Risk Factors For Liver Cancer Research Articles

Hepatitis B Testing Among Vietnamese in Metropolitan Atlanta: The Role of Healthcare-Related and Acculturation-Related Factors.

Compared to other racial/ethnic groups, U.S. Vietnamese have higher Hepatitis B infection prevalence, which is a major liver cancer risk factor. Increased testing could reduce this disparity. It is critical to understand subgroups of U.S. Vietnamese least likely to have been tested for Hepatitis B and design appropriate interventions. We examined healthcare- and acculturation-related factors influencing Hepatitis B testing among U.S. Vietnamese. Survey data of 100 U.S. Vietnamese attending health fairs/programs hosted by community-based organizations (2017-2018) were analyzed. Healthcare-related predictors included insurance and past 2-year checkup. Acculturation-related predictors included Vancouver Acculturation Index, percentage of lifetime in the U.S., and Vietnamese and English fluency. We conducted a multiple logistic regression controlling for age, sex, education, and household income. The sample was an average 37.5years old and 61.6% female. Insurance coverage was reported by 83.0%. Average percentage of lifetime in the U.S. was 56.8%. Seventy percent reported having received Hepatitis B testing. Hepatitis B testing was associated with health insurance (aOR = 2.61, 95% CI = [1.05-6.47], p = .04) but not any acculturation-related predictors CONCLUSION: Improving insurance coverage and options can be a strategy to increase Hepatitis B testing among U.S. Vietnamese. More education regarding Hepatitis B (e.g., via community-based, culturally-appropriate, lay health worker-led programs) is needed to ensure that individuals are aware of their testing status and pursue appropriate healthcare decisions.

Spatial clustering analysis and trend of liver cancer death rate in Shandong province, 1970-2013

Objective: To explore the spatial clustering and trend of liver cancer mortality in different counties of Shandong province from 1970 to 2013, and provide scientific basis for the development of liver cancer prevention and control plan. Methods: Cancer mortality data were obtained from Shandong Death Registration System and three national death cause surveys in China. Mortality rate and age adjusted mortality rate were used to describe the trend of liver cancer in different years. Difference decomposing method was applied to estimate the contribution of demographic and non-demographic factors to the change of mortality. Software ArcGIS 10.2 was used for spatial analysis, and software SaTScan 9.4 was used for spatial clustering analysis on liver cancer mortality. Results: From 2011 to 2013, the crude mortality rate of liver cancer (29.89/100 000) in Shandong increased by 208.00% and 35.37% respectively compared with that during 1970-1974 (9.72/100 000) and 1990-1992 (22.08/100 000) and was similar to that during 2004-2005 (30.44/100 000). While age standardized mortality rate (ASMR) increased first and then decreased. The ASMR during 2011-2013 (12.62/100 000) increased by 60.97% compared with that during 1970-1974 and decreased by 22.38% and 21.81% compared with that during 1990-1992 and 2004-2005, respectively. According to the difference decomposition analysis on liver cancer mortality in different years, the contribution of population factors to the liver cancer mortality rate increased from 3.38% during 1990-1992 to 29.36% during 2004-2005 and 46.16% during 2011-2013. However, the contribution of non-population factors to the increase of liver cancer mortality decreased. According to the spatial distribution of liver cancer mortality, the crude mortality rate of liver cancer in different counties were quite different, ranging from 9.33/100 000 to 65.33/100 000. Using the spatial scanning statistical software to analyze the spatial clustering of liver cancer mortality, multi areas with high mortality rate of liver cancer were found, and they were mainly distributed in Jiaodong peninsula from 2011 to 2013, covering 20 counties (cities, districts) in Qingdao, Yantai and Weihai. The risk of liver cancer mortality in this area was 1.54 times higher than that in other areas. The spatial clustering distribution of liver cancer mortality during 1970-1974 was significantly different from that during 2011-2013, the areas with high mortality rate during 1970-1974 were mainly distributed in central and western Shandong. Conclusions: There were significant temporal and spatial distribution changes in the mortality rate of liver cancer in Shandong from 1970 to 2013. According to these trends and their geographical and spatial distribution, we should further explore the risk factors of liver cancer, and formulate feasible and area specific prevention and control measures for liver cancer.

