Hepatocellular Carcinoma in Patients with Non-alcoholic Fatty Liver Disease IM R3 전유경 / Pf. 이동현

Worldwide estimated prevalence of NAFLD Younossi Z, et al. Nat Rev Gastroenterol Hepatol 2018.

Prevalence of NAFLD in Asia Loomba R, et al. Nat Rev Gastroenterol Hepatol 2013.

Natural history of NAFLD Fierbinteanu-Braticevici C, et al. Cell Biol Toxicol 2017.

Systematic review (1) Clinical-based cohort의 경우 대부분 500명 미만의 환자를 대상 Population-based cohort의 경우 10,000-800,000명의 환자를 대상으로 하였으나, other liver disease를 control로 한 연구는 no OLD 환자를 control로 삼았으나, NAFLD 환자가 817명에 불과 White DL, et al. Clin Gastroenterol Hepatol 2012.

Systematic review (2) NAFLD/NASH (5 of 7 studies) Study periods: 5.6-21 years Cumulative HCC mortality : 0-1% Cirrhosis related to NASH Median f/u: 3.2-7.2 years Cumulative HCC incidence : 2.4-12.8% Small sample size Inadequate control group White DL, et al. Clin Gastroenterol Hepatol 2012.

Incidence of HCC in patients with NAFLD NAFLD (490/296,707): 0.21 per 1,000 PY (95% CI=0.19-0.22 per 1,000 PY) 10 year cumulative incidence: 1.7% Cirrhotic: 10.63 per 1,000 PY (95% CI=9.46-11.91 per 1,000 PY) Non-cirrhotic: 0.08 per 1,000 PY Control (55/296,707): 0.02 per 1,000 PY (95% CI=0.02-0.03 per 1,000 PY) 10 year cumulative incidence: 0.18% Adjusted HR=7.62, 95% CI=5.76-10.09 High risk subgroup: men, ≥65 year, Hispanic, diabetes, high FIB-4

Temporal trends in the proportion of HCC (2004-2009) NAFLD: 9% annual increase All etiology: 11% annual increase (HCV: 13% annual increase) HCC in patients with NAFLD Lower risk of HCC: adjusted OR=2.62 (95% CI=2.28-3.00) HCV, adjusted OR=52.66; HBV, adjusted OR=33.44 Older at the time of diagnosis, more likely to be white Shorter survival time: adjusted HR=1.21 (95% CI=1.01-1.45) HCV, adjusted HR=0.95; HBV, adjusted HR=0.96

Limitation Retrospective population-based study Lack of clinical information Unable to conduct adjusting for clinical variables Misclassification bias Sensitive analyses Imperfect definition of NAFLD  Chart validation (PPV=89%, NPV=98%), Sensitive analyses Too low risk for evaluation ! Kanwal F, et al. Gastroenterology 2018. Younossi ZM, et al. Hepatology 2015.

Recent studies 169명의 HCC 환자가 발생한 연구는 HCC 환자 169명 만을 대상으로 분석 106명의 HCC 환자가 발생한 연구는 18,080명을 분석하였으나 single arm study 4 prospective studies, 2 retrospective analysis of prospective database, 19 retrospective studies Non-cirrhotic NAFLD/NASH: 2.7% at 10 years, 0.23 per 1,000 PY Cirrhosis: 6.7-15% at 5-10 years Reig M, et al. Transplantation 2018.

Prevalence rates of CLD over time 국민건강영양조사 National Health and Nutrition Examination Survey Younossi ZM, et al. Clin Gastroenterol Hepatol 2011.

Temporal trends in the etiology of underlying liver disease in patients with resected HCC Pais R, et al. Aliment Pharmacol Ther 2017.

Proportion of HCC occurring in the absence of Significant fibrosis according to the etiology Pais R, et al. Aliment Pharmacol Ther 2017. Stine JG, et al. Aliment Pharmacol Ther 2018.

