Retinoid and carotenoid status in serum and liver among patients at high-risk for liver cancer

BACKGROUND: Approximately 2.7 million Americans are chronically infected with hepatitis C virus (HCV). HCV patients with cirrhosis form the largest group of persons at high risk for hepatocellular carcinoma (HCC). Increased oxidative stress is regarded as a major mechanism of HCV-related liver disease progression. Deficiencies in retinoid and carotenoid antioxidants may represent a major modifiable risk factor for disease progression. This study aims to identify key predictors of serum antioxidant levels in patients with HCV, to examine the relationship between retinoid/carotenoid concentrations in serum and hepatic tissue, to quantify the association between systemic measures of oxidative stress and antioxidant status, and to examine the relationship between retinoids and stellate cell activation. METHODS: Patients undergoing liver biopsy (n = 69) provided fasting blood, fresh tissue, urine and completed a diet history questionnaire. Serum and questionnaire data from healthy volunteers (n = 11), normal liver tissue from public repositories and patients without liver disease (n = 11) were also collected. Urinary isoprostanes, serum and tissue retinoid concentrations were obtained by UHPLC-MS-MS. Immunohistochemistry for αSMA was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between urinary isoprostanes, αSMA levels, and retinoids were assessed using Spearman correlation coefficients and non-parametric tests were utilized to test differences among disease severity groups. RESULTS: There was a significant inverse association between serum retinol, lycopene, and RBP4 concentrations with fibrosis stage. Serum β-carotene and lycopene were strongly associated with their respective tissue concentrations. There was a weak downward trend of tissue retinyl palmitate with increasing fibrosis stage. Tissue retinyl palmitate was inversely and significantly correlated with hepatic αSMA expression, a marker for hepatic stellate cell activation (r = −0.31, P < 0.02). Urinary isoprostanes levels were inversely correlated with serum retinol, β-carotene, and RBP4. CONCLUSIONS: A decrease in serum retinol, β-carotene, and RBP4 is associated with early stage HCV. Retinoid and carotenoid levels decline as disease progresses, and our data suggest that this decline occurs early in the disease process, even before fibrosis is apparent. Measures of oxidative stress are associated with fibrosis stage and concurrent antioxidant depletion. Vitamin A loss is accompanied by stellate cell activation in hepatic tissue. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12876-016-0432-5) contains supplementary material, which is available to authorized users

Iron Status and Gestational Diabetes—A Meta-Analysis

A meta-analysis of the association of iron overload with gestational diabetes mellitus (GDM) may inform the health debate. We performed a meta-analysis investigating the association of iron biomarkers and dietary iron exposure with GDM. We identified 33 eligible studies (N = 44,110) published in 2001–2017. The standardized mean differences (SMD) in women who had GDM compared to pregnant women without were 0.25 µg/dL (95% CI: 0.001–0.50) for iron, 1.54 ng/mL (0.56–2.53) for ferritin, 1.05% (0.02 to 2.08) for transferrin saturation, and 0.81 g/dL (0.40–1.22) for hemoglobin. Adjusted odds ratio for GDM were 1.58 (95% CI: 1.20–2.08) for ferritin, 1.30 (1.01–1.67) for hemoglobin, and 1.48 (1.29–1.69) for dietary heme intake. We did not find any differences in TIBC or transferrin concentration in women with and without GDM. We also did not find any association of increased transferrin receptor or increased intake of total dietary iron, non-heme iron or supplemental iron, with increased odds ratios for GDM. Considerable heterogeneity was present among the studies (0–99%), but no evidence of publication bias. Accumulating evidence suggests that circulating and dietary iron biomarkers among pregnant women are associated with GDM, but the results should be interpreted with caution due to the high heterogeneity of analyses. Randomized trials investigating the benefits of iron reduction in women at high risk for GDM are warranted

Integrating Biomarkers into Translational Research on Diet and Cancer

Here, we elucidate dietary factors that contribute to or protect against liver and prostate cancer, and their relationship with underlying pathophysiologic mechanisms. Alpha-methylacyl-CoA racemase (AMACR) is an enzyme involved in fatty acid metabolism that is markedly over-expressed in virtually all prostate cancers (PCa), relative to benign tissue. Phytanic acid, one of AMACR’s primary substrates, is derived predominately from red meat and dairy product consumption. Epidemiological evidence suggests links between dairy/red meat intake, as well as phytanic acid levels, and elevated PCa risk. The first study investigates the relationships among dietary intake, serum and tissue concentrations of phytanic acid, and AMACR expression (mRNA and protein) in the histologically benign human prostate. Our data could not unify the hypothesis that excess levels of dietary phytanic acid are responsible for both the overexpression of AMACR in prostate cancer and the potential association between PCa risk and intake of dairy foods and red meat. The focus of the second part is vitamin A, iron, and the joint relationship of vitamin A and iron in patients at high risk for liver cancer. HCV patients with cirrhosis form the largest group of persons at high risk for hepatocellular carcinoma (HCC). Increased oxidative stress is regarded as a major mechanism of HCV-related liver disease progression. Deficiencies in retinoid and carotenoid antioxidants and increased iron may represent a major modifiable risk factor for HCC progression. We observed that a decrease in serum retinol, β-carotene, and RBP4 is associated with early stage HCV infection. Retinoid and carotenoid levels decline as disease progresses, and our data suggest that this decline occurs early in the disease process, even before fibrosis is apparent. Measures of oxidative stress are associated with fibrosis stage and concurrent antioxidant depletion. Vitamin A loss is accompanied by stellate cell activation in hepatic tissue. We observed an increase in serum iron biomarkers in CLD patients compared to controls. Serum retinoids were inversely associated with serum iron biomarkers. However, there was little evidence of a joint effect between iron and retinoids in early CLD

