Predictor Of Hepatocellular Carcinoma Risk Research Articles

Pan-viral serology uncovers distinct virome patterns as risk predictors of hepatocellular carcinoma and intrahepatic cholangiocarcinoma

This study evaluates the pan-serological profiles of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) compared to several diseased and non-diseased control populations to identify risk factors and biomarkers of liver cancer. We used phage immunoprecipitation sequencing, an anti-viral antibody screening method using a synthetic-phage-displayed human virome epitope library, to screen patient serum samples for exposure to over 1,280 strains of pathogenic and non-pathogenic viruses. Using machine learning methods to develop an HCC or iCCA viral score, we discovered that both viral scores were positively associated with several liver function markers in two separate at-risk populations independent of viral hepatitis status. The HCC score predicted all-cause mortality over 8 years in patients with chronic liver disease at risk of HCC, while the viral hepatitis status was not predictive of survival. These results suggest that non-hepatitis viral infections may contribute to HCC and iCCA development and could be biomarkers in at-risk populations.

Value of GPR, APPRI and FIB-4 in the early diagnosis of hepatocellular carcinoma: a prospective cohort study.

There is an urgent need for novel biomarkers that are inexpensive, effective and easily accessible to complement the early diagnosis of hepatocellular carcinoma. This study aimed to analyze the relationship between serum gamma-glutamate-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index, fibrosis index based on four factors and the risk of hepatocellular carcinoma, and to determine the optimal cut-offs for predicting hepatocellular carcinoma. Based on a prospective cohort study, 44 215 participants who were cancer-free at baseline (2011-13) were included in the study. Cox proportional hazard models and receiver operating characteristics curves were used to analyze the diagnostic value and optimal cut-off value of gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors in predicting hepatocellular carcinoma patients. Gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors can be used as early independent predictors of hepatocellular carcinoma risk. The risk of hepatocellular carcinoma in the fourth quantile of gamma-glutamyl-transpeptidase to platelet ratio and alkaline phosphatase-to-platelet ratio index was 4.04 times (hazard ratio=4.04, 95% confidence interval: 2.09, 7.80) and 2.59 times (hazard ratio=2.59, 95% confidence interval: 1.45, 4.61), respectively, compared with the first quantile. With fibrosis index based on four factors first quantile as a reference, fibrosis index based on four factors fourth quantile had the highest risk (hazard ratio=18.58, 95% confidence interval: 7.55, 45.72). Receiver operating characteristic results showed that fibrosis index based on four factors had a stronger ability to predict the risk of hepatocellular carcinoma (area under curve=0.81, 95% confidence interval: 0.80, 0.81), and similar results were shown for gender stratification. In the total population, the optimal cut-off values of gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors were 0.208, 0.629 and 1.942, respectively. Gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors were independent predictors of hepatocellular carcinoma risk. Amongst them, fibrosis index based on four factors shows a stronger predictive ability for hepatocellular carcinoma risk, and gamma-glutamyl-transpeptidase to platelet ratio and alkaline phosphatase-to-platelet ratio index can be used as complementary indicators.

Abstract 2258: Predictors of hepatocellular carcinoma development in nonalcoholic fatty liver disease

