Kataria Yachana, Deaton Ryan J, Enk Erika, Jin Ming, Petrauskaite Milita, Dong Linlin, Goldenberg Joseph R, Cotler Scott J, Jensen Donald M, van Breemen Richard B, Gann Peter H
Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA, USA.
Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
BMC Gastroenterol. 2016 Feb 29;16:30. doi: 10.1186/s12876-016-0432-5.
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.
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.
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.
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.
约270万美国人慢性感染丙型肝炎病毒（HCV）。肝硬化的HCV患者是肝细胞癌（HCC）高危人群中最大的群体。氧化应激增加被认为是HCV相关肝病进展的主要机制。类视黄醇和类胡萝卜素抗氧化剂缺乏可能是疾病进展的一个主要可改变风险因素。本研究旨在确定HCV患者血清抗氧化剂水平的关键预测因素，研究血清和肝组织中类视黄醇/类胡萝卜素浓度之间的关系，量化氧化应激的全身指标与抗氧化状态之间的关联，并研究类视黄醇与星状细胞活化之间的关系。
接受肝活检的患者（n = 69）提供空腹血、新鲜组织、尿液并完成饮食史问卷。还收集了健康志愿者（n = 11）的血清和问卷数据、公共储存库中的正常肝组织以及无肝病患者（n = 11）的数据。通过超高效液相色谱-串联质谱法测定尿中异前列腺素、血清和组织类视黄醇浓度。对福尔马林固定石蜡包埋切片进行αSMA免疫组织化学染色，随后通过数字图像分析进行定量。使用Spearman相关系数评估尿中异前列腺素、αSMA水平和类视黄醇之间的关联，并使用非参数检验来检验疾病严重程度组之间的差异。
血清视黄醇、番茄红素和RBP4浓度与纤维化分期呈显著负相关。血清β-胡萝卜素和番茄红素与其各自的组织浓度密切相关。随着纤维化分期增加，组织棕榈酸视黄酯呈微弱的下降趋势。组织棕榈酸视黄酯与肝星状细胞活化标志物肝αSMA表达呈负相关且具有显著性（r = -0.31，P < 0.02）。尿中异前列腺素水平与血清视黄醇、β-胡萝卜素和RBP4呈负相关。
血清视黄醇、β-胡萝卜素和RBP4降低与HCV早期阶段相关。随着疾病进展，类视黄醇和类胡萝卜素水平下降，我们的数据表明这种下降在疾病过程早期就会发生，甚至在纤维化明显之前。氧化应激指标与纤维化分期及同时存在的抗氧化剂消耗相关。肝脏组织中维生素A的丢失伴随着星状细胞活化。
