Impact of metabolic risk factors on HCC in patients with chronic HBV infection. 2018. 4. 19. R3 김민규 / Pf. 이윤빈

Gastroenterology 2017 ; 153 : 1006-1017 Journal of Gastroenterology and Hepatology 32 (2017) 667 - 676

Introduction Goal of CHB treatment Risk factor of HCC in CHB patients Early and sustained suppression of HBV replication Prevention of disease progression to cirrhosis/HCC Risk factor of HCC in CHB patients Demographic factors (Age, Male, Ethnicity, FHx.) Virologic factors (viral load, HBV genotype) Alcohol Hepatic fibrosis, cirrhosis Smoking Metabolic risk factors CHB 환자 치료의 근간은 생존율과 Survival과 QOL을 높이는 것이 되겠고, 그 방법으로는 HBV replication 을 줄이고, LC 와 HCC progression 의 risk 를 줄이는 것이다. CHB 환자들에게 있어 HCC로의 이행에 대해 현재까지 알려진 risk factor들을 보면, 대표적으로 나이, 성별과 같은 인구학적 요인, 그리고 잘 알려진대로 HBV viral load 와 genotype,alcohol 등이 있겠다. 이 중 Virologic facto에 관해서, 특히 HBV viral load에 대해서는 anti-viral agent들이 활발하게 개발되고 있고 그 결과 HCC progression rate가 눈에 뜨이게 감소하고 있으나 (Entecavir, Tenofovir 사용했을 때 annual risk : 0.01 – 1.4 (non-cirrhotic pts,), 0.9 – 5.4% (cirrhotic pts.) 이제 CHB pts. 에 대해서, HCCrisk를 낮추는 것과 관련하여 metabolic risk factor, Hepatic fibrosis(Fatty liver) 와의 관련성이 점차 높아지고 있어, 이와 관련된 2개의 코호트 연구 저널을 소개한다. Natural history of chronic hepatitis B: Special emphasis on disease progression and prognostic factors Journal of Hepatology 48 (2008) 335–352 The natural history of chronic hepatitis B virus (HBV) infection and disease is complex and highly variable. We review the natural history of chronic hepatitis B with emphasis on the rates of disease progression and factors influencing the course of the liver disease. Chronic hepatitis B is characterized by an early replicative phase (HBeAg positive chronic hepatitis) and a late low or non-replication phase with HBeAg seroconversion and liver disease remission (inactive carrier state). Most patients become inactive carriers after spontaneous HBeAg seroconversion with good prognosis, but progression to HBeAg negative chronic hepatitis due to HBV variants not expressing HBeAg occurs at a rate of 1–3 per 100 person years following HBeAg seroconversion. The incidence of cirrhosis appears to be about 2-fold higher in HBeAg negative compared to HBeAg positive chronic hepatitis. In the cirrhotic patient the 5-year cumulative risk of developing hepatocellular carcinoma is 17% in East Asia and 10% in the Western Europe and the United States and the 5-year liver related death rate is 15% in Europe and 14% in East Asia. There is a growing understanding of viral, host and environmental factors influencing disease progression, which ultimately could improve the management of chronic hepatitis B.

먼저 소개해드릴 저널은, 주논문 (influence of ~) Gastroenterology 2017 ; 153 : 1006-1017 Journal of Gastroenterology and Hepatology 32 (2017) 667 - 676 먼저 소개해드릴 저널은, 주논문 (influence of ~)

Method – Study design Study design Retrospective Cohort study 5373 Taiwanese civil servants(male) enrolled from the Government Employee’s Central Clinics Baseline examination (Lab, serologic status, anthropometric measures) taken 1989 to 1992 Followed up by national cancer registry and death certification system HCC, Deaths through 2010-12-31 Retrospective Cohort study

Method – Study population

Method – Definition, Statistical analysis Metabolic risk factors Obesity (BMI > 25kg/m2) Diabetes (hx. Of diagnosis/Tx. or fasting glucose > 126mg/dl) Elevated TG (TG > 150mg/dL) High BP ( > 130/85mmHg) Statistical analysis Kaplan-Meier curves : Cumulative incidence Wilcoxon test : Difference between strata Cox regression : HR, 95% Confidence Intervals(CI) Metaolic risk factors는 다음과 같이 정의 이용된 statistical analysis Kaplan Meier curve : Cumulative incidence Wilcoxon test : difference btw. Strata COX regression : HR , 95% Confidence intervals (CI)

Results – Baseline characteristics 우선 HBV carrier /와 아닌 사람의 baseline hx. 비교. TF, BP, cholesterol 등의 metabolic risk facto가 non carrier에서 유의미하게 높음. ALT, AST는 HBV carrier에서 높음. HBV carrie에서 metabolic risk sum자체도 noncarrier보다 유의하게 낮았습니다.