A saturated fatty acid-rich diet enhances hepatic lipogenesis and tumorigenesis in HCV core gene transgenic mice

Previous studies suggested that high consumption of saturated fatty acid (SFA) is a risk factor for liver cancer. However, it remains unclear how dietary SFA affects liver tumorigenesis. This study aimed to investigate the impact of a SFA-rich diet on hepatic tumorigenesis using hepatitis C virus core gene transgenic (HCVcpTg) mice that spontaneously developed hepatic steatosis and tumors with aging. Male HCVcpTg mice were treated for 15 months with a purified control diet or SFA-rich diet prepared by replacing soybean oil in the control diet with hydrogenated coconut oil, and phenotypic changes were assessed. In this special diet, almost all dietary fatty acids were SFA. Long-term feeding of SFA-rich diet to HCVcpTg mice increased hepatic steatosis, liver dysfunction, and the prevalence of liver tumors, likely due to stimulation of de novo lipogenesis, activation of the pro-inflammatory and pro-oncogenic transcription factor nuclear factor-kappa B (NF-κB), enhanced c-Jun N-terminal kinase/activator protein 1 (JNK/AP-1) signaling and induction of the oncogenes cyclin D1 and p62/sequestosome 1. The SFA-rich diet did not affect liver fibrosis or autophagy. Collectively, long-term SFA-rich diet consumption promoted hepatic tumorigenesis mainly through activation of lipogenesis, NF-κB, and JNK/AP-1 signaling. We therefore propose that HCV-infected patients should avoid excessive intake of SFA-rich foods to prevent liver cancer.

Social impacts of living with chronic hepatitis B in South Sudanese community in Australia

ABSTRACT Introduction: Chronic hepatitis B presents significant issues to public health and clinical practices. The infection requires lifelong clinical management and is a leading risk factor for liver cancer and liver cirrhosis. Limited studies currently exist on the social impacts of living with chronic hepatitis B, especially for people from Sub-Saharan Africa. The current study explored the experiences of South Sudanese people living with chronic hepatitis B in Australia. Methods: A qualitative inquiry using face-to-face interviews with fifteen South Sudanese people with chronic hepatitis B in Australia explored the social impacts of living with chronic hepatitis B. The study purposively sampled participants who self-identified as South Sudanese with hepatitis B and over 18 years of age. Interviews were coded and analysed using thematic analysis. Results: The study identified three themes relating to the experiences of living with chronic hepatitis B, and were grouped into psychological, interpersonal and healthcare system levels. Psychological level experiences related to the uncertainty of living with chronic hepatitis B and liver cancer risk, where participants expressed persistent fear of disease progression and anxiety around death related to the disease. Interpersonal level experiences involved the disclosure of hepatitis B and its social impacts including stigma, social distancing and isolation. Healthcare system level experiences included receiving mixed messages about hepatitis B, challenges with regular testing and difficulty receiving hepatitis B treatment. Conclusion: The findings provide valuable insights into the social impacts of hepatitis B. It underlines the importance of integrated public health interventions at the community level to improve knowledge and awareness of hepatitis B which address stigma in the South Sudanese community in Australia.

Abstract IA38: Racial/ethnic differences in liver fat, an obesity-associated risk factor for liver cancer

Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is thought to be the main driver for the recent rise of chronic liver disease and liver cancer. NAFLD is also associated with other obesity-related metabolic diseases. Relative fat deposition in the liver varies by race/ethnicity and may partially account for liver cancer disparities. Thus, we aimed to compare liver fat content across five racial/ethnic groups, assess their contribution to the metabolic syndrome (MetSx), and predict NAFLD using common blood biomarkers. Methods: We conducted a cross-sectional study within the Multiethnic Cohort. A total of 1,861 healthy men and women aged 60-77 years were recruited, after stratification on sex, ethnicity (African, Japanese, Latino, Native Hawaiian, or white ancestry), and six BMI categories (range, 17.1-49.8 kg/m2). We estimated total fat mass using DXA and liver fat content using abdominal MR imaging. Fasting blood was analyzed for ~50 markers including adipocytokines, insulin and IGFs, lipids and lipid-soluble micronutrients, liver enzymes, and steroid hormones, using multiple assay platforms. Liver fat amounts were compared across sex and ethnic groups after adjustment for age, total fat mass, and height. The contribution of liver fat to MetSx was estimated in multivariable-adjusted mediation analysis. A prediction model for NAFLD was developed using regularized logistic regression. Results: The correlation between liver fat and total fat was only moderate (rSp = 0.34) and varied across ethnic groups (0.20-0.55). Liver fat content was similar between the sexes but differed by ethnicity (p<.0001), with a four-fold range in NAFLD prevalence between Japanese Americans (57% in men, 72% in women) and African Americans (12%, 19%) after adjustment for total fat mass. Total fat-adjusted prevalence of MetSx also differed by ethnicity: compared to whites, it was higher among Japanese Americans and Native Hawaiian women and lower among African Americans and Latinos. This ethnic difference was significantly mediated by liver fat among African Americans (proportion mediated =19-24%), Japanese Americans (22-34%), and Native Hawaiian women (20%). The final prediction model for NAFLD included age, sex, BMI, waist circumference, waist/hip, and top five biomarker predictors (IGFBP2, HOMA-IR, TG, adiponectin, SHBG). Discrimination of NAFLD cases in a validation dataset had high accuracy (AUC=0.90), across ethnic groups (AUCs of 0.80-0.96), and was significantly improved by the biomarkers (p's for contrast<.0001, except in African Americans). Conclusions: Relative fat storage in the liver varies substantially by race/ethnicity. In particular, Japanese Americans and Native Hawaiian women appear to experience a greater metabolic burden from their propensity to store excess fat in ectopic areas, which is consistent with a stronger association of BMI with liver cancer in these groups. Key metabolism markers may be used to successfully detect and monitor NAFLD patients of in various ethnic groups. Citation Format: Unhee Lim, Lynne R. Wilkens, Kristine R. Monroe, Iona Cheng, Bruce S. Kristal, Johanna W. Lampe, Meredith A. Hullar, John Shepherd, Thomas Ernst, Loic Le Marchand. Racial/ethnic differences in liver fat, an obesity-associated risk factor for liver cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA38.

