This lecture will focus on breed relationships in canine liver disease. There are very few reports of breed-related disease in cats with liver disease. They include a reported increased prevalence of congenital portosystemic shunt (PSS) in Himalayan cats in Australia and liver involvement in generalised amyloidosis in Siamese cats and polycystic disease in longhaired cats. However, there are many more reports in the veterinary literature of increased prevalence in various dog breeds of a wide variety of liver diseases ranging from congenital portosystemic shunt (PSS) through gallbladder mucocoele to chronic hepatitis (CH). In many cases, these are true breed predilections, and in some cases the genetic reasons are being unravelled. However, in some cases the claims have not been substantiated by comparison with a reference population (such as Kennel Club or insurance company data). It is important to do this before claiming increased breed prevalence because it is all too easy for 'false' data to become established fact once they are published.
Why is recognising breed prevalence important? It helps with clinical diagnosis as it increases suspicion of disease (although it is important to remember that not all dogs of a particular breed with liver disease will necessarily have the 'breed-typical' disease, so breed-spotting is not a substitute for a complete work-up: just an aid). It also will hopefully help us further to elucidate the cause of the disease through genetic studies and therefore help us with more effective treatment. This will be easier with mono-genic diseases than polygenic conditions. The most complete and satisfying example of this in dogs is Bedlington Terriers and copper storage disease (CSD) which has allowed not only the identification of (at least one) of the genes responsible for the breed-associated CSD, but which has also therefore allowed more effective treatment with copper chelators and ultimately (we hope) a reduced frequency in the breed by selective breeding. However, even in Bedlingtons, the genetic basis for CSD seems to be more complicated than initially believed as Bedlingtons which are not homozygous for the described gene deletion have been reported with CSD. More recently, copper storage disease has been well described in a number of other dog breeds including Dalmatians, Labrador Retrievers and probably Dobermanns. Interestingly, there appear to be two distinct groups of CH in Labrador Retrievers: copper-associated and idiopathic. In the US and Holland, copper-associated disease predominates, whereas in the UK idiopathic disease predominates. The difference in prevalence in different countries may be environmental, but does argue strongly for genetic differences in pure-breed dog populations between countries. The Dutch are investigating the genetic basis of copper storage disease in their Labrador Retrievers but the results have yet to be published.
Breed relationships exist in canine CH. There are a number of potential reasons for these, outlined in Figure 1, although most of these potential causes have not been extensively investigated or proven. Idiopathic CH without predominant copper storage disease has been reported previously to have an increased prevalence in American and English Cocker Spaniels (males more than females), West Highland White Terriers (no particular sex predisposition), Dobermanns (strong female predisposition) and Labrador Retrievers (female bias). Much (although not all) of this data is based on a survey of 250 Swedish dogs on a histopathological database in 1991, compared to Swedish Kennel Club registrations. The results may therefore not be totally relevant to populations of dogs now and in different countries.
Figure 1. Potential reasons for genetic susceptibility to CH in dogs.
(a indicates there is current clear evidence for this mechanism in this species.)
Susceptibility to infectious causes of CH and/or to chronicity of infection rather than recovery
Susceptibility to autoimmune disease
Mutation of gene coding for protein involved in metal transport/storage/excretiona
Gene mutations resulting in hepatic accumulation of glycoprotein protease inhibitor
Increased susceptibility to chronic hepatic damage with toxic causes
We were approached by the health coordinators of the English Springer Spaniel (ESS) breed clubs in the UK a number of years ago after they had perceived an increase in acute and chronic liver disease in their breed. Initially, we were sceptical as we had not recognised this yet in our referral population. However, over the next few months, we began to hear of increasing numbers of affected dogs and there appeared to be a strong female predominance. To investigate whether our 'impression' was correct, we have just looked at the breed prevalence of CH in dogs based on 551 biopsy-confirmed cases from six pathology laboratories in the UK from 2001 to 2008. Out of the 551 dogs, 80 were ESS which was a significant over-representation of this breed when compared with a large control group of microchipped dogs. There was a female predominance in this breed. Other breeds over-represented included American and English Cocker Spaniels, Labrador Retrievers, Dobermanns, Dalmations, Great Danes, Cairn Terriers and Samoyeds. A recently published clinical study of CH in English Springer Spaniels (ESS) again demonstrated the high female predominance and also the poor prognosis in this breed.
Therefore, apparent breed associations to CH in the UK in 2008 include some of the 'usual suspects' (such as Cocker Spaniels, Dobermanns and Labrador Retrievers) and some 'new' breeds (such as ESS and Samoyeds). Personal communications to the author have suggested that ESS in Norway and Australia also get idiopathic CH whereas dogs in the US and Sweden do not appear to be affected. This is interesting and lends credence to a genetic tendency since Swedish dogs apparently have US rather than UK founders, whereas Norwegian and Australian ESS originate from the UK.
In addition to CH, breed relationships are reported in other canine liver diseases. Gallbladder mucocele is recognised with increasing frequency in a number of dog breeds with several predisposing factors. Shetland Sheepdogs seemed to be over-represented in an early study, and recently, investigators have identified a mutation in biliary phospholipase transporter in almost all affected dogs and also a few dogs of other breeds with mucocele.
There are strong breed associations in canine congenital portosystemic shunts: for example, patent ductus venosus in Irish Wolfhounds and extrahepatic shunts in Cairn Terriers have inherited tendencies but current evidence suggests this is polygenic in both breeds. There is also a proposed breed association in Scottish Terriers for 'idiopathic' elevations in alkaline phosphatase, which may represent an idiopathic vacuolar hepatopathy.
In conclusion, after a 'lull' of about 10 years, there are now many new and exciting data emerging about potential breed associations and aetiologies of CH and other diseases in dogs. With the new opportunities in publication of the canine genome, this should drive further work to elucidate disease mechanisms in different breeds.
Identifying breed prevalence and discovering genetic reasons for these will ultimately not only help dogs but also increase our knowledge of disease mechanisms which should be transferable to humans. Pure-bred dog populations represent a relatively inbred, reasonably genetically 'pure' but natural model of disease which has to be an excellent translational model between the transgenic mouse and the human.
References
1. Andersson M, Sevelius E. Breed, sex and age distribution in dogs with chronic liver disease: a demographic study. Journal of Small Animal Practice 1991;32:1–5.
2. Bexfield NH, Andres-Abdo C, et al. Chronic hepatitis in the English Springer Spaniel: clinical presentation, histological description and outcome. Veterinary Record 2011;169(16):415.
3. Hoffmann G, van den Ingh TS, et al. Copper-associated chronic hepatitis in Labrador Retrievers. Journal of Veterinary Internal Medicine 2006;20:856–861.
4. House JV, Covey HL, et al. Qualitative analysis of hepatic copper accumulation in chronic hepatitis in Labrador Retrievers at one institution in the United Kingdom. In: Proceedings of the British Small Animal Veterinary Association, Birmingham, UK, 2008:508.
5. Mealey KL, Minch JD, et al. RAn insertion mutation in ABCB4 is associated with gallbladder mucocele formation in dogs. Comparative Hepatology 2010;9:6.