Iron Status and Gestational Diabetes—A Meta-Analysis

A meta-analysis of the association of iron overload with gestational diabetes mellitus (GDM) may inform the health debate. We performed a meta-analysis investigating the association of iron biomarkers and dietary iron exposure with GDM. We identified 33 eligible studies (N = 44,110) published in 2001–2017. The standardized mean differences (SMD) in women who had GDM compared to pregnant women without were 0.25 µg/dL (95% CI: 0.001–0.50) for iron, 1.54 ng/mL (0.56–2.53) for ferritin, 1.05% (0.02 to 2.08) for transferrin saturation, and 0.81 g/dL (0.40–1.22) for hemoglobin. Adjusted odds ratio for GDM were 1.58 (95% CI: 1.20–2.08) for ferritin, 1.30 (1.01–1.67) for hemoglobin, and 1.48 (1.29–1.69) for dietary heme intake. We did not find any differences in TIBC or transferrin concentration in women with and without GDM. We also did not find any association of increased transferrin receptor or increased intake of total dietary iron, non-heme iron or supplemental iron, with increased odds ratios for GDM. Considerable heterogeneity was present among the studies (0–99%), but no evidence of publication bias. Accumulating evidence suggests that circulating and dietary iron biomarkers among pregnant women are associated with GDM, but the results should be interpreted with caution due to the high heterogeneity of analyses. Randomized trials investigating the benefits of iron reduction in women at high risk for GDM are warranted

Dietary influences on tissue concentrations of phytanic acid and AMACR expression in the benign human prostate

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR) is an enzyme involved in fatty acid metabolism that is markedly over-expressed in virtually all prostate cancers (PCa), relative to benign tissue. One of AMACR\u27s primary substrates, phytanic acid, is derived predominately from red meat and dairy product consumption. Epidemiological evidence suggests links between dairy/red meat intake, as well as phytanic acid levels, and elevated PCa risk. This study investigates the relationships among dietary intake, serum and tissue concentrations of phytanic acid, and AMACR expression (mRNA and protein) in the histologically benign human prostate. METHODS: Men undergoing radical prostatectomy for the treatment of localized disease provided a food frequency questionnaire (n = 68), fasting blood (n = 35), benign fresh frozen prostate tissue (n = 26), and formalin-fixed paraffin-embedded (FFPE) sections (n = 67). Serum and tissue phytanic acid concentrations were obtained by gas chromatography-mass spectrometry. We extracted RNA from epithelial cells using laser capture microdissection and quantified mRNA expression of AMACR and other genes involved in the peroxisomal phytanic acid metabolism pathway via qRT-PCR. Immunohistochemistry for AMACR was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between diet, serum, and tissue phytanic acid levels, as well as AMACR and other gene expression levels were assessed by partial Spearman correlation coefficients. RESULTS: High-fat dairy intake was the strongest predictor of circulating phytanic acid concentrations (r = 0.35, P = 0.04). Tissue phytanic acid concentrations were not associated with any dietary sources and were only weakly correlated with serum levels (r = 0.29, P = 0.15). AMACR gene expression was not associated with serum phytanic acid (r = 0.13, P = 0.47), prostatic phytanic acid concentrations (r = 0.03, P = 0.88), or AMACR protein expression (r = -0.16, P = 0.20). CONCLUSIONS: Our data underscore the complexity of the relationship between AMACR and its substrates and do not support the unifying hypothesis that excess levels of dietary phytanic acid are responsible for both the overexpression of AMACR in prostate cancer and the potential association between PCa risk and intake of dairy foods and red meat

Abstract 4480: Associations between phytanic acid and alpha-methylacyl-CoA racemase (AMACR) expression in the normal human prostate

Abstract Alpha-methylacyl-CoA racemase (AMACR) is an enzyme that is overexpressed in prostate cancer, with lower levels present in normal prostatic tissues. AMACR is involved in the metabolism of phytanic acid - a branched chain saturated fatty acid that has been linked with elevated risks of prostate cancer in several epidemiologic studies. Although considerable research has been done on AMACR as a clinical biomarker in prostate cancer, no study has evaluated the possible link between phytanic acid and AMACR gene expression in the normal human prostate, and thus the possibility that AMACR plays a causal role in prostate carcinogenesis. Fasting blood and histologcally benign prostate tissue samples were obtained from 31 men undergoing radical prostatectomy for the treatment of localized disease. Concentrations of phytanic acid in serum and tissues were determined by isotope dilution gas chromatography-mass spectrometry. RNA was extracted from epithelial cells isolated from fresh-frozen prostate tissues by laser capture microdissection, and AMACR mRNA levels were quantified using real time polymerase chain reaction. Tissue phytanic acid concentrations were not significantly correlated with serum levels nor with prostatic AMACR mRNA levels. Notably, AMACR was significantly inversely correlated with body mass index (Spearman correlation coefficient (r)= –0.43, p=0.02) and directly correlated with Gleason score (r=0.35, p=0.05). Stratification by body mass index revealed an unexpected inverse correlation between wAMACR gene expression levels and phytanic acid concentrations in the prostate (r= –0.95, p= 0.001) in obese men. In conclusion, blood and tissue levels of phytanic acid were not correlated, which suggests that blood measures should not be utilized as a surrogate measure of this fatty acid in the target organ. Contrary to expectation, tissue phytanic acid levels were significantly inversely associated with AMACR gene expression levels in the prostate, but only among obese men.These findings require confirmation in other, larger studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4480. doi:1538-7445.AM2012-448