Department of Internal Medicine, University Hospital of Patras, Patras, Greece.
Eur J Clin Invest. 2012 Apr;42(4):439-46. doi: 10.1111/j.1365-2362.2011.02609.x. Epub 2011 Oct 24.
Increased intestinal permeability in cirrhosis exerts a pivotal role in the pathogenesis of spontaneous bacterial peritonitis and other complications of cirrhosis through promotion of systemic endotoxemia. This study was designed to investigate whether the expression of tight junction (TJ) proteins, which regulate gut paracellular permeability, is altered in the intestinal mucosa of patients with liver cirrhosis and study its potential association with the stage of liver disease and the development of systemic endotoxemia.
Twenty-four patients with cirrhosis at a decompensated (n = 12, group A) or compensated condition (n = 12, group B) and 12 healthy controls (group C) were subjected to duodenal biopsy. The expression of the TJ proteins occludin and claudin-1 in the intestinal epithelium was evaluated by immunohistochemistry. Plasma endotoxin concentrations were also determined.
Patients with cirrhosis presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0·001), whilst endotoxemia was higher in decompensated disease (P < 0·05 vs. compensated cirrhosis). Patients with decompensated and compensated cirrhosis presented significantly reduced expression of occludin and claudin-1 as compared to controls (P < 0·01, respectively). These alterations were significantly more pronounced in decompensated patients as compared to compensated (P < 0·05). Regarding occludin, in patients with cirrhosis, a specific pattern of expression in the intestinal epithelium was observed, with a gradually increasing loss of expression from crypt to tip of the villi. Occludin and claudin-1 expression were inversely correlated with Child-Pugh score (P < 0·001), the grade of oesophageal varices (P < 0·01) and endotoxin concentrations (P < 0·001).
This study demonstrates for the first time that human liver cirrhosis induces significant alterations in enterocytes' TJs. These changes might represent an important cellular mechanism for intestinal barrier dysfunction and hyperpermeability in patients with liver cirrhosis.
肝硬化患者的肠道通透性增加，通过促进全身内毒素血症，在自发性细菌性腹膜炎和其他肝硬化并发症的发病机制中发挥关键作用。本研究旨在探讨肝硬化患者肠道黏膜中紧密连接（TJ）蛋白的表达是否发生改变，以及其与肝病分期和全身内毒素血症的发展之间的潜在关联。
对 24 例失代偿期（n=12，A 组）和代偿期（n=12，B 组）肝硬化患者和 12 例健康对照者（C 组）进行十二指肠活检。通过免疫组织化学方法评估肠道上皮 TJ 蛋白 occludin 和 claudin-1 的表达。还测定了血浆内毒素浓度。
与健康对照组相比，肝硬化患者的血清内毒素浓度显著升高（P<0·001），而失代偿期疾病患者的内毒素血症更高（P<0·05 与代偿期肝硬化相比）。与对照组相比，失代偿期和代偿期肝硬化患者的 occludin 和 claudin-1 表达均显著降低（分别为 P<0·01）。与代偿期患者相比，失代偿期患者的这些改变更为明显（P<0·05）。关于 occludin，在肝硬化患者中，观察到肠道上皮细胞中存在特定的表达模式，从隐窝到绒毛顶端，表达逐渐减少。occludin 和 claudin-1 的表达与 Child-Pugh 评分（P<0·001）、食管静脉曲张程度（P<0·01）和内毒素浓度（P<0·001）呈负相关。
本研究首次证明，人类肝硬化会引起肠细胞 TJ 显著改变。这些变化可能代表肝硬化患者肠道屏障功能障碍和高通透性的重要细胞机制。
