Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
J Hepatol. 2018 Aug;69(2):396-405. doi: 10.1016/j.jhep.2018.03.031. Epub 2018 Apr 12.
BACKGROUND & AIMS: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis.
Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis.
We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis.
Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans.
Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis.
在酒精性肝炎这一严重的临床病症中，胆汁淤积的严重程度是一个重要的疾病驱动因素，需要新的生物标志物和靶向治疗方法。我们旨在确定与酒精性肝炎相关的、尚未被广泛认知的胆汁淤积机制和生物标志物。
在此，我们分析了一组具有特征性的酒精性肝炎患者队列，并将临床和组织学参数以及结局与血清胆汁酸和成纤维细胞生长因子 19（FGF19）进行了相关性分析，FGF19 是胆汁酸合成的主要调节因子。
我们发现，与对照组相比，酒精性肝炎患者的总胆汁酸和结合胆汁酸显著增加。血清 FGF19 水平显著升高，并且酒精性肝炎患者的胆管上皮细胞和胆管细胞中 FGF19 的基因表达也被诱导。酒精性肝炎患者的新生胆汁酸合成（CYP7A1 基因表达和 C4 血清水平）显著降低。重要的是，总胆汁酸和结合胆汁酸与 FGF19 以及疾病严重程度（终末期肝病模型评分）呈正相关。总胆汁酸和结合胆汁酸与 FGF19 相关性最佳，终末期肝病模型评分与牛磺酸结合鹅脱氧胆酸相关性最佳。单变量分析显示，在所有酒精性肝炎患者中，FGF19 与胆红素以及γ-谷氨酰转移酶显著相关，与纤维化分期以及多形核白细胞浸润呈负相关。
血清 FGF19 和胆汁酸在酒精性肝炎患者中显著增加，而新生胆汁酸合成受到抑制。调节胆汁酸代谢或信号转导可能成为治疗人类酒精性肝炎的有前途的靶点。
了解驱动酒精性肝炎的潜在机制对于开发新的生物标志物和靶向治疗方法很重要。在此，我们描述了一种在酒精性肝炎患者中增加的分子。调节这种分子的分子途径可能为治疗酒精性肝炎提供有希望的靶点。
