Copper Toxicosis in Labrador Retrievers in United States: New Research

Two previously identified gene mutations (variants) might play a much smaller role in the development of copper toxicosis (CT) in populations of Labrador Retrievers in the United States, according to a recently published Michigan State University (MSU) research study.

CT also is called copper-associated hepatitis (CAH), chronic copper-associated hepatitis, and copper-associated liver disease, among others.

The takeaway from the study?

• The ATP7B (7B) gene variant increased the risk for CT in Labradors but many dogs with CT didn’t have the 7B gene variant. Similarly, there were many dogs with that variant that did not have CT.
• The ATP7A (7A) variant was not associated with CT in this study, but this may simply reflect that the effect is small rather than non-existent.
• The collective results suggest that genetic testing is not a reliable predictor of CT in Labradors.
• However, Labradors that possess two copies of the 7B gene variant appear to be at high risk for CT, but this genotype is only found in 2-3% of the Labrador Retriever population.
• Breeders should not breed Labradors with two 7B gene variants (mutations) to dogs with one or two copies of this gene variant, according to the researchers, to avoid passing on the 7B gene variant to puppies.

An article entitled “ATP7A, ATP7B, and RETN genotypes in Labrador Retrievers with and without copper-associated hepatopathy,” was recently published in the Journal of the American Veterinary Medical Association.https://www.researchgate.net/publication/360231606_ATP7A_ATP7B_and_RETN_genotypes_in_Labrador_Retrievers_with_and_without_copper-associated_hepatopathy

In their article, MSU researchers stated, “A complex and incompletely interplay of environmental copper exposures and genetic susceptibility are thought to be responsible for CAH [CT] in most breeds, including the Labrador Retriever.”

They also wrote while any breed of dog may be affected by CT, certain breeds, including Labradors, Dalmatians, Doberman Pinschers, and West Highland Terriers, are predisposed to the disease. Other research has shown that Bedlington Terriers also are predisposed to CT thanks to a COMMD1 gene mutation. Other experts have opined mixed breeds also may be diagnosed with CT.

The MSU researchers noted that in Dutch studies of Labradors, the 7A gene mutation was “associated” with decreased risk of CT and the 7B gene mutation with an increased risk. These gene mutations “might be involved in other breeds as well.”

Daniel Langlois, DVM, DACVIM, one of the MSU researchers, recently discussed the 2022 study designed to determine if specified protein gene mutations are associated with an increased risk of CT in Labradors in the United States. CT is fatal unless caught early and can only be diagnosed with a biopsy.

He and MSU researchers Brendan S. M. Nagler; Rebecca Smedley, DVM; Ya-Ting Yang, DVM; and Vilma Yuzbasilyan-Gurkan, Ph.D. examined their university vet school’s database of archived tissue specimens of 90 Labradors taken from 2013 to 2020. The tissues were from biopsies or necropsies.

Langlois heads the internal medicine section of the Department of Small Animal Clinical Science, College of Veterinary Medicine, where he is also a tenured associate professor.

He explains that all dogs have the 7A and 7B proteins but some have variants of the genes that might alter the normal function of the protein. The 7B protein plays a vital role to excrete copper from the liver and variants in the 7B gene may alter the ability to excrete copper. The 7A protein is necessary for the absorption of dietary copper, and variants in the 7A gene could decrease that absorption.

The MSU study showed:

• Labradors with the 7B gene variant might or might not have CT but those with a single copy of the variant 7B gene were more likely to have the CT disease than those with no copies of the 7B gene mutation.
• The RETN and 7A gene variants, believed to offer some protection against CT based on Dutch studies, didn’t appear to protect against the disease, and any possible protection is likely small. (The MSU article did not describe the function of the RETN protein.)
• Dogs with two 7B gene variants are likely to be at even greater risk for CT but this genotype is found in only 2% to 3% of the general Labrador population.

• 

  The 7B gene variant appears to play a role in CT in Labradors.

Langlois says that although the MSU study found few Labradors had two copies of the 7B gene, the available evidence (including other research and this MSU study) suggests that these dogs appear highly likely to develop CT.

