Kwang-Hyub Han

Epidemiology and Surveillance of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignancies and has a high mortality rate. The incidence of HCC differs greatly according to the geographic area. East and Southeast Asia, as well as middle and West Africas have the highest prevalence of HCC. The risk factors for developing HCC are well known and include cirrhosis, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcohol consumption, smoking, diabetes, and nonalcoholic steatohepatitis. Cirrhosis is the most significant risk factor, and there is a correlation between the degree of noninvasively measured liver fibrosis and the risk of HCC occurrence. HBV exerts carcinogenic effects by several mechanisms, including host genome integration, and studies have revealed that HBV replication predicts HCC development. HCV induces multistep carcinogenesis from inflammation, to fibrosis and liver cancer. HCC is an appropriate target for surveillance programs for early cancer detection. Currently, liver ultrasonography (US) combined with serum alpha-fetoprotein (AFP, a biomarker of HCC) measurement every 6 months is the standard method of HCC surveillance. Although US is the most widely used tool, its sensitivity in detecting early HCC (i.e., within the Milan criteria) during surveillance is only 63%. AFP is the representative biomarker for both HCC surveillance and diagnosis; however, the unsatisfactory performance of AFP as a surveillance tool means that a novel biomarker or combination with other serum markers is required. Des-gamma-carboxy prothrombin and AFP-L3 are candidate biomarkers that are complementary to AFP. The strategies of HCC surveillance vary in different countries according to the healthcare system, the resources available, and health insurance coverage. Many studies have shown that the rate of early cancer detection and rate of application of curative therapies were increased, as was the survival time, by HCC surveillance, which should now become a part of standard care, rather than just a recommendation. Improved US technology and the discovery of new biomarkers are necessary to make further progress in HCC surveillance.

Prevention of hepatocellular carcinoma in the Asia-Pacific region: consensus statements

Among approximately 650 000 people who die from hepatocellular carcinoma (HCC) each year, at least two‐thirds live in Asia. Efforts to improve early diagnosis and treatment have not yet impacted mortality. An Asia–Pacific Working Party convened in Hong Kong in June 2008 to consider ways to prevent HCC in this region. Separate reviews have summarized epidemiology of HCC, preventive approaches related to hepatitis B virus (HBV), hepatitis C virus (HCV) and non‐viral liver diseases, and the role of surveillance to detect HCC at a curative stage. We now present Consensus Statements from these deliberations and reviews. As chronic hepatitis B is the most common cause of HCC in Asia, effective hepatitis B vaccination programs are the most important strategy to reduce HCC incidence. Prevention of HCV by screening blood donors, universal precautions against blood contamination in health‐care settings and reducing HCV transmission from injection drug use are also vital. There is strong evidence that effective antiviral therapy to control HBV infection or eradicate HCV substantially reduces (but does not abolish) HCC risk. With hemochromatosis, family screening, early diagnosis and correcting iron overload to prevent liver fibrosis prevents HCC. There is currently insufficient evidence to give firm recommendations on alcohol, obesity/metabolic risk factors and other liver diseases. HCC surveillance for high‐risk groups is recommended in individual cases but cost‐effectiveness is not as high as infant hepatitis B vaccination and screening blood for HCV. Widespread application of HCC surveillance in Asia–Pacific countries depends on economic factors and health‐care priorities.

Specific mutations in the enhancer II/core promoter/precore regions of hepatitis B virus subgenotype C2 in Korean patients with hepatocellular carcinoma.

