Incident Hepatocellular Carcinoma Cases Research Articles

Viral Load-Based Prediction of Hepatocellular Carcinoma Risk in Noncirrhotic Patients With Chronic Hepatitis B : A Multinational Study for the Development and External Validation of a New Prognostic Model.

A nonlinear association between serum hepatitis B virus (HBV) DNA levels and hepatocellular carcinoma (HCC) risk has been suggested in patients with chronic hepatitis B (CHB). To develop and externally validate a prognostic model for HCC risk in noncirrhotic adult patients with CHB and no notable alanine aminotransferase (ALT) elevation. Multinational cohort study. A community-based cohort in Taiwan (REVEAL-HBV [Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus]; REACH-B [Risk Estimation for HCC in CHB] model cohort) and 8 hospital-based cohorts from Korea and Hong Kong (GAG-HCC [Guide with Age, Gender, HBV DNA-HCC] and CU-HCC [Chinese University-HCC] cohorts). Model development: 6949 patients with CHB from a Korean hospital-based cohort. External validation: 7429 patients with CHB combined from the Taiwanese cohort and 7 cohorts from Korea and Hong Kong. Incidence of HCC. Over median follow-up periods of 10.0 and 12.2 years, the derivation and validation cohorts identified 435 and 467 incident HCC cases, respectively. Baseline HBV DNA level was one of the strongest predictors of HCC development, demonstrating a nonlinear parabolic association in both cohorts, with moderate viral loads (around 6 log10 IU/mL) showing the highest HCC risk. Additional predictors included in the new model (Revised REACH-B) were age, sex, platelet count, ALT levels, and positive hepatitis B e antigen result. The model exhibited satisfactory discrimination and calibration, with c-statistics of 0.844 and 0.813 in the derivation and validation cohorts with multiple imputation, respectively. The model yielded a greater positive net benefit compared with other strategies in the 0% to 18% threshold. Validation in cohorts of other races and receiving antiviral treatment was lacking. Our new prognostic model, based on the nonlinear association between HBV viral loads and HCC risk, provides a valuable tool for predicting and stratifying HCC risk in noncirrhotic patients with CHB who are not currently indicated for antiviral treatment. Korean government.

Point-based risk score for the risk stratification and prediction of hepatocellular carcinoma: a population-based random survival forest modeling study

The precise associations between common clinical biomarkers and hepatocellular carcinoma (HCC) risk remain unclear but hold valuable insights for HCC risk stratification and prediction. We examined the linear and nonlinear associations between the baseline levels of 32 circulating biomarkers and HCC risk in the England cohort of UK Biobank (UKBB) (n=397,702). The participants were enrolled between 2006 and 2010 and followed up to 31st October 2022. The primary outcome is incident HCC cases. We then employed random survival forests (RSF) to select the top ten most informative biomarkers, considering their association with HCC, and developed a point-based risk score to predict HCC. The performance of the risk score was evaluated in three validation sets including UKBB Scotland and Wales cohort (n=52,721), UKBB non-White-British cohort (n=29,315), and the Taizhou Longitudinal Study in China (n=17,269). Twenty-five biomarkers were significantly associated with HCC risk, either linearly or nonlinearly. Based on the RSF model selected biomarkers, our point-based risk score showed a concordance index of 0.866 in the England cohort and varied between 0.814 and 0.849 in the three validation sets. HCC incidence rates ranged from 0.95 to 30.82 per 100,000 from the lowest to the highest quintiles of the risk score in the England cohort. Individuals in the highest risk quintile had a 32-73 times greater risk of HCC compared to those in the lowest quintile. Moreover, over 70% of HCC cases were detected in individuals within the top risk score quintile across all cohorts. Our simple risk score enables the identification of high-risk individuals of HCC in the general population. However, including some biomarkers, such as insulin-like growth factor 1, not routinely measured in clinical practice may increase the model's complexity, highlighting the need for more accessible biomarkers that can maintain or improve the predictive accuracy of the risk score. This work was supported by the National Natural Science Foundation of China (grant numbers: 82204125) and the Science and Technology Support Program of Taizhou (TS202224).