Results -  Follow-up of HCC according to different metabolic risk factors sum 핵심이 되는 Resuls. A,B Metabolic risk sum 이 올라갈수록, culumative incidence of HCC 와 liver related death 가 올라감. HCC : 4.83 % (optimal risk factor) -> 13.60% ( > 3 risk factors), age.., smoking, alcohol, FMx. 를 보정하고 난 이후에는 0 과 >3 의 HR가 2.32 B 는 기존에 알려진 CHB의 HCC risk factor 였던 DM과 obesity 를 별도로 고려한 것임. C Metabolic risk factor 개수가 많을수록 Liver related death도 늘어남, Adjusted Hazard Ratio : ≥ 3 metabolic risk factors vs 0 : 2.32 (1.18 – 4.54) Adjusted Hazard Ratio : ≥ 3 metabolic risk factors vs non-obese/non-diabetic : 2.61 (1.34 – 5.08)

Results -  Follow-up of Liver related Death according to different metabolic risk factors sum 핵심이 되는 Resuls. A,B Metabolic risk sum 이 올라갈수록, culumative incidence of HCC 와 liver related death 가 올라감. HCC : 4.83 % (optimal risk factor) -> 13.60% ( > 3 risk factors), age, smoking, alcohol, FMx. 를 보정하고 난 이후에는 0 과 >3 의 HR가 2.32 B 는 기존에 알려진 CHB의 HCC risk factor 였던 DM과 obeses를 별도로 고려한 것임. C Metabolic risk factor 개수가 많을수록 Liver related death도 늘어남, Adjusted Hazard Ratio : ≥ 3 metabolic risk factors vs 0 : 2.72 (1.32 – 5.59) Adjusted Hazard Ratio : ≥ 3 metabolic risk factors vs non-obese/non-diabetic : 2.96 (1.45 – 6.04)

Results -  Follow-up of HCC and Liver related Death according to different metabolic risk factors sum 핵심이 되는 Resuls. A,B Metabolic risk sum 이 올라갈수록, culumative incidence of HCC 와 liver related death 가 올라감. HCC : 4.83 % (optimal risk factor) -> 13.60% ( > 3 risk factors), age, smoking, alcohol, FMx. 를 보정하고 난 이후에는 0 과 >3 의 HR가 2.32 B 는 기존에 알려진 CHB의 HCC risk factor 였던 DM과 obeses를 별도로 고려한 것임. C Metabolic risk factor 개수가 많을수록 Liver related death도 늘어남, 1690 HBsAg (+) 환자 중에, 1454명은 Initial US 로 f/u 이 되었음.

Results - Follow-up of HCC and Liver related Death Effect modification by smoking Smoking 이 oxidative stress를 일으키고, 이는 NAFLD 의 pathogeniesis와 유사하다는 점을 고려하여, smoking 여부에 따라 Metabolic risk factors에 대한 HCC risk를 분석. Smoker와 never smoker을 나누어 보았을 때 metaolic risk factor sum 의 HCC risk 와 Liver related death 의 HR는 유의미했으나, Never smoker에서는 유의미하지 않았다.

– Metabolic risk factor burden and Fatty liver on follow ups Results – Metabolic risk factor burden and Fatty liver on follow ups HBV 환자들은 추후에 US f/u data가 있다. (1996-1996) Initial metabolic risk factor burden(처음 baseline 조사때 한 것) 이 많을수록 추후 Fatty liver의 OR이 늘어났

Discussion The Role of aggregate metabolic risk factors at HCC risk and Liver-related deaths among HBV carriers Metabolic risk factor burden , a predictor for HBV-related HCC Lower prevalence of metabolic risk-factors found at HBV carriers -> HBV infection and glucose/lipid metabolism Aggregate metabolic risk facor의 역할을 규명함 (이전에는 DM/obesity 가 NAFLD, HCC risk 를 높인다는 연구는 있었다) 그러나 aggregate 된 것 자체가 중요할 수 있겠다. Smoking 이 NAFLD 를 obese rat에서 일으킨다는 점이 알려져있고, 또한 smokin은 oxidate stress 일으키고 이는 NAFLD injury에도 해당하는 mechanis이다. 이번 study에서도 smoking이 HCC의 risk를 높인다는 점이보였다. (또한 metaolic risk burden과도 연관성)