Abstract Background: The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is predicted to increase with increasing worldwide prevalence. We aimed to identify predictors of HCC risk in patients with NAFLD, an unmet clinical need. Methods: We identified all patients diagnosed with NAFLD in the electronic health records (EHR) of a large US-based health system from 2004 to 2018. Information on demographics, body mass index (BMI), smoking status, serum biochemistries, comorbidities, albumin-bilirubin (ALBI) score, AST/√ALT ratio, fibrosis-4 index (FIB-4), and cirrhosis status were extracted from the EHR. Over an average 5.5 year at risk from date of first recorded NAFLD to the last contact with the healthcare system, date of HCC diagnosis or death, whichever occurred first, we identified 371 patients diagnosed with HCC. Cox proportional regression method with a stepwise approach was employed to identify independent predictors of HCC incidence. A Poisson regression method was used to estimate the incidence rate of HCC in NAFLD patients with a specified set of identified risk factors in the stepwise Cox regression analysis. Results. Among the 39,424 NAFLD patients, 57.8% were women, 44.5% were ever smokers, 27.3% had diabetes, 39.9% had dyslipidemia, 4.7% had Fibrosis-4 index (FIB-4)>2.67 (advanced fibrosis), and 3.7% had cirrhosis. The mean (standard deviation) age and BMI at first recorded diagnosis of NAFLD were 57.0 (11.4) years and 33.7 (7.4) kg/m2, respectively. The corresponding figures in 371 incident HCC cases were 65.1 (10.6) years of age, 31.9 (6.9) kg/m2 of BMI, 47.7% women, 52.8% ever smokers, 38.3% diabetes, 39.6% dyslipidemia, 17.8% FIB-4 >2.67, and 11.6% cirrhosis. All of these were independent factors for HCC risk. The estimated incidence rate of HCC for a male patient with NAFLD who was 65 years old, ever smoked, had BMI 30 kg/m3 and a history of diabetes and dyslipidemia, but had neither advanced fibrosis nor cirrhosis, was 3.02 (95% confidence interval [CI], 2.37-3.84) per 1000 person-years. The corresponding figures were 8.20 (95% CI, 5.78-11.62) for a male with advanced fibrosis but no cirrhosis and the same other characteristics as described above, and 18.05 (95% CI, 12.19-26.72) for the same patient with cirrhosis. On the other hand, the incidence of HCC for a male cirrhotic patient without a history of smoking or diabetes was 9.53 per 1000 person-years, a 47% reduction in risk. Conclusion. In this large cohort of NAFLD patients, we identified age, sex, BMI, smoking, diabetes, dyslipidemia, advanced fibrosis and cirrhosis as independent risk predictors for HCC. Although the effect of smoking and diabetes was relatively small in low-risk patients, their impact on high-risk NAFLD, especially those with advanced fibrosis or cirrhosis is discernable. Smoking cessation and treatment of diabetes may be potential strategies for reducing HCC risk in high-risk NAFLD patients. Citation Format: Jian-Min Yuan, Renwei Wang, Hung N. Luu, Jaideep Behari. Predictors of hepatocellular carcinoma development in nonalcoholic fatty liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2258.

The Applicability of ADA, AFU, and LAC in the Early Diagnosis and Disease Risk Assessment of Hepatitis B-Associated Liver Cirrhosis and Hepatocellular Carcinoma.

Objective: This study aimed to evaluate the applicability of adenosine deaminase (ADA), α-l-fucosidase (AFU), lactic acid (LAC), and their combined detection in the early diagnosis of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC).Methods: A retrospective analysis of hepatitis B-positive liver disease patients admitted between 2015 and 2020 was conducted. The receiver operating characteristic (ROC) curve was used to determine the diagnostic value of each indicator in LC and HCC, and binary logistic regression analysis was performed to determine the factors and risks related to the occurrence of the two conditions.Results: The levels of ADA, AFU, and LAC were significantly increased in patients with CHB, LC, and HCC (p < 0.05). The ROC curve showed that the sensitivity and specificity of ADA, AFU, LAC, and their combined detection in the CHB and LC groups as well as in the LC and HCC groups reflected different degrees of clinical value. In the CHB and LC groups, the adjusted odds ratio (OR) values of ADA, AFU, and LAC among patients in the high-level group were 3.218, 1.859, and 11.474, respectively, when the median was considered the cutoff point. When quartiles were considered the cutoff point, the OR risk values of the adjusted levels of ADA, AFU, and LAC were higher than those of the lowest-level group (Q1) (p < 0.05). In the LC and HCC groups, the adjusted OR values of ADA, AFU, and LAC among patients in the high-level group were 0.967, 2.365, and 38.368, respectively. When quartiles were considered the cutoff point, the OR risk values of AFU and LAC levels were higher than those of the lowest-level group (Q1) (p < 0.05).Conclusion: ADA, AFU, and LAC demonstrated good value in the early diagnosis of LC and HCC. The combined detection of ADA+AFU+LAC is more effective than single detection for the early diagnosis of the two conditions. ADA, AFU, and LAC can serve as risk predictors of LC, while AFU and LAC can be considered early risk predictors of HCC.

Risk and predictors of hepatocellular carcinoma for chronic hepatitis B patients with newly developed cirrhosis.