Pre-diagnostic plasma inflammatory proteins and risk of hepatocellular carcinoma in three population-based cohort studies from the United States and the United Kingdom.

Previous studies suggest a role for inflammation in hepatocarcinogenesis. However, no study has comprehensively evaluated associations between circulating inflammatory proteins and risk of hepatocellular carcinoma (HCC) among the general population. We conducted a nested case-control study in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) with 56 pairs of incident HCC cases and controls. External validation was performed in the UK Biobank (34 HCC cases and 48,471 non-HCC controls). Inflammatory protein levels were measured in pre-diagnostic plasma using the Olink® Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1-standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)-adjusted p < .05. In the NHS/HPFS, among 70 analyzed proteins with call rates >80%, 15 proteins had significant associations with HCC risk (pFDR < .05). Two proteins (stem cell factor, OR per SD = 0.31, 95% CI = 0.16-0.58; tumor necrosis factor superfamily member 12, OR per SD = 0.51, 95% CI = 0.31-0.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs per SD ranged from 1.73 for interleukin (IL)-10 to 2.35 for C-C motif chemokine-19. A total of 11 proteins were further replicated in the UK Biobank. Seven of the eight selected positively associated proteins also showed positive associations with HCC risk by enzyme-linked immunosorbent assay, with ORs ranging from 1.56 for IL-10 to 2.72 for hepatocyte growth factor. More studies are warranted to further investigate the roles of these observed inflammatory proteins in HCC etiology, early detection, risk stratification, and disease treatment.

Incidence and predictors of hepatocellular carcinoma in NAFLD without diagnosed cirrhosis: a nationwide real-world U.S. study.

A substantial proportion of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) do not have cirrhosis. Data regarding the incidence and predictors of HCC development in NAFLD without cirrhosis are limited. We conducted a large, national study of NAFLD patients without documented cirrhosis to examine the incidence and predictors for HCC development. This retrospective study included 751,603 NAFLD patients (54% female) without documented cirrhosis derived from the deidentified Optum Clinformatics® Data Mart Database. Patients with cirrhosis, platelets < 120,000/µL or FIB-4 values > 2.67 were excluded. The mean age was 53.7 ± 15.0years, 45.9% were male, 39.5% had diabetes, 57.6% were White, 18.4% Hispanic, 8.2% Black and 4.9% were Asian. The mean platelet count was 264,000 ± 72,000/µL, and 96.3% of patients had a FIB-4 < 1.30. Over 1,686,607 person-years of follow-up, there were 76 incident cases of HCC, resulting in an HCC incidence rate of 0.05 per 1000 person-years. There was a higher HCC incidence rate among patients with platelets ≤ 150,000/µL, versus those with platelets > 150,000/µL (0.23 per 1000 person-years, vs. 0.04 per 1000 person-years, p = 0.02) but not in subgroup analyses for age, sex, race/ethnicity or diabetes. Using multivariable Cox proportional hazards model adjusted multiple confounders, platelet count ≤ 150,000/µL remained an independent predictor of HCC development (adjusted HR 5.80, 95% CI 1.67-20.1, p = 0.006). HCC incidence in NAFLD without documented cirrhosis was below the threshold for cost-effective HCC surveillance in overall and multiple subgroup analyses. Platelet count < 150,000/µL may be a useful predictor of HCC development in this population.

Abstract B061: Nonalcoholic fatty liver disease (NAFLD) polygenic risk score and risk of hepatocellular carcinoma in a multiethnic population