Discussion Strength Limitations Well defined cohort, careful measurement of risk factors Large population Limitations Men (high incidence of HCC and metabolic SD) Race (Asian population) Metabolic risk factors measured at single point Author’s strength and Limitations. 10Yr cumulative HCC incidence for male HBC carrier , >3 met risk : 13.6%, smoker 에서는 25.0 %

Gastroenterology 2017 ; 153 : 1006-1017 Journal of Gastroenterology and Hepatology 32 (2017) 667 - 676

Method – Study design & Population Retrospective Cohort study Prince of Wales Hospital, Hong Kong CHB Patients who underwent liver biopsy 2006.01 – 2009.12 Database frozen, 2015.05 Study population CHB was diagnosed as HbsAg(+) for at least 6Months. Exclusion criteria가 주논문에 비해 더 조건이 많음.

Method - Definition Diagnosis of HCC Fatty liver Cirrhosis Histological confirmation At least two imaging techniques (SONO, CT, MRI, hepatic angiogram) One imaging technique + AFP > 400ng/mL Fatty liver steatosis ≥ 5% at histology Cirrhosis - Ishak fibrosis scoring system : 5,6 Cirrhosis was defined as Ishak fibrosis scoring system Steatohepatitis was defined as presence of steatosis > 5%, ballooning degeneration , and lobular inflammation.

Method – Definition (Ishak scoring system) Cirrhosis was defined as Ishak fibrosis scoring system Steatohepatitis was defined as presence of steatosis > 5%, ballooning degeneration , and lobular inflammation. Standish et al, Gut, 2006

Results Baseline characteristics. Fatty liver 와 아닌 사람의 비료 다음부분에서의 유의미한 부분 Fatty liver and Metabolic SD 의 facto들.

Results – 11 Pts. Who developed HCC 9명은 Histology proven fatty liver 였고 2명은 아니었음.

Results : Fatty liver and HCC risk Adjusted Hazard Ratio : Fatty liver vs Non-fatty liver : 7.272 (1.521-34.760) Adjusted Hazard Ratio : histology proven cirrhosis vs Non : 4.782 (1.336-17.11)

Results Fatty liver (steatosis >5%) 일수록, HCC 의 development 되는 risk 가 높았습니다. 다만 steatosis 의 degree가 높다고 HCC의 risk 가 높아지지는 않았습니다. 이외에 Univerable analysis : age, anti-viral Tx.(never or 5년미만) ,cirrhosis 일 때 HCC risk 가 올라갔고 Multivariable analysis : fatty liver, age, anti-viral, cirrhosis

Discussion Concurrent histologically proven fatty liver as independent risk factor of hepatocarcinogenesis among CHB patients. Limitations Small number Liver biopsy : invasive diagnostic tool for detecting fatty liver

Conclusion - comparison Gastroenterology J. of Gastroenterology and Hepatology Cohort study Taiwan, Male, GECC data. Hong Kong, Prince of Wales Hospital Subject No. 1690 270 Inclusion HBsAg(+), 40yr < Age < 65yr HBsAg(+), underwent Liver biopsy Exclusion Anti-HCV(+), AIH Alcoholics Pts. developed HCC <6months after Liver biopsy Detection of HCC National cancer registry Histology, Imaging (two modalities), Imaging(one modality) + AFP level Metabolic risk factors (Obesity, DM, TG, BP) Fatty Liver (Steatosis>5% at histology) Primary outcome HCC risk, Liver related Deaths HCC risk ≥ 3 metabolic risk factors vs. 0 Fatty liver vs. Non-fatty liver HR 2.32 ( 1.18 – 4.54) HR 7.27 (1.52 - 34.76) Liver related Deaths HR 2.72( 1.32 – 5.59) Gastroenterology는 Impact factor 6.5 이고, J. of gastroenterology and hepatology 는 1.19이다.

