1. HEPATOLOGY, Vol. 61, No. 6, 2015 1

2. Introduction At least 1 / 3 of liver cirrhosis (LC) Chronic hepatitis B (CHB) Significant proportion of CHB progress to hepatocellular carcinoma (HCC) Unless HCC is diagnosed in its early stage, a poor prognosis is expected owing to limited treatment options Early detection of LC in subclinical stage Can help identify high-risk of HCC earlier Join them in the optimized surveillance program 2

3. Introduction The concept of subclincal cirrhosis (SCC) has not been defined to date To diagnose LC, liver biopsy (LB) is the gold standard to date Limitations Invasiveness, sampling error, and inter- and intraobserver variability Noninvasive surrogates are required for early detection of LC in subclinical stage Liver stiffness measurement (LSM) Transient elastography (TE) is currently considered 3

4. Patients Total of 4,625 patients with CHB Excluded 1,644 and remaining 2,876 patients 2006.04 ~ 2012.12 at Severance Hospital, Yonsei University Exclusion criteria HCC at enrollment or past history HCC development within 6 months after enrollment Clinical cirrhosis Coinfection with hepatitis C, hepatitis D, or human immunodeficiency virus Right-sided heart failure Pregnancy loss to follow-up 4

5. Methods - Baseline Workup and Follow-up USG and laboratory workup (including AFP) Followed up every 6 months Diagnosis of HCC Guidelines of the American Association for the Study of Liver Diseases Diagnosis of clinical cirrhosis Platelet count of <100,000/mL USG findings suggestive of cirrhosis Blunted, nodular liver edge accompanied by splenomegaly (>12 cm) Clinical signs Portal hypertension, such as ascites, esophageal or gastric varices, and HE Subclinical stage of cirrhosis(SSC) Asymptomatic and without clinical evidence of LC 5

6. Methods - LSM Using TE FibroScan : well- trained technician LS values : kilopascals (kPa) HCC Risk REACH-B, Chinese University–Hepatocellular Carcinoma (CU-HCC) score LS-based risk scores modified REACH-B(mREACH-B) : LS value for HBV-DNA level LSM-HCC scores Liver Biopsy 6

7. Result Determination of the LS Cut-off value to define SCC Youden’s method (specificity & sensitivity) Predicting the development of HCC at 5 years LS cutoff of 13 kPa to define SCC SCC definition Nonclinical cirrhosis, but with an LS value 13 kPa 7

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13. Association Between the Change in LS Values and the Risk of Developing HCC Significantly higher cumulative incidence rate of HCC Baseline LS values < 13 kPa (n=814) follow-up LS values > 13 kPa (n=16; 2.0%) (vs < 13 kpa) Baseline LS values > 13 kPa (n=114) follow-up LS values > 13 kPa (n=37; 32.5%) (vs < 13kpa) Liver biopsy Without clinical cirrhosis 204 patients received LB at the time of enrollment F4 fibrosis -> LS value > 13 kPa Most patients (n=17; 80.9%) LS values > 13 kPa (n=27) -> not have histological cirrhosis 10 (37%) 13

14. Discussion TE can identify SCC Who are at increased risk of developing HCC among CHB patients (up to 4-fold ) The incidence rate of HCC in the SCC group Significantly higher than that in the non- SCC group (13.3 vs. 3.4 / 1,000 person-years) 14

15. Discussion Subcohort group Normal ALT group and AVT with group To exclude the confounding influence 5-year cumulative HCC incidence rate Without cirrhosis has been reported to be 3% in East Asia non-SCC group (1.8%), SCC group (5.2%), with cirrhosis(17%) TE-defined SCC can be defined as a new disease group with a distinctive risk of developing HCC Exactly between the groups with and without clinically cirrhosis 15

16. Discussion The usefulness of the LS value As a predictor of developing HCC in CHB patients Already demonstrated in several longitudinal studies Cut-off values : 13 kPa If a patient with SCC can be identified earlier using TE, the decision of starting AVT and a recall surveillance program can be appropriately made. AVT : not completely eliminate the risk of HCC Presence of underlying cirrhosis might affect HCC risk in spite of AVT Further studies TE for HCC into the current surveillance strategy is beneficial and cost-effective 16

17. 감사합니다 17