Abstract Purpose: Hepatocellular carcinoma (HCC) is the third cause of cancer mortality globally, with 10%-12% of cases attributable to nonalcoholic fatty liver disease (NAFLD). Genetic variants included in NAFLD polygenic risk scores (PRS) have been associated with HCC risk. Since these associations have been studied primarily among European ancestry populations, in the current study we assessed the transportability of a NAFLD PRS associated with HCC risk in a racially/ethnically diverse population. Methods: We conducted a nested case-control study including 275 incident HCC cases and 73,045 controls from the Multiethnic Cohort Study, using a 21-variant PRS for NAFLD created based on prior GWAS and replication studies on MEC participants and other populations. Associations between PRS (per standard deviation) and HCC were estimated using logistic regression adjusting for age, sex, and global ancestry. A stratified analysis was conducted by body mass index (BMI) due to the direct relationship of obesity with NAFLD and HCC. Results: The PRS was associated with HCC risk in the combined sample (ORper SD= 1.84, 95% CI: 1.64-2.06). Signifcant associations were observed in Japanese Americans [ORper SD=2.26 (1.87-2.72)], Latinos [ORper SD=1.89 (1.52-2.35)], Native Hawaiians [ORper SD=1.84 (1.26-2.69)], and with the associations being weaker and non-significant in whites [ORper SD=1.33 (0.92-1.93)] and African Americans [ORper SD=1.25 (0.90-1.75)]. The PRS association was stronger among those with BMI &amp;gt;= 25 kg/m2 for the combined sample (ORper SD :2.46, 95% CI:1.92-3.14), (P heterogeneity &amp;lt;0.0001); and all racial/ethnic groups [Latino: 3.01(1.88-4.81), African American: 2.72 (95% CI: 1.18-6.27), Hawaiian: 2.25 (1.17-4.32), Japanese: 2.13 (1.36-3.36), and White:2.11(1.10-4.04)]. Conclusion: A NAFLD PRS is applicable for HCC risk prediction across racial/ethnic populations. BMI may modifiy this PRS-HCC risk association. Citation Format: Homa Sadeghi, David Bogumil, David V. Conti, Christopher Haiman, Loïc Le Marchand, Veronica Wendy Setiawan. Nonalcoholic fatty liver disease (NAFLD) polygenic risk score and risk of hepatocellular carcinoma in a multiethnic population [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B061.

Increasing risk of hepatocellular carcinoma with successive generations in the United States among Mexican American adults: The Multiethnic Cohort.

US-born Latinos have a higher incidence of hepatocellular carcinoma (HCC) than foreign-born Latinos. Acculturation to unhealthy lifestyle behaviors and an immigrant self-selection effect may play a role. In this study, the authors examined the influence of generational status on HCC risk among Mexican American adults. The analytic cohort included 31,377 self-reported Mexican Americans from the Multiethnic Cohort Study (MEC). Generational status was categorized as: first-generation (Mexico-born; n=13,382), second-generation (US-born with one or two parents born in Mexico; n=13,081), or third-generation (US-born with both parents born in the United States; n=4914). Multivariable Cox proportional hazards regression was performed to examine the association between generational status and HCC incidence. In total, 213 incident HCC cases were identified during an average follow-up of 19.5years. After adjusting for lifestyle and neighborhood-level risk factors, second-generation and third-generation Mexican Americans had a 37% (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.98-1.92) and 66% (HR, 1.66; 95% CI, 1.11-2.49) increased risk of HCC, respectively, compared with first-generation Mexican Americans (p for trend=0.012). The increased risk associated with generational status was mainly observed in males (second-generation vs. first-generation: HR, 1.60 [95% CI, 1.05-2.44]; third-generation vs. first-generation: HR, 2.08 [95% CI, 1.29-3.37]). Increasing generational status of Mexican Americans is associated with a higher risk of HCC. Further studies are needed to identify factors that contribute to this increased risk.

Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study

Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S. The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC. Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0-8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m2), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P < .05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P < .001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54-4.07), years with cirrhosis (P= .004; OR, 1.06; 95% CI, 1.02-1.1), family history of liver cancer (P= .02; yes; OR, 2.69; 95% CI, 1.11-5.86), age (per 5 years; P= .02; OR, 1.17; 95% CI, 1.03-1.33), obesity (P= .02; yes; OR, 1.7; 95% CI, 1.08-2.73), aspartate aminotransferase (log(1+AST); P= .06; OR, 1.54; 95% CI, 0.97-2.42), alpha-fetoprotein (log(1+AFP); P= .07; OR, 1.32; 95% CI, 0.97-1.77), and albumin (P= .10; OR, 0.7; 95% CI, 0.46-1.07). Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years.