Recently, hepatitis B virus (HBV) genotypes and mutations have been reported to be related to hepatocellular carcinoma (HCC). This cross‐sectional case–control study examined the relationship between HCC and mutations in the enhancer II/core promoter and precore regions of HBV by comparing 135 Korean HCC patients infected with HBV genotype C2 (HBV/C2; HCC group) with 135 age‐, sex‐, and hepatitis B e antigen (HBeAg) status‐matched patients without HCC (non‐ HCC group). Age and sex were also matched between HBeAg‐positive and ‐negative patients. The prevalence of T1653, A1689, V1753, T1762/A1764, T1846, A1850, C1858, and A1896 mutations was evaluated in this population. The prevalence of the T1653 mutation in the box α region, the A1689 mutation in between the box α and β regions, and the T1762/A1764 mutations in the basal core promoter region was significantly higher in the HCC group compared to the non‐HCC group (8.9% vs. 2.2%, P = 0.017; 19.3% vs. 4.4%, P < 0.001; and 60.7% vs. 22.2%; P < 0.001). Among HBeAg‐negative patients, the frequency of the T1653 mutation was higher in the HCC group. Regardless of HBeAg status, the prevalence of the A1689, and T1762/A1764 mutations was higher in the HCC group than in the non‐HCC group. However, no association was observed between mutations in the precore region and HCC. Upon multivariate analysis, the presence of the T1653, A1689, and T1762/A1764 mutations was an independent predictive factor for HCC. The addition of the T1653 or A1689 mutation to T1762/A1764 increased the risk of HCC. In conclusion, the T1653, A1689, and/or T1762/A1764 mutations were associated with the development of HCC in Korean patients infected with HBV/C2. J. Med. Virol. 81:1002–1008, 2009.

No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations

BackgroundA recent genome-wide association study (GWAS) using chronic HBV (hepatitis B virus) carriers with and without hepatocellular carcinoma (HCC) in five independent Chinese populations found that one SNP (rs17401966) in KIF1B was associated with susceptibility to HCC. In the present study, a total of 580 HBV-derived HCC cases and 1351 individuals with chronic hepatitis B (CHB) or asymptomatic carrier (ASC) were used for replication studies in order to evaluate the reported association with HBV-derived HCC in other East Asian populations.ResultsWe did not detect any associations between rs17401966 and HCC in the Japanese cohorts (replication 1: OR = 1.09, 95 % CI = 0.82-1.43; replication 2: OR = 0.79, 95 % CI = 0.54-1.15), in the Korean cohort (replication 3: OR = 0.95, 95 % CI = 0.66-1.36), or in the Hong Kong Chinese cohort (replication 4: OR = 1.17, 95 % CI = 0.79-1.75). Meta-analysis using these cohorts also did not show any associations with P = 0.97.ConclusionsNone of the replication cohorts showed associations between rs17401966 and HBV-derived HCC. This may be due to differences in the genetic diversity among the Japanese, Korean and Chinese populations. Other reasons could be the high complexity of multivariate interactions between the genomic information and the phenotype that is manifesting. A much wider range of investigations is needed in order to elucidate the differences in HCC susceptibility among these Asian populations.

Accuracy of transient elastography in assessing liver fibrosis in chronic viral hepatitis: A multicentre, retrospective study

Transient elastography (TE) has become an alternative to liver biopsy (LB). This study investigated the diagnostic performance of liver stiffness (LS) measurement using TE in Korean patients with chronic hepatitis B and C (CHB and CHC).

Liver cancer in Korea

Hepatocellular carcinoma (HCC) is a highly malignant cancer and third major cause of death in Korean. It is more prevalent among men in the sixth to seventh decades. HCC is particularly prevalent in Korea where the age‐standardized incidence rate is 45.0/100 000 population in males and 12.0/100 000 population in females. The death rate from HCC is 20.0/100 000 population. Approximately 65–75% of HCC patients were positive for hepatitis B surface antigen (HBsAg), where 10–20% of patients were anti‐hepatitis C virus (HCV) positive. The high incidence rate of HCC in Korea is thought to be related to the high carrier rate of hepatitis B virus (HBV) in the general population. For primary prevention, a nationwide HBV vaccination program has been conducted since the late1980s in Korea. Although advances have been made in the various methods of management of HCC, there has been little overall survival improvement during the past 20 years. Only few patients are candidates for potentially curative forms of treatment. Therefore, the early detection of HCC is a key issue. When compared with clinical outcomes of HCC based on recent 10‐year institutional data, our screening and surveillance programs might enable early detection and increased applicability of curative treatments.