Surveillance

Cost-effectiveness of HCC surveillance Threshold incidence of HCC to trigger surveillance No experimental data Decision analysis Effective intervention: Life gain > 3 months Cost-effectiveness: Cost < $50,000 per year of life saved ($30,000~$150,000) Cost-effective in cirrhosis, if HCC annual incidence >1.5% Insufficient data in non-cirrhotic NAFLD (Cost-effective in HBV infection, if HCC annual incidence >0.2%) Decision analysis refers to a systematic, quantitative and interactive approach to addressing and evaluating important choices confronted by organisations in the private and public sector.  Naimark D, et al. J Gen Intern Med 1994. Laupacis A, et al. CMAJ 1992. Sarasin FP, et al. Am J Med 1996. Sherman M, et al. Best Pract Res Clin Gastroenterol 2014.

Recommendations for HCC surveillance EASL AASLD APASL Surveillance recommended Cirrhotic patients, Child-Pugh stage A and B; Cirrhotic patients, Child-Pugh stage C awaiting liver transplantation; Non-cirrhotic HBV patients at intermediate or high risk of HCC (PAGE-B ≥10); Non-cirrhotic F3 patients, regardless of aetiology may be considered for surveillance based on an individual risk assessment Asian male hepatitis B carriers over age 40; Asian female hepatitis B carriers over age 50; Hepatitis B carrier with family history of HCC; African and/or North American blacks with hepatitis B; Hepatitis B carriers with cirrhosis; Hepatitis C cirrhosis; Stage 4 PBC; Genetic hemochromatosis and cirrhosis; Alpha-1 antitrypsin deficiency and cirrhosis Other cirrhosis Surveillance benefit uncertain Hepatitis B carriers younger than 40 (males) or 50 (females) Hepatitis C and stage 3 fibrosis NAFLD without cirrhosis Cirrhotic hepatitis patients HBV HCV NASH Genetic hemochromatosis Primary biliary cirrhosis Alpha-1 antitrypsin deficiency Autoimmune hepatitis Other etiologies Non-cirrhotic chronic HBV carriers Asian females >50 years Asian males >40 years Africans > 20 years History of HCC in the family PR Galle, et al. J Heptol 2018. JA Marrero, et al. Hepatol 2018. M Omata, et al. Hepatol Int 2017.

Recommendations for HCC surveillance EASL AASLD APASL Surveillance recommended Cirrhotic patients, Child-Pugh stage A and B; Cirrhotic patients, Child-Pugh stage C awaiting liver transplantation; Non-cirrhotic HBV patients at intermediate or high risk of HCC (PAGE-B ≥10); Non-cirrhotic F3 patients, regardless of aetiology may be considered for surveillance based on an individual risk assessment Asian male hepatitis B carriers over age 40; Asian female hepatitis B carriers over age 50; Hepatitis B carrier with family history of HCC; African and/or North American blacks with hepatitis B; Hepatitis B carriers with cirrhosis; Hepatitis C cirrhosis; Stage 4 PBC; Genetic hemochromatosis and cirrhosis; Alpha-1 antitrypsin deficiency and cirrhosis Other cirrhosis Surveillance benefit uncertain Hepatitis B carriers younger than 40 (males) or 50 (females) Hepatitis C and stage 3 fibrosis NAFLD without cirrhosis Cirrhotic hepatitis patients HBV HCV NASH Genetic hemochromatosis Primary biliary cirrhosis Alpha-1 antitrypsin deficiency Autoimmune hepatitis Other etiologies Non-cirrhotic chronic HBV carriers Asian females >50 years Asian males >40 years Africans > 20 years History of HCC in the family Surveillance in NAFLD Cirrhosis: recommended F3: uncertain PR Galle, et al. J Heptol 2018. JA Marrero, et al. Hepatol 2018. M Omata, et al. Hepatol Int 2017.

Take Home Message Selective Patients? Surveillance