Daytime napping, nighttime sleeping duration, and risk of hepatocellular carcinoma and liver disease-related mortality

Background & AimsSleep duration has been linked to metabolic dysfunction and chronic inflammation, which may contribute to the development of liver cancer and chronic liver disease (CLD). However, little is known about the relationship between sleep or napping duration and hepatocellular carcinoma (HCC) risk and CLD mortality. MethodsWe followed 295,837 individuals in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. We examined the associations of nighttime sleep duration and daytime napping duration with risk of HCC incidence and CLD mortality. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs). ResultsA total of 357 incident HCC cases and 578 CLD deaths were identified after a median follow-up time of 15.5 years. After adjusting for confounder factors, we found U-shaped associations of nighttime sleep duration with the incidence of HCC (HR<5 vs. 7–8 h = 2.00, 95% CI: 1.22–3.26 and HR≥9 vs. 7–8 h = 1.63, 95% CI: 1.04–2.65) and CLD mortality (HR<5 vs. 7–8 h = 1.78, 95% CI: 1.18–2.69 and HR≥9 vs. 7–8 h = 1.91, 95% CI: 1.35–2.70). Daytime napping was associated with higher risk of HCC (HR≥1 vs. non-nappers = 1.46, 95% CI: 1.04–2.06) and higher CLD mortality (HR≥1 h vs. non-nappers = 1.54, 95% CI: 1.18–2.01) compared with no napping. ConclusionsWe observed U-shaped associations for nighttime sleeping and risk of HCC and CLD mortality. Additionally, longer daytime napping duration was associated with higher risk of HCC and CLD death. Our study suggests that clinical follow up of individuals at risk for liver cancer or living with a liver disease should include information on nighttime and daytime sleep. Impact and implicationsSleep or napping duration may play a role in the development of liver cancer and chronic liver disease, but little is known about the relationship between them. In addition, abnormal sleep patterns in patients with chronic liver disease may further promote the development of liver disease, creating a vicious cycle. Our study suggests that clinical follow up of individuals at risk for liver cancer or living with a liver disease should include information on nighttime and daytime sleep, as they can be potentially important factors in the development and progression of liver disease.

Healthful Plant-Based Dietary Pattern and Risk of Hepatocellular Carcinoma in a Multiethnic Population: A Cohort Study

BackgroundPlant-based dietary patterns assessed by a priori indices are associated with various health outcomes, but have rarely been examined in relation to liver cancer. ObjectivesThis study investigated the associations between plant-based diets and risk of hepatocellular carcinoma (HCC) and evaluated whether the associations vary by sex and race and ethnicity. MethodsData were from a total of 170,321 African American, Japanese American, Latino, Native Hawaiian, and White adults aged 45–75 y who completed a food frequency questionnaire in the Multiethnic Cohort Study. Cox models with adjustment for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC according to 3 plant-based diet scores: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). ResultsDuring a mean follow-up of 19.6 y, 722 incident HCC cases were identified. Multivariate-adjusted HR (95% CI) per 10-point increase was 0.82 (0.71–0.94) for PDI, 0.84 (0.74–0.96) for hPDI, and 1.08 (0.95–1.23) for uPDI. We found no significant differences by sex (all Pheterogeneity ≥ 0.53) or race and ethnicity (all Pheterogeneity ≥ 0.31). ConclusionGreater adherence to plant-based diets rich in healthy plant foods and low in less healthy plant foods is associated with a reduced risk of HCC in a multiethnic population.

Population-attributable risk of modifiable lifestyle factors to hepatocellular carcinoma: The multi-ethnic cohort.