Most studies on risk predictors of hepatocellular carcinoma (HCC) among cirrhotic chronic hepatitis B patients do not confirm the date at cirrhosis diagnosis. We examined HCC risk and predictors in chronic hepatitis B patients with newly diagnosed cirrhosis. 4155 HBsAg seropositive participants were followed every 6-12 months with seromarker testing. Cirrhosis was ascertained through abdominal ultrasonography and computerized linkage with national health insurance profiles. Predictors included in Cox proportional hazards models were age, HBeAg serostatus, serum levels of HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and ALDH2 rs671 genotypes. A total of 301 patients developed cirrhosis, 76 of whom later developed HCC after 2462 person-years, showing an average annual incidence of 3.1%. The 15-year cumulative HCC risk among cirrhotics was 39.8% with a lifetime (30-80 years old) HCC risk of 78.5%. The adjusted HR's (95% CI, P-value) were 14.26 (3.17-64.08, P = 0.0005) for age at cirrhosis diagnosis of ≥60 years (vs 30-39 years), 2.85 (1.49-5.46, P = 0.0015) for HBeAg seropositivity (vs HBeAg seronegativity with HBsAg levels <1000 IU/mL), 0.35 (0.20-0.59, P < 0.0001) for AA/AG genotypes of rs671 (vs GG genotype), 3.68 (1.70-7.99, P = 0.0010) for ALT levels >45 U/L (vs <15 U/L), 3.52 (1.78-6.93, P = 0.0003) for AFP levels >20 ng/mL (vs <10 ng/mL), and 2.64 (1.38-5.07, P = 0.0035) for HBsAg levels ≥1000 IU/mL (vs <1000 IU/mL among HBeAg seronegatives). Older age, GG genotype of ALDH2 rs671, HBeAg seropositivity, and elevated serum levels of ALT, AFP, and HBsAg at cirrhosis diagnosis were HCC risk predictors in cirrhotic chronic hepatitis B patients.

P0358 : Risk predictors of hepatocellular carcinoma among cirrhotic patients chronically infected with hepatitis B

P0358 : Risk predictors of hepatocellular carcinoma among cirrhotic patients chronically infected with hepatitis B

Aspartate aminotransferase to platelet ratio index as a prospective predictor of hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection.

APRI (aspartate aminotransferase [AST] to platelet ratio index) is widely used to assess fibrosis and cirrhosis risk, especially in hepatitis C virus (HCV)-infected patients. Few studies have evaluated APRI and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) risk. Prospective evidence is needed to assess whether APRI predicts HCC risk in HBV patients. In a prospectively enrolled clinical cohort of 855 HBV patients with a 1-year exclusion window (followed for > 1 year and did not develop HCC within 1 year), the predictive value of APRI in HCC risk was evaluated by Cox proportional hazards model using univariate and multivariate analyses and longitudinal analysis. Higher APRI prospectively conferred a significantly increased risk of HCC in univariate analysis (quartile analysis, P trend = 2.9 × 10(-7) ). This effect remained highly significant after adjusting for common host characteristics but not cirrhosis (P trend = 7.1 × 10(-5) ), and attenuated when cirrhosis is adjusted (P trend = 0.021). The effect remained prominent when the analysis was restricted to patients with a more stringent 2-year exclusion window (P trend = 0.008 in quartile analysis adjusting all characteristics including cirrhosis), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Longitudinal comparison demonstrated a persistently higher APRI value in HBV patients who developed HCC during follow-up than those remaining cancer free. APRI might be a marker of HCC risk in HBV patients in cirrhosis-dependent and -independent manners. Further studies are warranted to validate this finding and test its clinical applicability in HCC prevention.

Quantitative assessment of mutations in hepatitis B virus genome with liver cirrhosis and hepatocellular carcinoma development

