However, ursodeoxycholic acid has been suggested [22]. Some human patients with ABCB4-associated biliary disease benefit from treatment with ursodeoxycholic acid, a relatively hydrophilic and much less cytotoxic bile acid than most endogenous bile salts

[4]. Studies to determine bile composition in wildtype dogs and dogs with the ABCB 4 1583_1584G mutation should be performed in order to further characterize the disease. One would expect affected dogs to have bile with lower phospholipid concentrations than wildtype dogs, and thus a greater proportion of simple micelles rather than mixed micelles. These studies would also be important to determine how useful affected dogs would be as a model for the various biliary diseases in people that result from similar ABCB4 mutations. The authors speculate that occurrence of gallbladder mucoceles in dogs is inherited in a dominant C59 wnt cost AZD1480 fashion with incomplete penetrance, however further research is required to confirm the mode of

inheritance. While it is possible that the one unaffected carrier of the ABCB 4 1583_1584G insertion may develop biliary disease in the future, there was no evidence of disease at 9 years of age. No dogs in this study population were homozygous for the mutation. Because a more severe phenotype is observed in people homozygous for mutations resulting in elimination of ABCB4 protein function, one would speculate that the same would be true for dogs. In people with PFIC (type 3), the disease manifests Cyclooxygenase (COX) during early childhood and is fatal without a liver transplant [4]. It is possible that homozygosity for the mutation results in death of affected dogs either during embryonic development or in early puppyhood. In conclusion, the ABCB 4

1583_1584G is strongly associated with the diagnosis of gallbladder mucocele in dogs. Results of this study provide the first spontaneous animal model for Go6983 in vivo studying a number of potentially lethal or severely debilitating hepatobiliary diseases in people that are also associated with ABCB4 dysfunction. This canine model may be useful for studying potential medical and/or dietary treatments for ABCB4-associated hepatobiliary diseases in people. Acknowledgements The authors would like to thank Mary B. Mahaffey, DVM for promoting sample submission within the American Shetland Sheepdog Association. The authors would also like to thank all dog owners for donating samples and sharing data from their dogs’ medical records. This work was supported by a Washington State University College of Veterinary Medicine Intramural Grant and Proceeds from the Veterinary Clinical Pharmacology Laboratory at Washington State University. References 1. Pellicoro A, Faber KN: Review article: The function and regulation of proteins involved in bile salt biosynthesis and transport. Aliment Pharmacol Ther 2007, 26: 149–160.CrossRefPubMed 2. Elferink RO, Groen AK: Genetic defects in hepatobiliary transport.