Inherited liver shunts in dogs elucidate pathways regulating embryonic development and clinical disorders of the portal vein

Abstract

Congenital disorders of the hepatic portal vasculature are rare in man but occur frequently in certain dog breeds. In dogs, there are two main subtypes: intrahepatic portosystemic shunts, which are considered to stem from defective closure of the embryonic ductus venosus, and extrahepatic shunts, which connect the splanchnic vascular system with the vena cava or vena azygos. Both subtypes result in nearly complete bypass of the liver by the portal blood flow. In both subtypes the development of the smaller branches of the portal vein tree in the liver is impaired and terminal branches delivering portal blood to the liver lobules are often lacking. The clinical signs are due to poor liver growth, development, and function. Patency of the ductus venosus seems to be a digenic trait in Irish wolfhounds, whereas Cairn terriers with extrahepatic portosystemic shunts display a more complex inheritance. The genes involved in these disorders cannot be identified with the sporadic human cases, but in dogs, the genome-wide study of the extrahepatic form is at an advanced stage. The canine disease may lead to the identification of novel genes and pathways cooperating in growth and development of the hepatic portal vein tree. The same pathways likely regulate the development of the vascular system of regenerating livers during liver diseases such as hepatitis and cirrhosis. Therefore, the identification of these molecular pathways may provide a basis for future proregenerative intervention.

Fig. 1

Overview of the anatomy of a normal liver and of livers with intra- and extrahepatic portosystemic shunts. a No connection of blood vessels in the liver is seen within a normal liver resulting in a blood flow through the hepatic sinusoids. b In case of PSS, blood bypasses the liver sinusoids and is therefore not subjected to hepatic metabolism. The intrahepatic shunt represents an abnormal connection of the portal vein with the systemic circulation, which is seen inside the liver. c In the case of an extrahepatic shunt, the aberrant connection is located outside the liver

Fig. 2

Pedigree of test matings of Irish wolfhounds with intrahepatic shunt. An affected male was mated with two affected sisters. Squares represent males, circles represent females. Solid symbols are affected dogs and open symbols represent unaffected pups. Pups with uncertain phenotypes are filled gray (reprinted with permission from John Wiley and Sons; van Steenbeek et al. 2009)

Fig. 3

Pedigree of test matings with Cairn terriers with extrahepatic shunt. An affected female (#9) was used three times, with her unaffected father (#1), with her affected son (#21), and with an unrelated affected male (#10). Squares represent males, circles represent females. Solid symbols are affected dogs and open symbols are healthy dogs (reprinted with permission from John Wiley and Sons; van Straten et al. 2005)

Fig. 4

The relationship between the AHR pathway and the HIF1A pathway. Both pathways share ARNT and HSP90AA1 as key regulators