Conclusion - Further apporach Surveillance of CHB patients with multiple metabolic risk factors 간세포암종 진료가이드라인(2014) Randomized controlled trial of screening for hepatocellular carcinoma, J. cancer Res Clin Onclol(2004) AFP + US, every 6Mo 10 Yr cumulative HCC incidence HBV carrier, male, >3Met. Risk factors HBV carrier, male, > 3Met. Risk factor, smoker HBV-DNA level > 1,000,000 copies/mL 13.6% 25.0% 10% HCC의 영상의학적 진단에 따른 민감도 SONO :61~67% Contrast CT : 68~91% MRI : 81~100% Ref. : 간세포암종 진료가이드라인(2014) Randomized controlled trial of screening for hepatocellular carcinoma, J. cancer Res Clin Onclol(2004) Metabolic risk factor가 있는 HBV 환자들에서, surveillance의 간격을 줄여보거나, 또는 다른 modality (CT,MRI)를 이용해서 screen 하는 방법은 어떨까요. Chen et al, JAMA, 2006

Conclusion – Other GI cancer and metabolic risk factors Risk of GI cancer Metabolic SD, Obesity DM Gastric cancer BMI >25kg/m2 OR 1.22 (1.06 - 1.41) Meta-analysis, Eur K Cancer, 2009 RR 1.41 (1.10 - 1.81) Meta-analysis, Word J Gastroenterology, 2014 Colorectal cancer Weight gain at adulthood HR 1.23 (1.14 - 1.34) Meta-analysis, Am J Epidemiol, 2015 RR 1.38 (1.26 - 1.51) Meta-analysis, Am J Gastroenterology, 2011 Pancreatic cancer BMI>35kg/m2 vs BMI<23kg/m2 RR 1.72 (1.19 - 2.48) Cohort study, JAMA. 2001 RR 1.97 (1.78 - 2.18) Meta-analysis, Ann Surg Oncol, 2014 Cholangiocarcinoma Metabolic syndrome OR 1.56 (1.32 - 1.83) Hepatology. 2011 RR 1.60 (1.38 - 1.87) Meta-anaylsis, Eur J Cancer Prev. Gastric cancer Excess body weight is associated with an increased risk of gastric cancer [40-42]. In a meta-analysis of cohort studies identifying 9492 gastric cancer cases, excess body weight (defined as a body mass index [BMI] ≥25 kg/m2) was associated with an increased risk of gastric cancer (OR 1.22, 95% CI 1.06-1.41) Yang P, Zhou Y, Chen B, et al. Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur J Cancer 2009; 45:2867. Colon cancer A systematic review and meta-analysis of data from 13 studies reported that a weight gain between early adulthood and midlife was associated with a modest but significant increase in the risk of CRC (hazard ratio [HR] 1.23, 95% CI 1.14-1.34)  Karahalios A, English DR, Simpson JA. Weight change and risk of colorectal cancer: a systematic review and meta-analysis. Am J Epidemiol 2015; 181:832. Diabetes mellitus is associated with an elevated risk of CRC [81-90]. A meta-analysis of 14 studies (6 case-control and 8 cohort) estimated that the risk of colon cancer among diabetics was approximately 38 percent higher than nondiabetics (relative risk [RR] 1.38, 95% CI 1.26-1.51) Yuhara H, Steinmaus C, Cohen SE, et al. Is diabetes mellitus an independent risk factor for colon cancer and rectal cancer? Am J Gastroenterol 2011; 106:1911. Pancreas cancer and metabolic risk factors. RR for Pancreatic cancer, (DM 있는사람) 1.97 (95 % CI 1.78-2.18) Ref> Association of diabetes mellitus and pancreatic adenocarcinoma: a meta-analysis of 88 studies. Ann Surg Oncol. 2014 The mechanism underlying this association is unclear. However, at least some data suggest that the increased risk of pancreatic cancer in patients with metabolic diseases such as diabetes mellitus and other states of insulin resistance as well as obesity may be mediated by reduced levels of plasma adiponectin, a fat-derived hormone that has insulin-sensitizing and anti-inflammatory properties Pancreas cancer and BMI A BMI of at least 30 kg/m2 was associated with a significantly increased risk of pancreatic cancer compared with a BMI of less than 23 kg/m2 (RR 1.72, 95% CI 1.19-2.48) Cholangiocarcinoma DM and cholangiocarcinoma  RR 1.60, 95% CI 1.38-1.87) Jing W, Jin G, Zhou X, et al. Diabetes mellitus and increased risk of cholangiocarcinoma: a meta-analysis. Eur J Cancer Prev 2012; 21:24. 다른 GI cance에서도, metabolic risk facto에 대한 Risk가 분명 높다. 그러나 HBV환자, HCC가 가장 높다.

경청해 주셔서 감사합니다.