Abstract A102: Factors associated with psychological distress among chronic hepatitis B patients

Abstract Background: Psychosocial stress is a common comorbidity in chronic hepatitis B (CHB) patients. A diagnosis of CHB, the primary risk factor for liver cancer among Asian Americans, can be a significant source of psychological and emotional stress. Although the disease can be life-changing, there is a paucity of research on psychosocial stress in CHB patients. The purpose of this study is to examine the prevalence of serious psychological distress (SPD) and factors associated with SPD in Asian CHB patients. Method: It is a prospective study design with subjects identified from an existing patient cohort that were enrolled and then subsequently followed up. Information was gathered from the CHB patients using face-to-face interviews in Korean or English. Serious psychological distress was measured by the Kessler Scale (K6). Measures of stressful life events and Hepatitis B Quality of Life (HBQOL) (e.g., psychological well-being, anticipation anxiety, stigma) were used. A multivariate logistic regression model (including gender, age, level of education) was conducted for analysis. Results. Of 50 CHB patients 18 years and older, the 12-month prevalence of SPD was estimated at 20% using the optimal cut-off (>=13). In adjusted regression analysis, stressful life events and HBQOL-stigma were related to serous psychological distress: Those who had stressful life events (aOR=3.10, 95% CI 1.26-7.64) and those who had high scores of stigma (aOR=1.19, 95% CI 0.97-1.44, p=.08) had higher psychological distress. Those with more than a college education had decreased psychological distress (aOR=0.09, 95% CI 0.01-0.82). Conclusion: The finding indicates CHB patients had a higher prevalence of serious psychological distress than the general Asian population (2.6% from California Health Interview Survey). Stigma connected to hepatitis B diagnosis and stressful life events were important factors associated with mental health. This suggests that disease burden caused by hepatitis B infection may lead to poor mental health. Future studies will identify those who are at a high likelihood of developing a mental disorder and develop effective interventions for early detection of mental illness. Citation Format: Hee-Soon Juon, Grace Park, Klassen Ann, Hie-Won Hann. Factors associated with psychological distress among chronic hepatitis B patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A102.

Abstract PR13: Geospatial analytics and sensitivity/specificity assessments to inform liver cancer prevention

