Attenuation of congenital portosystemic shunt reduces inflammation in dogs.

Michael S Tivers,Adam G Gow,Victoria J Lipscomb,Rajiv Jalan,Richard J Mellanby,Ian Handel,Craig Gordon Ruaux

doi:10.1371/journal.pone.0117557

Abstract

Liver disease is a major cause of morbidity and mortality. One of the most significant complications in patients with liver disease is the development of neurological disturbances, termed hepatic encephalopathy. The pathogenesis of hepatic encephalopathy is incompletely understood, which has resulted in the development of a wide range of experimental models. Congenital portosystemic shunt is one of the most common congenital disorders diagnosed in client owned dogs. Our recent studies have demonstrated that the pathophysiology of canine hepatic encephalopathy is very similar to human hepatic encephalopathy, which provides strong support for the use of dogs with a congenital portosystemic shunt as a naturally occurring model of human hepatic encephalopathy. Specifically, we have demonstrated an important role for ammonia and inflammation in the development of hepatic encephalopathy in dogs with a congenital portosystemic shunt. Despite the apparent importance of inflammation in driving hepatic encephalopathy in dogs, it is unclear whether inflammation resolves following the successful treatment of liver disease. We hypothesized that haematological and biochemical evidence of inflammation, as gauged by neutrophil, lymphocyte and monocyte concentrations together with C-reactive protein concentrations, would decrease following successful treatment of congenital portosystemic shunts in dogs. One hundred and forty dogs with a congenital portosystemic shunt were enrolled into the study. We found that the proportion of dogs with a monocyte concentration above the reference range was significantly greater in dogs with hepatic encephalopathy at time of initial diagnosis. Importantly, neutrophil and monocyte concentrations significantly decreased following surgical congenital portosystemic shunt attenuation. We also found a significant decrease in C-reactive protein concentrations following surgical attenuation of congenital portosystemic shunts. Our study demonstrates that haematological and biochemical indices of inflammation reduce following successful treatment of the underlying liver disorder.

Highlights

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, affecting people suffering from significant liver disorders [1]
Similar to earlier findings in humans, our previous work has shown associations between inflammation and HE in dogs with congenital portosystemic shunt (cPSS). We demonstrated that both increased ammonia and systemic inflammatory response syndrome (SIRS) score were predictive of the presence of HE in dogs with cPSS [12]
The central finding of this study was that inflammation was significantly associated with the presence of HE in dogs with cPSS and that inflammation significantly reduced following successful surgical treatment

Summary

Introduction

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, affecting people suffering from significant liver disorders [1]. A variety of other factors have been implicated in the pathogenesis of HE, inflammation, with systemic inflammatory response syndrome (SIRS) and sepsis being a common trigger for overt HE [2,3]. Circulating inflammatory cytokines including TNFα, IL-1β and IL-6 are implicated in a variety of roles in potentiating HE [2]. Studies have shown direct correlations between IL-6 and TNFα and the severity of HE and hyperammonemia [4,5,6,7]. Inflammation, in the absence of concurrent infection, has been associated with more severe HE in people with liver disease [8]

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