Lifestyle factors are well associated with risk of hepatocellular carcinoma (HCC). However, the impact of reducing adverse lifestyle behaviours on population-level burden of HCC is uncertain. We conducted prospective analysis of the population-based multi-ethnic cohort (MEC) with linkage to cancer registries. The association of lifestyle factors (smoking, alcohol, diet quality assessed by alternate Mediterranean diet score, coffee drinking, physical activity and body mass index) with HCC incidence was examined using Cox regression. Population-attributable risk (PAR, %) for the overall, lean and overweight/obese populations was determined. A total of 753 incident cases of HCC were identified in 181,346 participants over median follow-up of 23.1 years. Lifestyle factors associated with elevated HCC risk included former/current smoking, heavy alcohol use, poor diet quality, lower coffee intake and obesity, but not physical activity. The lifestyle factor with highest PAR was lower coffee intake (21.3%; 95% CI: 8.9%-33.0%), followed by current smoking (15.1%; 11.1%-19.0%), obesity (14.5%; 9.2%-19.8%), heavy alcohol use (7.1%; 3.5%-10.6%) and lower diet quality (4.1%; 0.1%-8.1%). The combined PAR of all high-risk lifestyle factors was 51.9% (95% CI: 30.1%-68.6%). A higher combined PAR was observed among lean (65.2%, 26.8%-85.7%) compared to overweight/obese (37.4%, 11.7%-58.3%) participants. Adjusting for viral hepatitis status in a linked MEC-Medicare dataset resulted in similar PAR results. Modifying lifestyle factors, particularly coffee intake, may have a substantial impact on HCC burden in diverse populations, with greater impact among lean adults. Diet and lifestyle counselling should be incorporated into HCC prevention strategies.

Risk prediction of hepatobiliary and pancreatic cancers in elderly Chinese: The Dongfeng-Tongji cohort.

Hepatobiliary and pancreatic (HBP) cancers are among the deadliest malignancies. The objective of the study is to build cost-effective models to identify high-risk individuals for early diagnosis and substantially to reduce the burden of HBP cancers. Based on the prospective Dongfeng-Tongji cohort with ∼6 years follow-up, we identified 162 incident cases of hepatocellular carcinoma (HCC), 53 of biliary tract cancer (BTC), and 58 of pancreatic cancer (PC). We matched three controls to each case by age, sex, and hospital. We applied conditional logistic regression to identify predictive clinical variables, from which we constructed clinical risk scores (CRSs). We evaluated the utility of CRSs in stratifying high-risk individuals by 10-fold cross-validation. Among 50 variables we screened, 6 were independent predictors of HCC, with the top ones being hepatitis (OR= 8.51, 95% CI (3.83, 18.9)), plateletcrit (OR= 0.57, 95% CI (0.42, 0.78)), and alanine aminotransferase (OR= 2.06, 95% CI (1.39, 3.06)). Gallstone (OR= 2.70, 95% CI (1.17, 6.24)) and direct bilirubin (OR= 1.58, 95% CI (1.08, 2.31)) were predictive of BTC, while hyperlipidemia (OR= 2.56, 95% CI (1.12, 5.82)) and fasting blood glucose (OR= 2.00, 95% CI (1.26, 3.15)) were predictive of PC. The CRSs achieved AUCs of 0.784 for HCC, 0.648 for BTC, and 0.666 for PC, respectively. When applying to the full cohort with age and sex included as predictors, the AUCs were increased to 0.818, 0.704, and 0.699, respectively. Disease history and routine clinical variables are predictive of incident HBP cancers in elderly Chinese.

Dietary inflammatory and insulinemic potential, risk of hepatocellular carcinoma, and chronic liver disease mortality.