Abstract Background: Liver cancer rates are rising, particularly in minority populations. Risk factors for liver cancer, such as alcohol/drug use, metabolic disorders, and viral hepatitis B/C (HBV/HCV), are generally modifiable through lifestyle interventions, vaccinations, and treatments. However, resources are often limited and strategies to prioritize geographic areas most in need of cancer prevention are needed. Recommendations exist to focus prevention efforts on groups with the highest rates of liver cancer, namely Hispanics, Blacks, and individuals born 1950-1959 who are at high risk for HCV. We compare the sensitivity/specificity of this approach to a dual approach that couples liver cancer disease cluster statistics with neighborhood-level demographic data to inform liver cancer prevention. Methods: Pennsylvania (PA) Liver Cancer Registry data from 2007-2014 were linked to the 2010 U.S. Census data via a geocode at the census tract level with ArcGIS software. Using the space-time scan statistic in SaTScan and relative risk estimates from BayesX, we also identified high-risk clusters or geographic areas with significantly elevated rates of incident liver cancer, adjusted for age, gender, and diagnosis year. Analyses were conducted using elliptical spatial windows and Poisson models. Census tracts in the top 80th percentile for percentage of Hispanics, Blacks or those born between 1950-1959 were also identified. The sensitivity, specificity, and positive predictive value (PPV) of a census tract being located in a high-risk cluster and/or testing positive or negative for at least one of three neighborhood variables (higher % Black, % Hispanic, 1950-1959 birth cohort) were calculated. Results: There were 9,460 cases of liver cancer diagnosed in PA. Five high-risk clusters were identified (relative risks ranged from 1.83-3.73, all p<0.05). Of 3,217 census tracts in PA, 412 were located in one of the 5 high-risk clusters, whereas 1,596 were positive for at least one of 3 neighborhood demographic variables. Within high-risk clusters, 365 census tracts also had a higher percentage of the birth cohort, Blacks or Hispanics. While sensitivity was relatively high (88.66%), specificity (56.1%) and PPV (22.8%; i.e., the chance a census tract with at least one demographic variable truly was located in a high-risk cluster) were low. Conclusions: Coupling disease cluster statistics with neighborhood demographic data refines the identification of areas that carry a greater than expected burden of liver cancer and reduces intervention targets more than neighborhood demographics alone. However, additional analyses are needed to improve the sensitivity/specificity of this combined geospatial approach. Consideration of other patient and neighborhood level socioeconomic data is also being explored and will be presented to further inform the prioritization of liver cancer prevention efforts. This abstract is also being presented as Poster C014. Citation Format: Shannon M. Lynch, Daniel Wiese, Kristen Sorice, Minhhuyen Nguyen, Evelyn Gonzalez, Kevin Henry. Geospatial analytics and sensitivity/specificity assessments to inform liver cancer prevention [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR13.

Abstract C087: The relationship between alcohol, physical activity, and obesity in Mexican-origin adults

Abstract Background. Alcohol intake, lack of physical activity (PA), and obesity are risk factors for liver cancer. Although studies indicate that PA and alcohol intake are positively associated with one another, this relationship is less studied in Hispanics, who have the highest rates of liver cancer in the U.S. Furthermore, the relationship between alcohol intake and obesity is nuanced, with current drinkers having lower risk of obesity than never drinkers. The first aim of this study was to assess the relationship between alcohol intake and PA in Hispanic adults; secondary aims were to assess the effects of PA and alcohol on body mass index (BMI) and assess differences by gender and country of birth. Methods. We used data from the Mano a Mano Cohort, a cohort of Mexican-origin individuals living in the greater Houston area, for individuals recruited since 2012. Data included self-reported PA, alcohol intake (never, former, and current drinker), and demographic characteristics; trained field staff measured BMI. PA was categorized as high (≥1500 MET minutes/week), moderate (≥600 MET minutes/week) or low. We used logistic regression to assess the association between PA and alcohol intake with BMI, including an interaction term. Results. This sample (n=3,899) had an average age of 49, were mostly women, and had not attained a high school degree. Most were obese (60%) and never drinkers (67%). Never drinkers had more individuals with low (42%) than moderate (32%) or high levels of PA (26%). Current drinkers had more individuals achieving high PA (32%) than either never (26%) or former drinkers (24%). Obese, compared to non-obese, individuals did less PA and had a greater proportion of never drinkers. High PA was protective against obesity in the full sample (Adjusted Odds Ratio [AOR]=0.81, 95%CI: 0.68-0.95, p<.05), in females (AOR=0.73, 95%CI: 0.60-0.89, p<.01), and in Mexican-born individuals (AOR=0.79, 95%CI: 0.66-0.95, p<.05). Current drinking was protective against obesity in Mexican-born individuals (AOR=0.77, 95%CI: 0.61-0.97, p<.05), and was associated with significantly lower BMI in the full sample, males, and Mexican-born individuals. Among never drinkers, compared to those with low PA, those with high PA were significantly less likely to be obese (AOR=0.79, 95%CI: 0.65-0.96, p<.05). The only significant interaction between PA and alcohol use was in male never drinkers; as compared to those with low PA, those with high PA had significantly higher BMI (Beta=2.67, 95%CI: 1.02-4.32, p<.01). Conclusions. In this study of Mexican-origin adults, both high PA and current drinking were independently protective against obesity. However, for the full sample and most sub-groups, never drinkers with high PA were the only group significantly protected against obesity. The difference in the independent and interaction results illustrates the importance of evaluating multiple risk behaviors together to inform liver cancer prevention efforts in Mexican-origin adults. Citation Format: Natalia I Heredia, Qiong Dong, Shine Chang, Lorna H McNeill. The relationship between alcohol, physical activity, and obesity in Mexican-origin adults [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C087.

The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling.

