Warner Dennis, Vatsalya Vatsalya, Zirnheld Kara H, Warner Jeffrey B, Hardesty Josiah E, Umhau John C, McClain Craig J, Maddipati Krishnarao, Kirpich Irina A
Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of LouisvilleLouisvilleKYUSA.
Robley Rex Veterans Medical CenterLouisvilleKYUSA.
Hepatol Commun. 2021 Feb 9;5(6):947-960. doi: 10.1002/hep4.1686. eCollection 2021 Jun.
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol-associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)-derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA-derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End-Stage Liver Disease score <20). Lipoxygenase-derived LA metabolites (13-hydroxy-octadecadienoic acid [13-HODE] and 13-oxo-octadecadienoic acid) were markedly elevated only in patients with mAH. The cytochrome P450-derived LA epoxides 9,10-epoxy-octadecenoic acid (9,10-EpOME) and 12,13-EpOME were decreased in all patients regardless of the presence or absence of liver injury. LA-derived diols 9,10-dihydroxy-octadecenoic acid (9,10-DiHOME) and 12,13-DiHOME as well as the corresponding diol/epoxide ratio were elevated in the mAH group, specifically compared to patients with mild liver injury. We found that 13-HODE and 12,13-EpOME (elevated and decreased, respectively) in combination with elevated interleukin-1β as independent predictors can effectively predict altered liver function as defined by elevated bilirubin levels. Specific changes in LA metabolites in individuals who are heavy drinkers can distinguish individuals with mAH from those with mild ALD.
酒精性肝病（ALD）是一系列肝脏疾病，范围从脂肪变性到脂肪性肝炎、纤维化和肝硬化。酒精性肝炎（AH）是ALD的一种急性且通常较为严重的形式，具有较高的发病率和死亡率。ALD进展和严重程度的机制及介质尚未完全明确，有效的治疗选择也有限。各种生物活性脂质介质最近已成为ALD发病机制中的重要因素。本研究旨在检测重度饮酒者血浆中源自亚油酸（LA）的脂质代谢产物的变化，并评估这些分子与肝损伤和全身炎症标志物之间的关联。对66名重度饮酒者和29名社交饮酒但其他方面健康的志愿者进行了血浆中源自LA的代谢产物分析。根据血浆丙氨酸氨基转移酶（ALT）水平，15名患者无肝损伤（ALT≤40 U/L），33名患者有轻度肝损伤（ALT>40 U/L），18名被诊断为中度AH（mAH）（终末期肝病模型评分<20）。仅在mAH患者中，脂氧合酶衍生的LA代谢产物（13-羟基-十八碳二烯酸[13-HODE]和13-氧代-十八碳二烯酸）显著升高。无论有无肝损伤，细胞色素P450衍生的LA环氧化物9,10-环氧-十八碳烯酸（9,10-EpOME）和12,13-EpOME在所有患者中均降低。与轻度肝损伤患者相比，mAH组中LA衍生的二醇9,10-二羟基-十八碳烯酸（9,10-DiHOME）和12,13-DiHOME以及相应的二醇/环氧化物比值升高。我们发现，13-HODE和12,13-EpOME（分别为升高和降低）与升高的白细胞介素-1β作为独立预测因子相结合，可以有效预测以胆红素水平升高定义的肝功能改变。重度饮酒者中LA代谢产物的特定变化可以将mAH患者与轻度ALD患者区分开来。
