Search

Background: Nonalcoholic fatty liver disease (NAFLD) is a major contributor to the rising incidence of hepatocellular carcinoma (HCC). Magnesium is a major cation in cellular activities. Epidemiological data on magnesium level and its relation to HCC are sparse. This study aimed to examine the associations between serum levels of magnesium and the risk of HCC among patients with NAFLD. Methods: A total of 26,053 patients with NAFLD were identified in the University of Pittsburgh Medical Center Electronic Health Records from 2004 through 2018. After an average of 5.15 years of follow‐up, 395 patients developed HCC after the first measurement of serum magnesium. Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% CIs of HCC incidence associated with quartile levels of serum magnesium after adjustment for age, sex, race, body mass index, diuretics use, history of type 2 diabetes, history of hypertension, history of hyperlipidemia, and tobacco smoking. Results: Patients with NAFLD who developed HCC had a significantly lower mean (± standard deviation) serum magnesium (0.769 ± 0.131 mmol/L) than those who remained free of HCC (0.789 ± 0.125 mmol/L; p =.003). Compared with the lowest quartile, the HRs (95% CIs) of HCC second, third, and fourth quartiles of serum magnesium were 0.87 (0.67–1.12), 0.77 (0.57–1.04), and 0.73 (0.56–0.96), respectively, after adjustment for multiple potential confounders (Ptrend =.02). Conclusion: This finding suggests higher levels of serum magnesium were significantly associated with decreased risk of HCC among patients with NAFLD. Monitoring serum magnesium levels among those with nonalcoholic fatty liver disease may be beneficial in hepatocellular carcinoma primary prevention. [ABSTRACT FROM AUTHOR]

Background: Blood neutrophil to lymphocyte ratio (NLR) or lymphocyte count may be important markers for immune function. Previous work has shown higher NLR was associated with higher risk of hepatitis B‐related hepatocellular carcinoma (HCC). However, studies in non‐alcoholic fatty liver disease (NAFLD) patients are lacking. Methods: Utilizing the University of Pittsburgh Medical Center (UPMC) electronic health records, we created a retrospective cohort of 27,834 patients diagnosed with NAFLD from 2004 to 2018 with complete NLR data. After an average 5.5 years of follow‐up, 203 patients developed HCC. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence associated with different levels of NLR and lymphocyte count. Results: Compared with the lowest tertile of NLR (<1.97), the highest tertile of NLR (≥3.09) was statistically significantly associated with a 43% higher risk of HCC incidence (HR = 1.43, 95% CI: 1.01–2.03, ptrend = 0.031) after adjustment for age, sex, race, body mass index, smoking status, history of type 2 diabetes, hyperlipidemia, hypertension, and fibrosis‐4 score category. Conversely the highest tertile of lymphocyte count (≥2.15 K/ul) was significantly associated with a 36% lower risk of HCC (HR = 0.64, 95% CI: 0.43–0.94, ptrend = 0.028) compared to the lowest tertile (<1.55 K/ul). There was no association between neutrophil count and HCC risk. Conclusions: Higher NLR and lower lymphocyte count are associated with significantly higher risk of HCC among NAFLD patients. These findings warrant further investigation of immune response and surveillance in association with HCC development in NAFLD patients. [ABSTRACT FROM AUTHOR]

It is difficult to identify people with nonalcoholic fatty liver disease (NAFLD) who are at high risk for developing hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat (HFC‐PRS) derived from non‐Asians has been reported to be associated with HCC risk in European populations. However, population‐level data of this risk in Asian populations are lacking. Utilizing resources from 24,333 participants of the Singapore Chinese Health Study (SCHS), we examined the relationship between the HFC‐PRS and HCC risk. In addition, we constructed and evaluated a NAFLD‐related PRS (NAFLD‐PRS) with HCC risk in the SCHS. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence with both HFC‐PRS and NAFLD‐PRS. The HFC‐PRS and NAFLD‐PRS were highly correlated (Spearman r = 0.79, p < 0.001). The highest quartiles of both the HFC‐PRS and the NAFLD‐PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared with their respective lowest quartile. Conclusion: The PRS for hepatic fat content or NAFLD may be useful for assessing HCC risk in both Asian and European populations. The findings of this and prior studies support a potential causal role of genetically determined NAFLD in HCC development. [ABSTRACT FROM AUTHOR]