An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/β-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/β-catenin transcription. The effect of p22 on TCF/β-catenin transcription was dose dependent and inhibited by dominant-negative TCF4. HBV p22 activated synthetic and native Wnt target gene promoter reporters, and TCF/β-catenin target gene expression in vivo. Importantly, HBV p22 activated Wnt signaling on its own and in addition to Wnt or β-catenin induced Wnt signaling. Furthermore, HBV p22 elevated TCF/β-catenin transcription above constitutive activation in colon cancer cells due to mutations in downstream genes of the Wnt pathway, namely APC and CTNNB1. Collectively, our data identifies a previously unappreciated role for the HBV pre-core protein p22 in elevating Wnt signaling. Understanding the molecular mechanisms of p22 activity will provide insight into how Wnt signaling is fine-tuned in cancer.

Diet and liver cancer risk: a narrative review of epidemiological evidence.

Primary liver cancer is the third leading cause of cancer-related death worldwide. Most patients are diagnosed at late stages with poor prognosis; thus, identification of modifiable risk factors for primary prevention of liver cancer is urgently needed. The well-established risk factors of liver cancer include chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), heavy alcohol consumption, metabolic diseases such as obesity and diabetes, and aflatoxin exposure. However, a large proportion of cancer cases worldwide cannot be explained by current known risk factors. Dietary factors have been suspected as important, but dietary aetiology of liver cancer remains poorly understood. In this review, we summarised and evaluated the observational studies of diet including single nutrients, food and food groups, as well as dietary patterns with the risk of developing liver cancer. Although there are large knowledge gaps between diet and liver cancer risk, current epidemiological evidence supports an important role of diet in liver cancer development. For example, exposure to aflatoxin, heavy alcohol drinking and possibly dairy product (not including yogurt) intake increase, while intake of coffee, fish and tea, light-to-moderate alcohol drinking and several healthy dietary patterns (e.g. Alternative Healthy Eating Index) may decrease liver cancer risk. Future studies with large sample size and accurate diet measurement are warranted and need to consider issues such as the possible aetiological heterogeneity between liver cancer subtypes, the influence of chronic HBV or HCV infection, the high-risk populations (e.g. cirrhosis) and a potential interplay with host gut microbiota or genetic variations.

Comparison of High Fat and Low Fat Diets on Histopathological Changes in Liver in a Mouse Model of 4NQO‐induced Oral Cancer

IntroductionWorldwide, liver cancer remains among the top ten most common cancers. Risk factors for liver cancer include tobacco usage, alcohol consumption, obesity, and sex. Administration of 4‐nitroquinoline 1‐oxide (4NQO) in drinking water mimics the effects of tobacco and leads to oral carcinoma in mice. The purpose of this study was to compare the effects of high and low in saturated fat diets (HF and LF, respectively), and sex, on liver histopathology in 4NQO‐treated mice and controls. We hypothesized that 4NQO’s carcinogenic effects would cause histopathological changes in the liver. We also hypothesized that a HF diet would increase inflammation, steatosis, and fibrosis when compared to the LF diet.Materials and methodsMale and female C57Bl/6 mice (Jackson Labs, 36 each gender), 5 weeks old, were divided into a low fat (10 kcal% fat; LF) or HF (60 kcal% fat) diet. Within each dietary group, mice were randomly assigned to one of 3 water treatment groups for 17 weeks: water alone (control); propylene glycol in water (1.25%; PG‐H2O); or 4NQO in PG‐H2O (50 mg/ml; 4NQO). After 17 weeks, all mice were given water alone for 6 weeks prior to euthanasia. Livers were harvested, portions were frozen or formalin fixed, sectioned, and stained with hematoxylin and eosin (H&E). Histopathology criteria used for tissue assessment included steatosis, fibrosis, and lymphoid cell infiltration. Frozen liver samples were hydrolyzed and a colorimetric test was used to measure triglyceride content. Trichrome staining of collagen was performed, and slides were graded visually for fibrosis using an adapted Metavir scale. T‐cells (CD3+ cells), macrophages (CD68+ cells), and neutrophils (Ly6+ cells) were detected by immunohistochemistry, counted, and normalized to tissue area. Statistical analysis was done using GraphPad Prism 7.0. All animal work was in compliance with the regulations of IACUC at Midwestern University, Downers Grove, IL.ResultsCompared to water controls, 4NQO‐treatment significantly increased hepatic inflammatory cell infiltration by neutrophils (11± 1 vs. 31± 3 cells/mm2), T cells (76 ± 7 vs. 99 ± 6 cells/mm2), and macrophages (468 ± 40 vs. 562 ± 25 cells/mm2). Infiltration with inflammatory cells was accompanied by liver fibrosis. Interestingly, HF diet caused hepatic histopathologic changes with severe fatty changes in males, and only moderate fatty changes in female control mice. Thus, triglyceride content was significantly higher in HF males when compared to all other control groups (HF male 14.0 ± 3.2 %, LF male 2.9 ± 0.8 %, HF female 3.2 ± 0.4 %, and LF female 2.3 ± 0.5 %). Fatty change was significantly reduced by 4NQO treatment, possibly as a result of cachexia.ConclusionThis mouse model of oral cancer, initially established to mimic the effects of smoking, may be extended to serve as a model for the effects of tobacco and diet on liver as well.Support or Funding InformationWe recognize the Midwestern University Deans of the College of Dental Medicine and the College of Graduate studies for their support of this research. Student research was supported by the Office of Research and Sponsored Programs.