Leflunomide increases the risk of silent liver fibrosis in patients with rheumatoid arthritis receiving methotrexate

IntroductionWe identified silent liver fibrosis in patients with rheumatoid arthritis (RA) using transient elastography, and investigated medication that correlated with abnormal liver stiffness measurement (LSM) values.MethodsWe consecutively enrolled 105 patients with RA taking methotrexate over 24 weeks with normal liver functions and no history of underlying chronic liver disease. Blood tests were performed, and body mass index and metabolic syndrome were assessed. We checked LSM values, and adopted 5.3 kPa as the cutoff for abnormal LSM values. The cumulative doses of medications including methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, prednisolone, meloxicam, and celecoxib were calculated.ResultsThe median age of patients (20 men and 85 women) was 52.4 years. The median LSM value was 4.7 kPa and 24 (22.9%) patients had abnormal LSM values. Gamma-glutamyltranspeptidase levels and the cumulative doses of leflunomide and prednisolone significantly correlated with LSM values (P<0.05). The cumulative dose of leflunomide, but not methotrexate, was significantly higher in patients with abnormal LSM values than that in patients with normal LSM values (P = 0.008). When RA patients receiving leflunomide plus methotrexate were classified into two groups according to the optimal cutoff cumulative dose of leflunomide (19,170 mg), abnormal LSM values were more frequently identified in patients with high cumulative dose of leflunomide (odds ratio, 12.750; P<0.001).ConclusionsThe cumulative dose of leflunomide was the only independent predictor of abnormal LSM values in patients with RA who had received methotrexate for more than six months.

Hepatitis B virus infection after renal transplantation in the presence of antibody to hepatitis B surface antigen immunity.

Background and Aim:  Hepatitis B virus (HBV) infection has been known to be hampered by immunity against hepatitis B surface antigen (HBsAg). However, HBV with mutations within the common antigenic epitope of HBsAg, the ‘a’ determinant region, can escape from humoral immunity. Moreover, HBV infection by ‘a’ determinant mutants in chronic HBV patients has been reported after renal transplantation. In the present study, the authors investigated HBV infection after renal transplantation despite passive immunization or resolved HBV infection.

Digestive cancer management in Asia: Position statements: A report on GI Oncology Summit in 2011

Background and Aim:  With the rising incidence of digestive cancers in the Asia Pacific region and the advancement in diagnosis, management and palliation in these conditions, the clinical burden on oncologists is ever increasing. This Summit meeting was called to discuss the optimal management of digestive cancers and the role of Gastroenterologists

Lesson from 610 liver resections of hepatocellular carcinoma in a single center over 10 years

BackgroundRecent advances in surgical techniques and perioperative management have led to improved surgical outcomes, especially perioperative outcomes. The aim of this study was to review our experience with hepatic resection for hepatocellular carcinoma (HCC) over a ten-year period to determine how to improve long-term surgical outcomes.MethodsFrom January 1996 to December 2007, 610 patients underwent curative resection for HCC at Yonsei University Health System, Seoul, Korea. Prognostic factors for disease-free and overall survival were identified, and surgical outcomes were compared between two time periods: before 2003 and after 2003.ResultsThe 1-, 3-, and 5-year overall survival rates were 90.1%, 74.9% and 64.4%, respectively. The patients after 2003 tended to have improved overall survival. The survival rate after recurrence in patients with tumors > 3 cm was significantly greater after 2003. (P = 0.044).ConclusionsThe improved survival rates after 2003 may be explained by better selection of surgical candidates, a reduced perioperative transfusion rate due to improved surgical techniques, and active multimodal treatment for recurrent HCC.