Extrahepatic Surgery in Cirrhosis Significantly Increases Portal Pressure in Preclinical Animal Models

Abstract

Background: Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model.Methods: Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured in-vivo. Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed.Results: Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model.Conclusion: In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis.

Surgical site infections are independently associated with the development of postoperative acute-on-chronic liver failure in liver cirrhosis

“…Recently, in animal models of cirrhosis, portal pressure was significantly elevated after extrahepatic injury and associated with clinical signs of decompensation. [40] Moreover, recent studies confirm significant reduction of postprocedural ACLF episodes and short-term mortality in patients with preoperative TIPS and patients with optimized TIPS stent diameter. [41,42] Organ/space SSIs affect deeper lying compartments, which might require antibiotic therapy with high tissue penetration.…”

“…Clinically significant portal hypertension might be a main driver promoting postsurgical ACLF. Recently, in animal models of cirrhosis, portal pressure was significantly elevated after extrahepatic injury and associated with clinical signs of decompensation 40 . Moreover, recent studies confirm significant reduction of postprocedural ACLF episodes and short-term mortality in patients with preoperative TIPS and patients with optimized TIPS stent diameter 41,42 …”

Clinical Guideline on Perioperative Management of Patients with Advanced Chronic Liver Disease

“…In ACLD patients, we can find changes in hepatic flow with the creation of arterio-venous fistulas, reduction in hepatocyte function with a decrease in proteins synthesis, and destruction of the bile canaliculi with a decrease in the ability to excrete metabolites through the bile [ 69 ]. Moreover, animal models demonstrated that extrahepatic surgery can increase portal pressure [ 70 ].…”

Prospect of Animal Models for Acute-on-chronic Liver Failure: A Mini-review

“…26 Nevertheless, preceding findings highlighted the success of sham operation and/or common bile ligation combined with LPS or CCl 4 inhalation in establishing ACLF. [67][68][69] Recently, Karus et al 70 highlighted the combination of bile duct ligation, ethanol binge drinking, repetitive LPS injections, transnasal stool inoculation and cecal ligation and puncture, a complicated approach to generate a new rat model of cholestatic liver cirrhosis-developing ACLF. The differences in final outcomes might impede the selection and rational application of these models to investigate ACLF pathophysiology.…”