Systematic Review with Meta-Analysis: Low-Level Alcohol Consumption and the Risk of Liver Cancer.

Background/AimsMultiple meta-analyses and observational studies have reported that alcohol is a risk factor for liver cancer. However, whether there is a safe level of alcohol consumption remains unclear. We performed a systematic review and meta-analysis of the correlation between low-level alcohol consumption and the risk of liver cancer.MethodsNested case-control studies and cohort studies involving the general population published prior to July 2019 were searched. In total, 28 publications (31 cohorts) with 4,899 incident cases and 10,859 liver cancer-related deaths were included. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.ResultsCompared with those with low levels of alcohol consumption, moderate and heavy drinkers (≥1 drink/day for females and ≥2 drinks/day for males) had pooled ORs of 1.418 (95% CI, 1.192 to 1.687; p<0.001) for liver cancer incidence and 1.167 (95% CI, 1.056 to 1.290; p=0.003) for liver cancer mortality. The pooled OR for liver disease-related mortality for those with more than low levels of alcohol consumption was 3.220 (95% CI, 2.116 to 4.898; p<0.001) and that for all-cause mortality was 1.166 (95% CI, 1.065 to 1.278; p=0.001). The sensitivity analysis showed that none of the studies had a strong effect on the pooled OR. The Egger test, Begg rank correlation test, and the funnel plot showed no overt indication of publication bias.ConclusionsContinuous consumption of more than a low-level of alcohol (≥1 drink/day for females and ≥2 drinks/day for males) is related to a higher risk of liver cancer.

Comprehensive evaluation of SPATS2 expression and its prognostic potential in liver cancer.

Spermatogenesis associated serine rich 2 (SPATS2) has been reported to be dysregulated in few types of cancer; however, no reports have investigated SPATS2 in liver cancer. The aim of the present study was to investigate SPATS2 expression in liver cancer and to analyze its association with the prognosis of liver cancer patients.We examined the differential expression of SPATS2 in liver cancer by exploring The Cancer Genome Atlas (TCGA) database. The diagnostic efficiency of SPATS2 was obtained by Receiver Operating Characteristic (ROC) curve. The Chi-Squared test was used to assess clinical relevance. Survival analysis and Cox regression model were used to detect the effect of SPATS2 on the survival of liver cancer patients. Gene Set Enrichment Analysis (GSEA) was used to identify signaling pathways related to SPATS2 expression.SPATS2 is highly expressed in liver cancer (P < 2.2e-16) and has the high diagnostic ability (AUC = 0.964). Survival analysis showed that patients with high SPATS2 expression have an apparently shorter overall survival (OS, P < .0001) and relapse-free survival (RFS, P < .0001). Cox regression analysis showed that high SPATS2 expression might be an independent risk factor for liver cancer (OS, HR = 2.41, P = .000; RFS, HR = 1.90, P < .001). GSEA analysis identified 3 signaling pathways (Mitotic spindle, G2 M checkpoint, E2F targets) that were enriched in the presence of high SPATS2 expression.SPATS2 expression could be a novel diagnostic and prognostic biomarker in liver cancer.

Small Nucleolar RNA Host Gene 1 (SNHG1) and Chromosome 2 Open Reading Frame 48 (C2orf48) as Potential Prognostic Signatures for Liver Cancer by Constructing Regulatory Networks.

