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

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

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

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

5. Systematic review (1)
Clinical-based cohort의 경우 대부분 500명 미만의 환자를 대상
Population-based cohort의 경우 10, ,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.

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

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

9. 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= )
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= )
HCV, adjusted HR=0.95; HBV, adjusted HR=0.96

10. 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.

11. 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: % at 5-10 years
Reig M, et al. Transplantation 2018.

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

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

14. 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.

15. Surveillance

16. 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.

17. 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.

18. 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.

19. Take Home Message
Selective
Patients?
Surveillance