There is limited research on the effect of dietary quality on hepatocellular carcinoma (HCC) risk in populations with relatively high risk of HCC. Using data from Singapore Chinese Health Study, a prospective cohort study, of 63 257 Chinese aged 45 to 74, we assessed four diet‐quality index (DQI) scores: the Alternative Health Eating Index‐2010 (AHEI‐2010), Alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI). We identified 561 incident HCC cases among the cohort participants after a mean of 17.6 years of follow‐up. Cox proportional hazard regression model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for HCC in relation to these DQI scores. Unconditional logistic regression method was used to evaluate the associations between DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). High scores of AHEI‐2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend <.05). Compared with the lowest quartile, HRs (95% CIs) of HCC for the highest quartile of AHEI‐2010, aMED and DASH were 0.69 (0.53‐0.89), 0.70 (0.52‐0.95) and 0.67 (0.51‐0.87), respectively. No significant association between HDI and HCC risk was observed. Among HBsAg‐negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED (HRQ4vsQ1 = 0.46, 95% CI: 0.23‐0.94, Ptrend =.10). These findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC. What's new? Can improving the daily diet of high‐risk populations lower their risk of hepatocellular carcinoma (HCC)? In this large, prospective Asian study, the authors found that the answer is yes. Three different diet‐quality index (DQI) scores were associated with a significant drop in HCC risk, by as much as 30%. These included the AHEI‐2010, aMED, and DASH. These findings suggest that public‐health programs emphasizing dietary modification may offer an effective strategy for the prevention of HCC. [ABSTRACT FROM AUTHOR]

Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of hepatocellular carcinoma (HCC). We conducted a nested case–control study of 347 HCC cases and 691 matched controls within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8- epi -prostaglandin F2α (8- epi -PGF2α), a biomarker of oxidative stress, and prostaglandin E2 (PGE2) metabolite (PGE-M), a biomarker of the inflammation mediator PGE2, were determined in baseline urine samples using validated mass spectrometry assays. 8- epi- PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 versus 0.80 pmol/mg creatinine, P < 0.001). The relative risks of developing HCC for the highest relative to the lowest quartile of 8- epi- PGF2α were 2.55 (95% confidence interval = 1.62–4.01, P trend < 0.001). This positive 8- epi -PGF2α–HCC risk association was independent of smoking status, alcohol consumption and hepatitis B or liver cirrhosis and was present 10 years before the clinical manifestation of HCC. This study did not find any significant association between urinary PEG-M and HCC risk. This study provides direct evidence in support of the critical role of oxidative stress in the development of HCC regardless of its underlying causes. [ABSTRACT FROM AUTHOR]

ABO blood type is an inherited characteristic. The associations between ABO blood type and risk of all cancer and specific cancers were examined in a prospective cohort study of 18,244 Chinese men enrolled in 1986. During the 25 years of follow-up, 3,973 men developed cancer including 964 lung cancers, 624 colorectal cancers, 560 gastric cancers, 353 liver cancers, and 172 urinary bladder cancers. Hazard ratios (HR) for all cancer and specific cancers by ABO blood type were calculated using Cox proportional hazards models. Compared with blood type A, blood type B was associated with statistically significant reduced risk of all cancers (HR, 0.91, 95% CI:0.84, 0.99). Both blood types B and AB were associated with significantly lower risk of gastrointestinal cancer and colorectal cancer, respectively. Blood type B was also associated with significantly lower risk of stomach cancer and bladder cancer, while blood type AB was associated with significantly increased risk of liver cancer. By histological type, blood types B and AB were associated with lower risk of epidermoid carcinoma and adenocarcinoma, but were not associated with risk of sarcoma, lymphoma, leukemia or other cell types of cancer. The findings of this study support a role of genetic traits related to ABO blood type in the development of cancers in the gastrointestinal and urinary tracts. [ABSTRACT FROM AUTHOR]

Background & Aim Lipidomic signature of lipid metabolism suggests that omega-6 polyunsaturated fatty acids ( PUFA) may play a role in oncogenesis of hepatocellular carcinoma ( HCC). Hence, we examined the association between dietary fatty acids and risk of HCC. Methods We used data from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 Chinese men and women aged 45-74 years enrolled between 1993 and 1998. Information on current diet assessed via a validated semi-quantitative food frequency questionnaire, medical history and lifestyle factors were obtained through in-person interview, and incidence of HCC recorded through 31 Dec 2010. We also examined the association between dietary fatty acids and HCC risk using a case-control set of 92 cases and 274 controls with available serological biomarkers of chronic infections with hepatitis B virus ( HBV) and hepatitis C virus ( HCV) nested within this cohort. Results Among the dietary fat components examined, which included saturated, monounsaturated, omega-3 and omega-6 PUFA, only omega-6 PUFA intake displayed a dose-dependent, positive association with HCC risk (p for trend = 0.02). Compared to the lowest quartile, the hazard ratio for the highest quartile intake was 1.49 [(95% confidence interval ( CI):1.08-2.07)]. In the nested case-control study, only among individuals negative for serology markers of chronic infection with HBV or HCV, those who consumed above median levels of dietary omega-6 PUFA had increased HCC risk (odds ratio = 4.36, 95% CI = 1.59-11.94) compared to those with lower intake. Conclusion Dietary omega-6 PUFA may be implicated in the risk of non-viral hepatitis related HCC. [ABSTRACT FROM AUTHOR]