Diet modulates inflammation and insulin response and may be an important modifiable factor in the primary prevention of hepatocellular carcinoma (HCC) and chronic liver disease (CLD). We developed the empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores to assess the inflammatory and insulinemic potentials of diet. We prospectively examined the associations of EDIP and EDIH at baseline with the following HCC risk and CLD mortality. We followed 485 931 individuals in the National Institutes of Health-American Association of Retired Persons Diet and Health Study since 1995. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). We confirmed 635 incident HCC cases and 993 CLD deaths. Participants in the highest compared with those in the lowest EDIP quartile had a 1.35 times higher risk of developing HCC (95% CI = 1.08 to 1.70, Ptrend = .0005) and a 1.70 times higher CLD mortality (95% CI = 1.41 to 2.04, Ptrend < .0001). For the same comparison, participants with the highest EDIH were at increased risk of HCC (HR = 1.53, 95% CI = 1.20 to 1.95, Ptrend = .0004) and CLD mortality (HR = 1.72, 95% CI = 1.42 to 2.01, Ptrend < .0001). Similar positive associations of scores with HCC risk and CLD mortality were observed for both women and men. Moreover, individuals in both the highest EDIP and EDIH tertiles had a 92% increased HCC risk (95% CI = 1.43 to 2.58) and 98% increased CLD mortality (95% CI = 1.27 to 3.08) compared with those in both lowest tertiles. Our findings suggest that inflammation and hyperinsulinemia are potential mechanisms linking diet to HCC development and CLD mortality.

Hepatitis C prevalence and elimination planning in Pakistan, a bottom-up approach accounting for provincial variation.

In Pakistan, substantial changes to hepatitis C virus (HCV) programming and treatment have occurred since the 2008 nationwide serosurvey estimated a 4.8% anti-HCV prevalence. In the absence of an updated national study, this analysis uses provincial data to estimate a national prevalence and the interventions needed to achieve elimination. Using a Delphi process, epidemiologic HCV data for the four provinces of Pakistan (accounting for 97% of the population) were reviewed with 21 subject-matter experts in Pakistan. Province-level estimates were inputted into a mathematical model to estimate the national HCV disease burden in the absence of intervention (Base), and if the World Health Organization (WHO) elimination targets are achieved by 2030 (80% reduction in new infections, 90% diagnosis coverage, 80% treatment coverage, and 65% reduction in mortality: WHO Elimination). An estimated 9,746,000 (7,573,000-10,006,000) Pakistanis were living with viraemic HCV as of January 1, 2021; a viraemic prevalence of 4.3% (3.3-4.4). WHO Elimination would require an annual average of 18.8million screens, 1.1million treatments, and 46,700 new infections prevented anually between 2022 and 2030. Elimination would reduce total infections by 7,045,000, save 152,000 lives and prevent 104,000 incident cases of hepatocellular carcinoma from 2015 to 2030. Blood surveys, programmatic data, and expert panel input uncovered more HCV infections and lower treatment numbers in the provinces than estimated using national extrapolations, demonstrating the benefits of a bottom-up approach. Screening and treatment must increase 20 times and 5 times, respectively, to curb the HCV epidemic in Pakistan and achieve elimination by 2030.

Abstract C106: Risk of hepatocellular carcinoma among people living with HIV in the United States