// Lei Yu 1, 2, * , Bao-fang Zhang 3, * , Ming-liang Cheng 2 , Xue-ke Zhao 2 , Quan Zhang 2 , Ya-xin Hu 2 , Hua-juan Liu 2 , Mao Mu 2 , Bi Wang 2, 4 , Guo-zhen Yang 2 , Li-li Zhu 2 , Shuai Zhang 5 , Yu-mei Yao 2 , Yi-ju Cheng 2 , Wang-sheng Li 6 1 The First Affiliated Hospital of Jinan University, Guangdong 510632, Guangzhou, China 2 The Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou, China 3 The First Affiliated Hospital, Soochow University, Suzhou 215006, Jiangsu, China 4 Department of Eugenics and Genetics, Guiyang Maternal and Child Health-Care Hospital, Guiyang 550003, Guizhou, China 5 Department of Interventional Radiology, Cancer Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, China 6 Department of Clinical Laboratory, Liupanshui People’s Hospital, Liupanshui 553401, Guizhou, China * These authors contributed equally to this work and should be considered as co-first authors Correspondence to: Ming-liang Cheng, e-mail: gmcmingliang_cheng@163.com Guo-zhen Yang, e-mail: gmcguozhen_yang@163.com Keywords: hepatitis B virus, hepatocellular carcinoma, liver cirrhosis, mutation, risk Received: February 29, 2016 Accepted: April 28, 2016 Published: May 17, 2016 ABSTRACT The long-term outcomes of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection are associated with specific HBV genotypes and mutations in the virus genome. However, a number of gene-disease association studies have yielded inconsistent results in the field. To investigate this inconsistency, we conducted a meta-analysis from 118 studies involving a total of 9,418 HCC cases, 2,697 LC cases, and 18,785 HBV-infected participants for 11 mutations of HBV to evaluate the epidemiological evidence of the relationship. Overall, 10 mutants (Pre-S mutation, A1762T/G1764A double mutations, G1896A, G1899A, T1753V, C1653T, G1766A, A1762T, G1764A, T1768A) were significantly associated with increased HCC risk with odds ratio (OR) range from 1.80 to 4.27, while no associations were found for C1858T. We found a significant dose–risk relationship between the number of mutations in HBV genome and HCC, in which high risks for HCC were associated with mutation numbers more than 5 (OR = 18.45, 95% CI: 7.86–43.29). By pooling 15 prospective studies, A1762T/G1764A, Pre-S, T1753V, and C1653T mutation was identified as good predictor of HCC risk, showing ORs from 1.73 to 4.54. In addition, significantly elevated LC risks were associated with 6 mutants (A1762T/G1764A double mutations, G1896A, G1899A, T1753V, C1653T, Pre-S mutation), with OR range from 1.76 to 4.10. Our results suggested that HBV mutations alone or in combination may be of clinical significance for predicting hepatocarcinogenesis.

Hepatocellular Carcinoma Risk Prediction Model for the General Population: The Predictive Power of Transaminases

Risk prediction models for hepatocellular carcinoma are available for individuals with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections who are at high risk but not for the general population with average or unknown risk. We developed five simple risk prediction models based on clinically available data from the general population. A prospective cohort of 428 584 subjects from a private health screening firm in Taiwan was divided into two subgroups-one with known HCV test results (n = 130 533 subjects) and the other without (n = 298 051 subjects). A total of 1668 incident hepatocellular carcinomas occurred during an average follow-up of 8.5 years. Model inputs included age, sex, health history-related variables; HBV or HCV infection-related variables; serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alfa-fetoprotein (AFP), as well as other variables of routine blood panels for liver function. Cox proportional hazards regression method was used to identify risk predictors of hepatocellular carcinoma. Receiver operating characteristic curves were used to assess discriminatory accuracy of the models. Models were internally validated. All statistical tests were two-sided. Age, sex, health history, HBV and HCV status, and serum ALT, AST, AFP levels were statistically significant independent predictors of hepatocellular carcinoma risk (all P < .05). Use of serum transaminases only in a model showed a higher discrimination compared with HBV or HCV only (for transaminases, area under the curve [AUC] = 0.912, 95% confidence interval [CI] = 0.909 to 0.915; for HBV, AUC = 0.840, 95% CI = 0.833 to 0.848; and for HCV, AUC = 0.841, 95% CI = 0.834 to 0.847). Adding HBV and HCV data to the transaminase-only model improved the discrimination (AUC = 0.933, 95% CI = 0.929 to 0.949). Internal validation showed high discriminatory accuracy and calibration of these models. Models with transaminase data were best able to predict hepatocellular carcinoma risk even among subjects with unknown or HBV- or HCV-negative infection status.

Natural history of chronic hepatitis B: what exactly has REVEAL Revealed?