Dietary catechins are phytochemicals with both antioxidative and prooxidative stress properties. Green tea is a major source of catechins and may be associated with hepatocellular carcinoma (HCC) risk, but the catechin-HCC relationship has not been evaluated using a biomarker-based approach. A nested case-control study of HCC (211 cases and 1,067 matched controls) was conducted within the Shanghai Cohort Study, which enrolled 18,244 men between 1986 and 1989. Concentrations of specific catechins, including epicatechin, epigallocatechin (EGC), and 4′-O-methyl-epigallocatechin, were measured in urine specimens that had been collected prior to HCC diagnosis. None of the catechins measured were associated with HCC risk. In stratified analyses, there was a statistically significant trend for an association of higher urinary EGC with increased HCC risk among subjects with positive serology for hepatitis B surface antigen (P for trend = 0.02). This positive EGC-HCC association became stronger for hepatitis B surface antigen–positive persons who also had low serum retinol levels (for detectable levels vs. undetectable levels, odds ratio = 2.62, 95% confidence interval: 1.25, 5.51). There was no evidence supporting a protective role of catechins in the development of HCC. Instead, exposure to high levels of catechins may increase the risk of developing HCC for high-risk individuals. [ABSTRACT FROM PUBLISHER]

Background: Earlier, we reported a highly statistically significant association between T-helper 1 (Th1) and Th2 cytokine genotypes and hepatocellular carcinoma (HCC) risk among natives of southern Guangxi, China, a hyperendemic region for HCC. Epidermal growth factor (EGF) plays a critical role in malignant transformation of hepatocytes and tumor progression. A polymorphism in the EGF gene (61A > G) results in elevation of EGF in liver tissues and blood. Epidemiological data are sparse on the possible association between EGF genetic polymorphism and HCC risk.Methods: The EGF 61A > G polymorphism, multiple Th1 and Th2 genotypes, and environmental risk factors for HCC were determined on 117 HCC cases and 225 healthy control subjects among non-Asians of Los Angeles County, California, a low-risk population for HCC, and 250 HCC cases and 245 controls of southern Guangxi, China.Results: Following adjustment for all known or suspected HCC risk factors, non-Asians in Los Angeles who possessed at least one copy of the high activity 61*G allele of the EGF gene showed a statistically non-significant, 78% increased risk of HCC compared with those possessing the EGF A/A genotype. This EGF-HCC risk association significantly strengthened among heavy users of alcohol [odds ratio (OR) = 3.44, 95% confidence interval (CI) = 0.93-12.76, P = 0.065)], and among individuals carrying the high-risk Th1/Th2 genotypes for HCC (OR = 3.34, 95% CI = 1.24-9.03, P = 0.017). No association between EGF genotype and HCC risk was observed among Chinese in southern Guangxi, China.Conclusion: Genetic polymorphism in the EGF gene resulting in elevated level of EGF, may contribute to HCC risk among low-risk non-Asians in Los Angeles. [ABSTRACT FROM AUTHOR]

Background: Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6.Methods: First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case-control studies: 1 in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County.Results: Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (P(trend) = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18-4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele.Conclusions: This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis-related HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. The increasing incidence rate of HCC in developed countries has been linked to increasing prevalence of metabolic dysfunction-associated fatty liver disease, which has characteristics of altered bile acid metabolism that may predate hepatocarcinogenesis. The aim of the present study was to assess the association of circulating bile acid levels in pre-diagnostic serum with the risk of developing HCC in a general population in Singapore. Primary conjugated bile acids were most strongly associated with increased risk of HCC whereas the ratios of secondary over primary bile acids were significantly associated with reduced risk. These results support a contributing role of dysmetabolism of bile acids in the development of HCC. The modulation of bile acid metabolism through alteration of gut microbiota may be an effective strategy for primary prevention against HCC in individuals with metabolic dysfunction-associated fatty liver disease. Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy with poor prognosis. Rising incidence of HCC may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development. Thirty-five bile acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays in pre-diagnostic serum of 100 HCC cases and 100 matched controls from the Singapore Chinese Health Study. Conditional logistic regression was used to assess associations for bile acid levels with risk of HCC. Conjugated primary bile acids were significantly elevated whereas the ratios of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls. The respective odds ratios and 95% confidence intervals of HCC were 6.09 (1.75–21.21) for highest vs. lowest tertile of cholic acid species and 30.11 (5.88–154.31) for chenodeoxycholic acid species. Doubling ratio of taurine-over glycine-conjugated chenodeoxycholic acid was associated significantly with 40% increased risk of HCC whereas doubling ratio of secondary over primary bile acid species was associated with 30–40% reduced risk of HCC. In conclusion, elevated primary bile acids and taurine over glycine-conjugated ratios were strongly associated with HCC risk whereas the ratios of secondary bile acids over primary bile acids were inversely associated with HCC risk. [ABSTRACT FROM AUTHOR]