Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation in vitro and in vivo in a rat model.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Francque
Sven
S
Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium. sven.francque@uza.be
Wamutu
Sam
S
Chatterjee
Shyama
S
Van Marck
Eric
E
Herman
Arnold
A
Ramon
Albert
A
Jung
Alexander
A
Vermeulen
Wim
W
De Winter
Benedicte
B
Pelckmans
Paul
P
Michielsen
Peter
P
D000818:Animals; D001011:Aorta; D001783:Blood Flow Velocity; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics; D006975:Hypertension, Portal / Q000209:etiology*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D017082:Portal Pressure; D051381:Rats; D017208:Rats, Wistar; D013152:Splanchnic Circulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation
D016207:Cytokines; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D009195:Peroxidase