs in HBeAg-positive patients between NA treatment and no treatment: a metaanalysis Virology J 2011;8:72-83

The incidence of LTCs in patients with preexisting cirrhosis between NA treatment and no treatment: a meta-analysis Virology J 2011;8:72-83

The incidence of LTCs in patients without preexisting cirrhosis between NA treatment and no treatment: a meta-analysis Virology J 2011;8:72-83

The incidence of LTCs between patients with and without pre-existing compensated cirrhosis among the NA treatment groups: a meta-analysis Virology J 2011;8:72-83

Management of HBV related liver disease Goal in HBV related liver disease : suppress HBV replication reduce hepatitis activity prevent hepatic decompensation prevent HCC development prolong survival

The secondary prevention of HCC is detecting HCC at an earlier stage Secondary Prevention of HCC (II) J Cancer Res Clin Oncol 2004; 130: 417 422

Tertiary Prevention of HCC in Patients with HBV Infection Cumulative HCC recurrence related to the initial viral load at the time of tumor resection Am J Gastroenterol 2008;103:1663-73

Tertiary Prevention of HCC in Patients with HBV Infection Persistent hepatitis B viral replication increases the recurrence of HCC after curative resection British Journal of Surgery 2009; 96: 975 981

Tertiary Prevention of HCC in Patients with HBV Infection Interferon after curative treatment of HCC in patients with viral hepatitis British Journal of Surgery 2009; 96: 975 981

Tertiary Prevention of HCC in Patients with HBV Infection Interferon after curative treatment of HCC in patients with viral hepatitis British Journal of Surgery 2009; 96: 975 981

HCV-induced hepatocarcinogenesis Journal of Hepatology 2009; 51: 810 820

Association HCV infection and the risk of HCC Host and environmental factors in determining progression of HCC: older age at diagnosis, duration of infection, male sex, severity of liver disease at presentation, co-morbidities such as porphyria cutanea tarda, heavy alcohol intake, diabetes mellitus, steatosis, obesity and co-infections, especially with HBV. Int J Cancer 2004; 112:1075 1080

Effects of IFN on development of HCC groups: a meta-analysis of randomized controlled trials In HCV-infected patients Int J Cancer 2011;129:1254-1264

Proposed model of liver carcinogenesis by alcohol intake CYP2E1 ROS Lipid peroxidation MDA 4HNE Alcohol (CH 3 CH 2 OH) Acetaldehyde (CH 3 CHO) Protein + DNA Adducts ADH Acetate (CH 3 COO) Krebs Cycle ALDH Transformation, Altered cell signaling. Foci Development? HCC? Am J Epidemiol 2002;155:323 331

Effects of alcohol on development and progression of HCC Am J Epidemiol 2002;155:323 31.

Effects of alcohol on development and progression of HCC Am J Epidemiol 2002;155:323 31

The association between obesity and HCC British Journal of Cancer 2007; 97: 1005 1008

The Association between Diabetes and HCC Int J Cancer 2012; 130:1639 1648

Fasting Serum Glucose Level and Cancer Risk in Korean Men and Women JAMA. 2005;293:194-202

Expanding the Natural History of Nonalcoholic Steatohepatitis: From Cryptogenic Cirrhosis to HCC GASTROENTEROLOGY 2002;123:134 140

Coffee consumption and risk of HCC: A Meta-Analysis The mechanisms by which coffee reduces the risk of liver disease: Caffeine, cafestol and ditrepens - similar to enzymes involved in carcinogen detoxification. HEPATOLOGY 2007;46:430-435

Coffee consumption and risk of HCC: A Meta-Analysis RRs of HCC for coffee drinkers versus non-drinkers among carriers of HBV and/or HCV or other chronic liver diseases HEPATOLOGY 2007;46:430-435

Other risk factors for HCC Autoimmune hepatitis Hemochromatosis α1 -Antitrypsin Deficiency Wison s disease Alagille syndrome, Hypercitrullinemia, Glycogenosis type 1 Oral contraceptives, Anabolic steroids Tobacco Smoking Aflatoxin B1 Diet and Toxic Agents :HCC risk - linoleic acid (OR 0.35, 95% CI 0.18 0.69) - b-carotene (OR 0.48, 95% CI 0.24 0.93) - high intakes of milk and yoghurt, eggs, white meats and fruit - diet containing tributyrin Host Genetic Factors - polymorphism

Prevention of HCC HBV vaccination Perinatal hepatitis B immunoglobulin Safe sex Treatment Of hepatitis C Primary prevention (Prevention of viral hepatitis) Prevent Needle sharing Antiviral therapy for HBV Avoid excessive alcohol Secondary prevention (Prevention of HCC in susceptible patients Antiviral therapy forhcv Safe food storage to prevent aflatoxin Regular HCC surveillance by ultrasound and/ or alpha fetoprotein Early HCC detection Early curative treatment of HCC