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Gut barrier dysfunction can result in the liver being exposed to an elevated level of gut‐derived bacterial products via portal circulation. Growing evidence suggests that systemic exposure to these bacterial products promotes liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, prospective studies have not examined the association between biomarkers of gut barrier dysfunction and HCC risk in a population of hepatitis B or C viral (HBV/HCV) carriers. We investigated whether prediagnostic, circulating biomarkers of gut barrier dysfunction were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)‐HBV and REVEAL‐HCV cohorts from Taiwan. REVEAL‐HBV included 185 cases and 161 matched controls, and REVEAL‐HCV 96 cases and 96 matched controls. The biomarkers quantitated were immunoglobulin A (IgA), IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and LPS‐binding protein (LBP). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarker levels and HCC were calculated using multivariable‐adjusted logistic regression. A doubling of the circulating levels of antiflagellin IgA or LBP was associated with a 76% to 93% increased risk of HBV‐related HCC (OR per one unit change in log2 antiflagellin IgA = 1.76, 95% CI: 1.06‐2.93; OR for LBP = 1.93, 95% CI: 1.10‐3.38). None of the other markers were associated with an increased risk of HBV‐related or HCV‐related HCC. Results were similar when cases diagnosed in the first 5 years of follow‐up were excluded. Our findings contribute to understanding the interplay of gut barrier dysfunction and primary liver cancer etiology. [ABSTRACT FROM AUTHOR]

Simple Summary: To date: no prospective cohort studies have been used to investigate the role of circulating immunologic markers as they relate to the progression of liver disease in those chronically infected with hepatitis C (HCV). Using data/samples from a prospective cohort of chronically HCV-infected individuals, we sampled 68 individuals who developed cirrhosis, 91 controls who did not develop cirrhosis, and 94 individuals who developed hepatocellular carcinoma (HCC). Using baseline plasma, we examined levels of 102 markers in individuals who developed cirrhosis vs. controls and those who developed HCC vs. cirrhosis. The findings from this study highlight the important role of immunological markers in predicting HCV-related cirrhosis. Background: Chronic hepatitis C virus (HCV) infection can affect immune response and inflammatory pathways, leading to severe liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Methods: In a prospective cohort of chronically HCV-infected individuals, we sampled 68 individuals who developed cirrhosis, 91 controls who did not develop cirrhosis, and 94 individuals who developed HCC. Unconditional odds ratios (ORs) from polytomous logistic regression models and canonical discriminant analyses (CDAs) were used to compare categorical (C) baseline plasma levels for 102 markers in individuals who developed cirrhosis vs. controls and those who developed HCC vs. cirrhosis. Leave-one-out cross validation was used to produce receiver operating characteristic curves to assess predictive ability of markers. Lastly, biological pathways were assessed in association with cirrhotic development compared to controls. Results: After multivariable adjustment, DEFA-1 (OR: C2v.C1 = 7.73; p < 0.0001), ITGAM (OR: C2v.C1 = 4.03; p = 0.0002), SCF (OR: C4v.C1 = 0.19; p-trend = 0.0001), and CCL11 (OR: C4v.C1 = 0.31; p-trend= 0.002) were all associated with development of cirrhosis compared to controls; these markers, together with clinical/demographics variables, improved prediction of cirrhosis from 55.7% (in clinical/demographic-only model) to 74.9% accuracy. A twelve-marker model based on CDA results further increased prediction of cirrhosis to 88.0%. While six biological pathways were found to be associated with cirrhosis, cell adhesion was the only pathway associated with cirrhosis after Bonferroni correction. In contrast to cirrhosis, DEFA-1 and ITGAM levels were inversely associated with HCC risk. Conclusions: Pending validation, these findings highlight the important role of immunological markers in predicting HCV-related cirrhosis even 11 years post-enrollment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the dominant histologic type of liver cancer, accounting for 75% of cases. Growing evidence suggests that the cross‐talk between the gut microbiome and metabolome (ie, gut‐liver axis) are related to the development of hepatic inflammation, and ultimately, HCC. Bile acids are metabolites, derived from cholesterol and synthesized in the liver, which may have a critical role in regulation of the gut‐liver axis. We investigated whether prediagnostic circulating bile acids were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)‐Hepatitis B Virus (HBV) and REVEAL‐Hepatitis C Virus (HCV) cohorts from Taiwan. Fifteen bile acids were quantitated using liquid chromatography, from 185 cases and 161 matched controls in REVEAL‐HBV and 96 cases and 96 matched controls in REVEAL‐HCV. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between bile acid levels and HCC were calculated using multivariable‐adjusted logistic regression. Higher levels of glycine and taurine conjugated primary bile acids were associated with a 2‐ to 8‐fold increased risk of HBV‐ (eg, glycocholic acid ORQ4vsQ1 = 3.38, 95% CI: 1.48‐7.71, Ptrend <.003) and HCV‐related HCC (eg, OR = 8.16, 95% CI: 2.21‐30.18, Ptrend <.001). However, higher levels of the secondary bile acid deoxycholic acid were inversely associated with HBV‐related HCC risk (OR = 0.41, 95% CI: 0.19‐0.88, Ptrend =.02). Our study provides evidence that higher concentrations of bile acids—specifically, conjugated primary bile acids—are associated with increased HCC risk. However, our study does not support the hypothesis that higher levels of secondary bile acids increase liver cancer risk; indeed, deoxycholic acid may be associated with a decreased HCC risk. What's new? The bacteria in the gut convert bile acids into secondary bile acids. In rodents, these acids increase the risk of hepatocellular carcinoma (HCC). In this study, however, the authors found that the same does not apply to humans. Instead, primary bile acids are associated with an increased risk, at least in patients with hepatitis B or C viral infection. Secondary bile acids, such as deoxycholic acid, may even decrease HCC risk. The human microbiome is intricately linked with hepatic metabolic processes, known as the gut‐liver axis, and the present study highlights the need to examine this cross‐talk between the microbiome and metabolome. [ABSTRACT FROM AUTHOR]