BackgroundLiver cancer is a common malignant tumor with poor prognosis. The present study sought to identify potential signatures that can predict the prognosis of patients with liver cancer.Material/MethodsThe RNA sequencing (RNA-seq) and clinical information of liver cancer patients were obtained from the Cancer Genome Atlas (TCGA) database. Differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were identified between liver cancer and adjacent normal tissues. After predicting lncRNA–miRNA and miRNA–mRNA pairs using online databases, the competing endogenous RNA (ceRNA) networks were constructed. Furthermore, the prognostic value of these differentially expressed genes was evaluated using univariate and multivariate Cox regression analyses.ResultsAfter constructing the ceRNA network, 2 lncRNAs small nucleolar RNA host gene 1 (SNHG1) and chromosome 2 open reading frame 48 (C2orf48) with the most nodes were identified. Correlation analysis revealed that SNHG1 was correlated with miR-195 and C2orf48 was correlated with miR-195 and miR-93. High expression of SNHG1, C2orf48, and miR-93 can contribute to poorer clinical outcomes compared to low expression. Furthermore, low miR-195 expression was correlated with shorter survival time than was high expression. SNHG1 and C2orf48 were closely associated with histology grade. Univariate and multivariate Cox regression analyses confirmed that SNHG1 and C2orf48 are risk factors for liver cancer.ConclusionsOur findings revealed that SNHG1 and C2orf48 possess potential prognostic value and should be considered as possible biomarkers for predicting clinical outcomes for patients with liver cancer.

Assessment of external risk factors of hepatocellular cancer development and markers of genetic predisposition to its development in the ethnic group of yakut - men

To establish the main external and genetically determined risk factors for the development of hepatocellular cancer in the ethnic group of male Yakuts living in the Republic of Sakha (Yakutia) [RS (Y)] in the epidemiologically unfavorable conditions of the incidence of viral hepatitis. A total of 97 male Yakuts were examined, including 44 people diagnosed with hepatocellular cancer and 53 people diagnosed with chronic viral hepatitis. HCC risk factors were identified by analyzing medical records and questioning patients. In the experimental and control groups, genetic studies of single nucleotide polymorphisms of genes mapped on the X-chromosome and involved in the activation of antiviral immunity along the TLR7 signaling pathway were performed. In 100% of patients with hepatocellular cancer, infection with hepatitis B, C, D viruses or co - infection with these agents was detected. Every fourth patient with HCC in the RS (Y) was infected with hepatitis D. The course of hepatocellular cancer associated with HDV was characterized by rapid progression of liver cirrhosis, development of portal hypertension, bleeding from varicose veins of the stomach and esophagus (36.4%) and edematous ascitic syndrome (63.6%). In addition to viral agents, additional risk factors for liver cancer were identified, such as alcohol abuse, overweight, diabetes mellitus, and smoking. Among the studied variation sites of genes localized on the X-chromosome and encoding the reaction of innate antiviral immunity, no genetic marker was found with a sufficient degree of confidence determining the likelihood of hepatocellular cancer developing. The high incidence of hepatocellular carcinoma of the male population in the RS (Y) is due to the widespread prevalence of parenteral viral hepatitis, especially viral hepatitis D. Due to the introduction of mass vaccination of the population against hepatitis B in the Russian Federation in the foreseeable future in the RS (Y) we should see a decrease in the proportion of hepatocellular cancer associated with hepatitis B and D viruses, and therefore the focus should be on the treatment and prevention of hepatitis C virus and non - infectious risk factors.

The Burden and Trends of Primary Liver Cancer Caused by Specific Etiologies from 1990 to 2017 at the Global, Regional, National, Age, and Sex Level Results from the Global Burden of Disease Study 2017

Background: Liver cancer is one of the leading causes of cancer-related deaths worldwide. The primary causes of liver cancer include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol consumption, nonalcoholic fatty liver disease, and other factors. Aims: The objective of this study was to evaluate the global and sex-, age-, region-, country-, and etiology-related liver cancer burden, as well as the trends in liver cancer caused by different etiologies. Methods: The causes of liver cancer from 1990 to 2017, including global, regional, and national liver cancer incidence, mortality, and etiology, were collected from the Global Burden of Disease study 2017, and the time-dependent change in the trends of liver cancer burden was evaluated by annual percentage change. Results: The global liver cancer incidence and mortality have been increasing. There were 950,000 newly-diagnosed liver cancer cases and over 800,000 deaths in 2017, which is more than twice the numbers recorded in 1990. HBV and HCV are the major causes of liver cancer. HBV is the major risk factor of liver cancer in Asia, while HCV and alcohol abuse are the major risk factors in the high sociodemographic index and high human development index regions. The mean onset age and incidence of liver cancer with different etiologies have gradually increased in the past 30 years. Conclusions: The global incidence is still rising and the causes have national, regional, or population specificities. More targeted prevention strategies must be developed for the different etiologic types in order to reduce liver cancer burden.

