Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulationin vitroandin vivoin a rat model

Abstract

Steatosis, without fibrosis, may lead to changes in liver blood flow, which are poorly understood, and to date have not been correlated to portal pressure and related haemodynamics. To study the temporal relation between progressive steatosis, portal pressure, systemic haemodynamics, vascular responsiveness, mesenteric and portal blood flow in methionine-choline-deficient diet (MCDD)-fed rats. Male Wistar rats fed the MCDD were examined at week (w) 0-1-2-3-4-5-6-7-8, respectively, including systemic haemodynamics and portal pressure. At w0-4-8, in vivo blood flow was measured in the portal vein and the superior mesenteric artery. Dose-response curves to phenylephrine (PE) were established in abdominal aortic rings. Histology showed 100% steatosis from w3 on. Fibrosis was absent. Significant inflammation was nearly absent upon w4. Portal pressure slightly increased at w2, reached a maximum at w4 [9.4 +/- 0.3 vs 2.9 +/- 0.6 mmHg at w0 (P=0.003)] and remained stable upon w8. Mean arterial blood pressure (MABP) decreased from w2 on [98.7 +/- 5.7 mmHg on w4 compared with 123.8 +/- 1.8 on w0 (P=0.002)]. Portal flow increased from 1.85 +/- 0.11 to 3.07 +/- 0.44 ml/min/100 g on w0 and w8 respectively (P=0.039). Mesenteric artery flow increased from 3.40 +/- 0.26 to 4.56 +/- 0.30 ml/min/100 g on w0 and w8 respectively (P=0.043). Vascular responsiveness to PE gradually decreased from 138 +/- 3% on w0 to 110 +/- 5% on w4 (P=0.013). Steatohepatitis induces significant portal hypertension (PHT) in the absence of fibrosis, associated with an increase in mesenteric arterial and portal venous flow, arterial hyporesponsiveness to vasoconstrictors and a decrease in MABP, indicating the presence of splanchnic vasodilation and hyperdynamic circulation. These alterations resemble those seen in cirrhotic PHT.