Chronic hepatitis B virus (HBV) infection is a serious public health problem because of its worldwide prevalence and potential to cause adverse consequences. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study carried out in Taiwan was used to investigate the natural history of chronic hepatitis B. The REVEAL-HBV study has established an HBV viral load paradigm in the natural history of chronic hepatitis B (CHB). Serum HBV DNA level has been shown to be significantly and independently associated with incidence of hepatocellular carcinoma (HCC) and cirrhosis and liver-related mortality across a biological gradient. It is also a major predictor of HBsAg seroclearance. Genetic features including HBV genotype and basal core promoter A1762T/G1764A mutant, and precore G1896A mutant were documented as predictors of HCC risk. Inactive HBV carriers still had an increased risk on HCC development and liver-related mortality compared with HBsAg -seronegatives. Nomograms focusing on facilitating risk communication between patients and clinicians were developed incorporating non-invasive clinical parameters to predict long-term HCC risk. These will hopefully contribute to evidence-based decisions in the clinical management of CHB patients. A somewhat provocative and novel finding from the REVEAL-HBV study is the association of chronic HBV infection in active replication with an increased pancreatic cancer risk especially in women less than 50 years old. This finding will hopefully spur further research in this area seeking confirmatory evidence. Finally, we hope that the REVEAL-HBV study will continue to be a source of data to answer other important questions in chronic hepatitis B research going forward.

Hepatitis C Virus Seromarkers and Subsequent Risk of Hepatocellular Carcinoma: Long-Term Predictors From a Community-Based Cohort Study

Hepatitis C virus (HCV) contributes to one third of hepatocellular carcinoma cases worldwide. Long-term predictors for HCV-related hepatocellular carcinoma are essential for early intervention. Serum HCV RNA and ALT levels and HCV genotype were assessed for their predictability of hepatocellular carcinoma risk. A prospective cohort of 925 participants positive for antibodies against HCV and age 30 to 65 years was recruited and followed from 1991 to 2006. Serum HCV RNA and ALT levels and HCV genotypes at enrollment and during follow-up were examined. Newly developed hepatocellular carcinoma was identified by health examination and computerized linkage with national cancer registration and death certification profiles. Multivariate adjusted hazard ratios with 95% CIs were estimated using Cox regression models. Fifty-five participants newly developed hepatocellular carcinoma during 8,476 person-years of follow-up, giving an incidence rate of 648.9 per 100,000 person-years. The cumulative hepatocellular carcinoma risk increased from 1.1% for HCV RNA seronegative status to 6.4% for low HCV RNA levels and to 14.7% for high HCV RNA levels (P < .001). The cumulative risk also increased with elevated serum ALT levels from 1.7% for persistently ≤ 15 U/L to 4.2% for ever more than 15 U/L but never more than 45 U/L and to 13.8% for ALT ever ≥ 45 U/L (P < .001). Having HCV genotype 1 was associated with a higher cumulative hepatocellular carcinoma risk (12.6%) than not having HCV genotype 1 (4.5%; P < .001). Elevated serum levels of HCV RNA and ALT and HCV genotype 1 infection are independent risk predictors of hepatocellular carcinoma. These findings have strong implications for the management of chronic HCV.

Metabolic Factors and Risk of Hepatocellular Carcinoma by Chronic Hepatitis B/C Infection: A Follow-up Study in Taiwan

This study investigated whether obesity, diabetes, and other metabolic factors are independently associated with hepatocellular carcinoma (HCC), stratified by hepatitis B virus (HBV) and hepatitis C virus (HCV) serostatus, and explored the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC. A total of 23,820 residents in Taiwan were recruited and followed up for 14 years. All analyses were stratified by hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at enrollment, and 218 subjects positive for both seromarkers were excluded. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted relative risk (RR(a)) and 95% confidence interval (95% CI) were estimated using Cox proportional hazards models. Extreme obesity (body mass index >or=30 kg/m(2)) was independently associated with a 4-fold risk of HCC (RR(a), 4.13; 95% CI, 1.38-12.4) among anti-HCV-seropositive subjects and a 2-fold risk (RR(a), 2.36; 95% CI, 0.91-6.17) in persons without HBV and HCV infections, after controlling for other metabolic components, but not in HBsAg-seropositive subjects (RR(a), 1.36; 95% CI, 0.64-2.89). Diabetes was associated with HCC in all 3 groups, with the highest risk in those with HCV infection (RR(a), 3.52; 95% CI, 1.29-9.24) and lowest in HBV carriers (RR(a), 2.27; 95% CI, 1.10-4.66). We found more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and hepatitis. The finding that both obesity and diabetes are predictors of HCC risk, possibly differently depending on HBV and HCV infection status, may shed some light in preventing HCC.

495 Viral load is a strong predictor of hepatocellular carcinoma risk in people chronically infected with hepatitis B virus and with normal serum alanine aminotransaminase level

495 Viral load is a strong predictor of hepatocellular carcinoma risk in people chronically infected with hepatitis B virus and with normal serum alanine aminotransaminase level