Canine congenital portosystemic shunting: Novel insights into etiology, metabolism, diagnosis and treatment

Ammonia is an essential substrate in many vital biochemical pathways. Hyperammonemia (i.e. high levels of ammonia) however, is a dangerous condition that leads to hepatic encephalopathy (HE) and in severe cases to coma and death. Congenital portosystemic shunts (CPSS), the most common cause of hyperammonemia in dogs, are vascular anomalies that directly connect the portal venous system with the systemic venous circulation, bypassing the liver parenchyma. The current thesis investigated the etiology of CPSS, its effect on hepatic ammonia metabolism, the diagnostic value of serum fasting bile acids (FBA) and ammonia (FA) concentrations for portosystemic shunting and conservative treatment possibilities for hyperammonemia.
A possible genetic basis and the mode of inheritance of CPSS was investigated in Cairn Terriers by measuring the prevalence of CPSS in the general population and in three test matings of successfully operated dogs with CPSS. CPSS was concluded to be a genetic disease in the Cairn Terriers. The inheritance is autosomal and most likely polygenetic or monogenetic with variable expression.
The effect of CPSS on hepatic ammonia metabolism was investigated by evaluating gene expression profiling of urea cycle enzymes (UCE) and glutamate-ammonia ligase (GLUL) in dogs with CPSS before and after surgical closure of the shunt. Immunohistochemistry was performed on UCE and GLUL in liver samples of healthy dogs and dogs with CPSS to investigate a possible zonal distribution within the liver lobule. Furthermore, the effect of increasing ammonia concentrations on the expression of UCE was investigated in primary hepatocytes in vitro. Results of these studies revealed that gene expression of UCE in CPSS dogs was down-regulated. In addition, UCE lacked the periportal distribution seen in healthy dogs. GLUL demonstrated a zonal distribution both in healthy and CPSS dogs. The diagnostic value of FBA, FA and the ammonia tolerance test (ATT) for their association with PSS in dogs was investigated in 271 dogs suspected of CPSS by evaluating the sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) and positive and negative likelihood ratios (LR+ and LR- respectively). For dogs suspected of CPSS, the ATT and the FBA had the highest sensitivity (100 and 98% respectively) and NPV (100% and 96% respectively) for PSS. The combination of increased FBA and FA had the highest PPV (97%) and a LR+ (29). PSS would therefore be ruled out in a symptomatic dog with normal FBA or ATT and would be highly probable when both FBA and FA are increased. In purebred populations, the NPV of all tests was 100% making FBA was the most suitable test for screening purposes.
The efficacy of sodium benzoate (SB), sodium phenylacetate (SPA) and sodium phenylbutyrate (SPB) was studied for the treatment of hyperammonemia. Results do not indicate the use of these drugs for the treatment of hyperammonemia in CPSS dogs.