However, researchers also noted that the “prevalence and the significance” of these gene mutations in Labradors from the United States have not been studied in detail. “The inappropriate testing and application of results could have unintended consequences for the clinical management of individual patients as well as for the genetic diversity of the population. Additional studies of these variants and their association with pathologic copper accumulation are needed before routine clinical testing can be recommended.”

PRACTICAL EFFECTS OF THE STUDY

Taking into account past and more recent studies of CT, Dr. Richard Gastellum of At Home Pet Doctor, LLC in Buena Vista, CO recommends the following for owners of breeds pre-disposed to Copper Toxicity which include the Bedlington Terrier, Labrador Retriever, West Highland White Terrier, Dalmatian, and Doberman Pinscher:

• 

  Educate canine owners about this uncommon condition so they can be watchful for changes in their pets that could signal a potential problem.

• If you have a Labrador female that you intend to breed, have a genetic analysis done to determine if she has the ATP7B gene mutation. The test may come back heterozygous (meaning one copy of the gene mutation) or homozygous (two copies).  Consider not breeding to a stud dog that has one or two copies of the ATP7B gene mutation.  In the case of the Bedlington Terrier, detection of a mutation in the COMMD1 gene is also warranted.
• If you have a male or female adult pre-disposed breed, consider annual blood chemistry analysis done starting at 2 years of age.  If CT is silently occurring, copper accumulation in the liver will eventually lead to changes in the liver biochemical profile.
• Also, for pre-disposed breeds consider feeding a food with known reduced copper concentration.

Gastellum says that research has shown that CT does occur in non-pre-disposed breeds, mixed-breeds, and in dogs without the ATP7B gene mutation.  Data also shows that only 2-3% of the general Labrador Retriever population is homozygous (i.e. has two copies) for the ATP7 mutant gene. See: (https://www.researchgate.net/publication/360231606_ATP7A_ATP7B_and_RETN_genotypes_in_Labrador_Retrievers_with_and_without_copper-associated_hepatopathy

He adds, “Clearly, other factors, probably environmental and genetic are at play in the development of Copper Toxicosis.  Hopefully, future research into this condition will help parse out these factors.”

Lisa Nordstog of Snowberry Labradors of Belton MO, says she won’t change her breeding practices because of the MSU study. Her practices are already in line with what the MSU recommends for breeders. Nordstog currently uses the results of 7B and 7A genetic tests as one tool to decide appropriate breedings.

She’s been breeding Labradors for more than thirty-five years and learned the hard way about CT when one of her females produced a couple of puppies that died of CT. At the time, she had never heard of CT. She subsequently learned her female had one 7B gene mutation and the stud had two copies.

Since then, she breeds in combinations where only one parent carries the 7B gene mutation but would prefer to breed clear dogs to clear dogs to prevent the potential of another heartbreak. When selecting a stud dog, she says CT isn’t a controlling factor unless both potential parents carry the 7B gene mutation. If so, she won’t breed those dogs to one another. She’ll only breed her females that tested clear of the 7B gene mutation if the stud dog has one or two copies of the 7B gene variant or hasn’t been tested.

But she recognizes that CT is a very complex disease with both genetic and environmental components and hopes more research studies will be conducted.

Cindy Freeman of Quail Run Labradors in Rochester, WA, hasn’t encountered CT in her thirty-five plus years as a breeder but tests both males and females for CT gene mutations. “I have several who carry the 7B gene mutation but fortunately, only one copy.  I make sure I do NOT double up on it.  The tests are just tools but I always figure it better to be safe than sorry.” That means she will only breed her dogs with one 7B gene mutation to canines clear of that mutation. She plans to breed one of her females, that’s tested clear of the 7B gene mutation, to a stud dog that hasn’t been tested. She intends to test all the puppies to determine if any have the 7B gene mutation.

MSU Study

MSU researchers classified dogs into one of three study groups:

1. Control population: Dogs that were seven years or older and whose tissue sample showed rhodanine scores of less than or equal to 1. Rhodanine is a solution that stains copper on slides. The average age for these dogs was 11 and included 12 males and 17 females. Their tissue samples showed an average copper concentration of 278 ug/g.
2. CT population: Dogs 2 to 17 years of age were included in this group, with an average age of 7 years. They had an average rhodanine score of 3.5 and an average copper concentration of 1,486 ug/g. Seventeen males and 28 females were in this group.
3. IM (Grey Zone) Dogs with an accumulation of copper between dogs with CT and normal dogs. The average age of these dogs was nine, with an average rhodanine score of 2 and an average copper quantity of 526 ug/g. Sixteen dogs fell into this category: seven males and nine females.