Contribution of high body mass index and alcohol use to liver cancer-related mortality: A study based on 195 countries or territories

BackgroundHigh body mass index (BMI) and alcohol use are well-defined risk factors for liver cancer. AimsWe aim to describe the contribution of high BMI and alcohol use to liver-cancer-related death at the global and national levels. MethodsThe data of liver cancer-related mortality attributable to all known risk factors, high BMI, and alcohol use were collected from the Global Burden of Disease database. The estimated average percentage change was used to quantify the liver cancer age-standardized mortality rate (ASMR) trends. ResultsGlobally, approximately 819,435 liver cancer-related deaths occurred in 2017, among which 415,867, 98,552, and 129,287 deaths could be ascribed to all 9 known risk factors, high BMI, and alcohol use, respectively. The overall ASMR increased from 4.42 per 100,000 to 5.17 per 100,000 in the study period. The liver cancer ASMR attributable to high BMI consistently increased at the global level and in most countries. The alcohol use-related liver cancer mortality decreased by 0.17% per year during the study period. However, a significant increase was found after 2008. ConclusionThe increase in high BMI-related liver cancer mortality suggests scarce attention to overweight and highlights its priority in future prevention schedules for liver cancer. Effective prevention measures are still needed to mitigate the adverse impact of alcohol consumption.

Deregulated Lysophosphatidic Acid Metabolism and Signaling in Liver Cancer.

Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.

In silico Simulation to Quantify Liver Cancer Risk with Smoking

Incidence of liver cancer is continuously increasing. American Cancer Society predicts about 42,030 new cases of liver cancer (29,480 in men and 12,550 in women) and 31,780 (21,600 men and 10,180 women) deaths due to liver cancer in 2019. There is a consensus that smoking is one of the known risk factors for liver cancer. Studies showed that current smokers have higher risk than former smokers. The purpose of this study to check a reduction in liver cancer risk by varying smoking status (from current to former) through a multi-parameterized neural network (NN). A multi-parameterized neural network (NN) was trained and tested with the National Health Interview Survey (NHIS) data collected from 1997 to 2017 and the Prostate, Lung, Colorectal, Ovarian cancer screening trail data collected from 1993 to 2001. Among a total of 795,163 persons interviewed, 478 were diagnosed with liver cancer. The features used as inputs for NN include age, race, BMI, race, Hispanic ethnicity, exercise habits, smoking, and drinking habits, diabetes, emphysema, stroke, hypertension, heart disease, arthritis, another cancer, family history of cancer. The NN was trained on 70% of the data and tested on 30% and the tested population was stratified as low, medium, and high risk for the liver cancer. Both training and testing datasets were stratified for low, medium, and high risk groups. Amongst high-risk group, 17 persons were selected those were obese (BMI > 0.30), current smokers, relatively heavy drinkers (drinks > 100 days/year) and not diagnosed for liver cancer at the survey time. The smoking status was changed from current smoker to former smoker in the input features of NN and the variation in their risks was studied. The areas under the curve of the conventional receiver operating characteristic plots for our neural network are 0.83 and 0.85 for the training and testing datasets, respectively. A considerable reduction (maximum reduction is 77.7%) in the risk values of the selected 17 people were observed by changing their status from current smoker to former smokers. Amongst these people, 35% (6 people) were shifted from high risk group to medium risk group. Normally, NN is used either for prediction or diagnosis. However, this study is using NN to simulate the variation of cancer risk with changes in habits/life style. The results indicate that the use of a NN based on personal health information cannot only be used for the stratification of large population for liver cancer risk but can also be used for simulating the cancer risk with varying lifestyle.

Raw Garlic Consumption and Risk of Liver Cancer: A Population-Based Case-Control Study in Eastern China.

Although the major risk factors for liver cancer have been established, preventive factors for liver cancer have not been fully explored. We evaluated the association between raw garlic consumption and liver cancer in a large population-based case-control study in Eastern China. The study was conducted in Jiangsu, China, from 2003 to 2010. A total of 2011 incident liver cancer cases and 7933 randomly selected population-controls were interviewed. Epidemiological data including raw garlic intake and other exposures were collected, and serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were assayed. Overall, eating raw garlic twice or more per week was inversely associated with liver cancer, with an adjusted odds ratio (aOR) of 0.77 (95% confidence interval (CI): 0.62–0.96) compared to those ingesting no raw garlic or less than twice per week. In stratified analyses, high intake of raw garlic was inversely associated with liver cancer among Hepatitis B surface antigen (HBsAg) negative individuals, frequent alcohol drinkers, those having history of eating mold-contaminated food or drinking raw water, and those without family history of liver cancer. Marginal interactions on an additive scale were observed between low raw garlic intake and HBsAg positivity (attributable proportion due to interaction (AP) = 0.31, 95% CI: -0.01–0.62) and heavy alcohol drinking (AP = 0.28, 95% CI: 0.00–0.57). Raw garlic consumption is inversely associated with liver cancer. Such an association shed some light on the potential etiologic role of garlic intake on liver cancer, which in turn might provide a possible dietary intervention to reduce liver cancer in Chinese population.