Abstract Background: Hepatocellular carcinoma (HCC) is the primary histological subtype of liver cancer, comprising up to 75% of such cases in the U.S. People living with HIV (PLWH) have a higher risk of HCC than the general population. A higher proportion of PLWH are coinfected with hepatitis B (HBV) or hepatitis C virus (HCV) due to shared transmission modalities such as injection drug use. Highly active antiretroviral therapy has improved survival from HIV infection, creating increased opportunities to develop liver cancer due to prolonged hepatic inflammation caused by chronic infection with HBV or HCV. Methods: We used data from the HIV/AIDS Cancer Match (HACM), a population-based HIV and cancer registry linkage in the U.S. We compared HCC risk in PLWH to the general population using standardized incidence ratios (SIRs), standardized by race/ethnicity, age group, HIV transmission risk group, calendar period, and registry. SIRs were estimated by race/ethnicity, age group, HIV transmission risk group, and calendar period. Poisson regression was used to estimate incidence rate ratios (RRs) among PLWH by race/ethnicity, age group, HIV transmission risk group and calendar period. In addition, data from Symphony Health, a Texas based health aggregator of medical claims determined the prevalence of HBV and/or HCV infection among people with HCC. Adjusted odds ratios identified predictors of HBV and HCV infection in PLWH with HCC. Results: There were 1,530 incident HCC cases from 2001–2016 in PLWH during over 4 million person-years of follow up. Compared to the general population, the overall SIR was 2.92 (95% CI 2.75-3.09). The risk of HCC was strongly elevated across all racial/ethnic and age groups. Rates were highest among NH-White PLWH (SIR 3.86; 95% CI 3.48-4.27) PLWH aged 40-49 (SIR 4.81; 95% CI 4.31-5.35) or aged 20-39 (SIR 4.15; 95% CI 2.82-5.89). Among PLWH, HCC risk was similar across racial/ethnic groups but increased with age. Compared to men who had sex with men (MSM), men who injected drugs had almost 4 times the risk of HCC (RR 3.93; 95% CI 3.38-4.55) while female PWID had a 60% increased risk (RR 1.61; 95% CI 1.28-2.01), and men with other or unknown HIV transmission had a 50% increased risk (RR 1.48; 95% CI 1.27-1.73). Between 2001-2004 and 2013-2016, rates of HCC declined 16% (RR 0.84; 95% CI 0.69-1.03). Using Symphony Health data, there were a total of 146 HCC cases, 38 coinfected with HBV, 84 with HCV, and 16 triply infected cases. Compared to MSMs, persons who inject drugs (PWID) had 85% decreased odds of HBV infection (aOR 0.15; 95% CI 0.05-0.50) and 8 times the odds of HCV infection (aOR 8.03; 95% CI 2.61-24.7). Conclusions: Utilizing recently updated population-based linked-surveillance data, we found risk of HCC has declined over time among PLWH, though rates remain significantly elevated compared to the general population, with particularly high risk among people who inject drugs. Prevention and treatment of HBV and HCV are needed to reduce HCC risk in this population. Citation Format: Jennifer K. McGee-Avila, Ilona Argirion, Thomas R. O’Brien, Eric Engels, Marie-Josèphe Horner, Qianlai Luo, Meredith Shiels. Risk of hepatocellular carcinoma among people living with HIV in the United States [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C106.

Alcohol consumption and hepatocellular carcinoma: novel insights from a prospective cohort study and nonlinear Mendelian randomization analysis

BackgroundHeavy drinking was well associated with an increased risk of hepatocellular carcinoma (HCC), whereas the effect of low-to-moderate drinking on HCC remains under debate.MethodsParticipants from the UK Biobank with detailed information on alcohol use and free of common diseases were included. Daily pure alcohol intake (g/day) was calculated, and the predominant alcoholic beverage type was assigned for each participant. Additive Cox regression model and nonlinear Mendelian randomization (NLMR) analyses were performed to evaluate the association of alcohol intake with HCC.ResultsOf 329,164 participants (52.3% females, mean [SD] age = 56.7 [8.0] years), 201 incident HCC cases were recorded during the median follow-up of 12.6 years. The best-fitted Cox regression model suggested a J-shaped relationship between daily alcohol intake level and HCC risk. However, NLMR analysis did not detect a nonlinear correlation between alcohol use and HCC (nonlinearity P-value: 0.386). The J-shaped correlation pattern was detected only in subjects who mainly drank wine but not in those who mainly drank beer, spirits, or fortified wine. Moderate wine drinking showed a significant alanine transaminase (ALT)- and aspartate aminotransferase-lowering effect compared to that of the nondrinkers. In low-risk populations of HCC including women, people aged < 60 years, subjects with normal ALT levels, and those carrying non-risk genotypes of PNPLA3 rs738409 and TM6SF2 rs58542926, we observed a J-shaped correlation between alcohol use and HCC; however, a positive dose–response correlation was found in their respective counterparts, even in those predominantly drinking wine.ConclusionsLow-to-moderate drinking may be inversely associated with the risk of HCC in low-risk populations, which may be largely driven by wine drinking. However, those in high-risk populations of HCC, such as men and older people, and those with abnormal ALT levels and carry genetic risk variants, should abstain from drinking alcohol. Given the small HCC case number, further validations with larger case numbers are warranted in future works.

Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality

Alcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk. To investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality. This prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021. Self-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment. The primary outcomes were incident cirrhosis and HCC cases and liver disease-related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models. A total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease-related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease-related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease-related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease-related mortality in persons with excessive drinking and obesity. This study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease-related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.