Researchers found that dogs that possessed at least one 7B variant gene had significantly higher rhodanine scores (more copper) than other dogs in the study. Dogs with at least one 7B gene variant were  3.1 times more likely to have CT than those in the Control and Grey Zone populations. They found, however, 25% of the Control dogs and 31% of the Grey Zone canines actually had a 7B variant gene despite not having CT. According to researchers, 47% of their CT dogs did not have the 7B variant. According to Langlois, this highlights the variability in 7B genotypes across the study populations.

Only three dogs in the study had two 7B gene variants in the CT population group. All had CT.

Researchers noted that while the 7B gene variant is associated with a heightened risk for CT, the identification of this variant in the Labrador population is complex. In their study, nearly half of the CT dogs did not possess a 7B gene variant.

While the MSU findings supported a contributory role for the 7B gene variant in the development of CT,  they didn’t detect any association (a connection with these gene mutations and the presence of CT) of the 7A or RETN variant with CT. This does not mean that there is no effect, as they noted both variants were associated with decreased copper and partially protective against CT in Dutch populations of Labradors. However, MSU researchers noted that “Even if the ATP7A variant protects against copper accumulation, the effect is of questionable clinical relevance. Variant ATP7A frequencies were nearly identical in dogs with CT (CAH group) and those without CT and control dogs.”

Because some CT dogs did not have the 7B gene variant and some control dogs did have the variant, researchers questioned the routine use of genetic testing for the 7B gene variant or pursuing a liver biopsy based on a genetic test finding of a single copy of the 7B gene variant. “[M]any dogs with CAH would be missed with this approach.” Conversely, if a biopsy was done only because a dog had a single 7B gene variant, dogs without CT would be subject to unnecessary medical procedures. Twenty-five percent of the older dogs in the Control group had one 7B gene variant.

However, researchers noted that testing for the 7B gene variant “could have more value in breeding programs than in clinical practice settings.” They labeled breeding two dogs each with two 7B gene mutations to each other ill-advised “considering the heightened risk” for CT in their offspring. But they also noted attempts to eliminate this gene variant in its entirety “could decrease genetic diversity and have unintended consequences.”

Langlois also recommends not breeding a dog with two 7B gene mutations to another dog with one 7B gene mutation because some of the puppies would inherit two 7B gene variants, placing them at heightened risk for CT.

OTHER CT FACTORS/SUGGESTIONS

MSU researchers noted the importance of nongenetic factors, including the amount and bioavailability of dietary copper, that play a “substantial” role in CT development.

“This underscores the need for detailed studies that consider the collective influence of both environmental and genetic factors in disease development and progression. For example, the ATP7B variant might be of minimal concern in the absence of excess dietary copper, or dietary copper might minimally alter hepatic copper in the absence of genetic modifier.”

Langlois says that no one knows for sure the acceptable upper limit of copper in food but practitioners noticed an increase in CT in the 1990s when commercial companies changed the type of copper (from copper oxide to more absorbable copper sulfate and other copper chelates) added to kibble.

He doesn’t have a specific recommendation for brands of commercial kibble but notes that Royal Canin for Dobermans and Royal Canin for Labradors both have a low copper content (2.7 grams copper per 1000 kcal per the manufacturer of the Lab food) as does the Scoop diet. https://www.safedogfood.com/our-story/

Langlois says more research needs to be done to set acceptable lower and upper limits of the copper content in dog food.

In the meantime, Langlois suggests feeding all canines food that has a lower rather higher content of copper. He recommends that dogs of all breeds considered predisposed to the CT disease have their blood checked annually, starting at age two or three, to monitor liver enzyme levels that may indicate damage to the liver.

RELATED ARTICLES:

https://www.caryunkelbach.com/liver-disease-veterinary-experts-say-too-much-copper-in-commercial-dog-food/

https://www.caryunkelbach.com/copper-toxicosis-in-labrador-retrievers-ongoing-research-and-updated-information/

https://www.caryunkelbach.com/copper-toxicosis-labrador-retrievers/