Exposure To Perfluoroalkyl Substances And Risk Of Hepatocellular Carcinoma In The Multiethnic Cohort

BACKGROUND AND AIM: Exposure to per- and polyfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data are lacking. We examined associations of PFAS exposure, altered metabolic pathways, and risk of non-viral HCC. METHODS: In this nested case-control study, prediagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort Study (MEC). Cases and controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach. RESULTS: High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES&amp;#x3e;55 &amp;#x3bc;g/L) were associated with more than 4 fold increased risk of HCC (OR=4.5; 95% CI: 1.2-16.0). The pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were in turn associated with HCC risk. We identified four metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short chain fatty acid), α-Ketoisovaleric acid (a branched-chain α-keto acid), and 7alpha-Hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC. CONCLUSTIONS: Exposure to high levels of PFOS was associated with increased risk of HCC, and the likely mechanisms were via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are warranted to confirm these findings. Key Words: Chemical exposure, exposome, perfluorinated alkyl substance, hepatocellular carcinoma, metabolome, bile acid, metabolic pathway

Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort

Background & AimsExposure to poly- and perfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data is lacking. We examined associations between PFAS exposure, altered metabolic pathways, and risk of non-viral HCC.MethodsIn this nested case-control study, pre-diagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort (MEC) study. Cases/controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome-wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach.ResultsHigh perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES; >55 μg/L) were associated with 4.5-fold increased risk of HCC (odds ratio 4.5, 95% CI 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk. We identified 4 metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short-chain fatty acid), α-ketoisovaleric acid (a branched-chain α-keto acid), and 7α-hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC.ConclusionThis proof-of-concept analysis shows that exposure to high PFOS levels was associated with increased risk of non-viral HCC, likely via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are needed to confirm these findings.Lay summaryPer- and polyfluoroalkyl substances (PFAS), often referred to as “forever chemicals” because they are difficult to break down and stay in the human body for years, are extremely common and can cause liver damage. In a first of its kind study, we found that exposure to high levels of perfluorooctanesulfonic acid, one of the most common PFAS chemicals, was linked to increased risk of hepatocellular carcinoma in humans. Hepatocellular carcinoma is difficult to treat and is one of the most common forms of liver cancer, and these findings may provide new avenues for helping to prevent this disease.

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)&amp;gt;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 &amp;gt;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.

Hepatocellular carcinoma in Stockholm, Sweden 2003–2018: a population-based cohort study

Background and aims Available epidemiological data on hepatocellular carcinoma (HCC) originate mainly from centre-based or disease-specific cohorts and may not reflect the general population. This population-based register study presents the incidence, aetiologies, treatments, survival, and differences related to sex or socioeconomic status in patients with HCC from Stockholm, which constitutes more than a fifth of the Swedish population. Methods ICD-10 codes identified incident HCC cases in the regional administrative health care database 2003–2018. Administrative coding on diseases, socioeconomic status, and dispensed drugs were used to identify risk factors and therapies. Two validation analyses 2014–2015 studied the correctness of register-based aetiologies and reasons for providing only best supportive care (BSC). Results We identified 2,245 incident cases of HCC. The incidence increased from 6 to 7.5 per 100,000 inhabitants over the time-period. The most common aetiologies were hepatitis C (26%), non-alcoholic fatty liver disease (22%), and alcohol-related liver disease (19%). Five-year survival probability was 79% after liver transplantation, 60% after resection, and 35% after ablation but <10% for chemoembolization, Sorafenib, and BSC. The proportion receiving any treatment increased but half of the patients only received BSC. At least 14% of potentially treatable HCC (surveillance indicated but not performed) received only BSC 2014–2015. We found no significant differences in treatments or outcomes between socioeconomic groups. Conclusions The incidence of HCC is rising in Stockholm, Sweden but is still low by global comparison. Near half of all patients still receive only BSC and study data suggest that surveillance practices are incomplete.