Copper Toxicosis in Labrador Retrievers

Labrador Retriever breeder Kim Jacobson knew something was wrong with her seven-month-old pup when she saw his brown-colored urine that spring day in 2015. She immediately contacted her vet but had no inkling of the seriousness of Patron’s condition. Months and several thousands of dollars of vet bills later, this well-respected breeder made the heart-wrenching decision to put down Patron. Diagnosed with copper toxicosis (CT), he couldn’t recover. Patron was just eleven months old and our Ranger’s nephew.

CT is an “inherited metabolic disease” affecting not only Labradors but other breeds and can result in liver failure, according to Casey Carl, DVM, of Paw Print Genetics (PPG) of Spokane, Washington. He explains that dogs with this disease have a decreased ability to excrete dietary copper from the body, causing excessive copper storage in tissues and organs which can result in liver damage, cirrhosis and the inability of the liver to function properly.

All breeds and mixed breeds may contract CT, says Dr. David Twedt, one of this nation’s leading experts in CT for the past forty-plus years. Dr. Twedt, a professor at the Colorado State University’s College of Veterinary Medicine and Biomedical Sciences (CSU), identifies not only Labradors but also Bedlington Terriers and Dalmatians as well as possibly Doberman Pinchers and West Highland White Terriers as breeds with a known genetic makeup for the disease.

In January 2016, Dutch researchers identified a mutation of one gene ATP7B (7B gene mutation) as associated with an increased risk of CT in Labradors. Dr. Carl says genetics only account for 42% of the overall CT risk for any given Labrador. In addition, he notes that “given that dogs without the known ATP7B mutation have been shown to develop CT, it can be assumed that there are other, undiscovered genetic mutations that also increase CT risk.” Therefore, he adds, the ATP7B gene mutation only contributes a fraction of the overall CT genetic risk factors. Dr. Carl also says the remaining 58% of the overall risk of Labrador CT is caused by non-inherited, environmental factors including dietary intake of copper from food and water.

Two American companies now offer a DNA test for the 7B gene mutation as well as for a mutation of the ATP7A gene (7A gene mutation) which offers an unknown amount of protection from the CT disease in Labradors with the 7B gene mutation.

Experts agree that Labradors with one or two copies of the 7B gene mutation may or may not develop the CT disease. But, if a Labrador has one or two copies of the 7B gene mutation, he/she is much more at risk for CT. However, studies show that Labradors may develop CT even if they don’t have the 7B gene mutation.

Dr. Carl and other experts concur that a liver biopsy is the only way to know for certain if dogs have CT. They also agree that a larger database of DNA and liver biopsy results would facilitate additional research into the genetic makeup of CT in Labradors.

Dr. David Roberts, a general practitioner of veterinary medicine for the last thirty-six years in Colorado, suggests one way to create a large database for future studies of CT in Labradors. He recommends that your vet take a liver biopsy during a routine spay or neuter of a Labrador at the age of one year or older. He says the biopsy procedure can be done very easily during a spay, with a minimal charge and minimal additional anesthesia time for the biopsy. Results of the biopsy then could be sent to a database for further study of the disease. However, a separate “keyhole” or laparoscopic abdominal incision would be required for a liver biopsy on males but could be done during a neuter when the dog is under anesthesia, he adds.

PATRON      

Jacobson’s vet first thought Patron had a urinary tract infection. Two rounds of antibiotics later, his brown-colored urine hadn’t cleared up. Next came blood tests which showed really high liver enzyme levels. Jacobson immediately changed Patron’s diet from kibble to cooked turkey and rice. He only drank bottled water. His urine remained brown. Jacobson’s vet suggested a deworming medicine which she’d heard might help. He seemed better for a week but then his liver enzyme levels returned to their highs.

Jacobson recalls that her cute, show prospect puppy then looked like a dairy cow, with a pot belly and backbones protruding from his yellow fur. His copper enzymes remained high and his urine became the color of benzine- a very dark reddish color. She gave the go ahead for a liver biopsy. Lab results showed the copper level in his liver was 3,500 ppm. The normal range is 120-400 ppm, according to CSU. Patron had CT.

Heartbroken, Jacobson looked for answers. She learned that PPG was collecting samples of blood and DNA swabs for a future study about CT in Labradors. Jacobson, who had been in close touch with Patron’s well-respected breeder, Lisa Butler of Snowberry Labradors, suggested sending DNA samples of Patron relatives to PPG. Ranger’s DNA samples were sent to PPG in November 2015 after Butler asked us to participate. She also sent samples from her Missy (Naughty’s and Ranger’s dam), and Naughty (Patron’s dam and Ranger’s sister). In addition, Butler notified the owners of the sires of Naughty’s and Missy’s litters about Patron’s diagnosis and recommended that they send DNA samples from those stud dogs to PPG.

PPG TEST VALIDATION

In 2016, PPG used the Dutch research study to develop and validate two independent tests for both the 7B and 7A gene mutations, according to Blake Ballif, PhD, PPG’s Laboratory and Scientific Director. For several months, his laboratory ran quality control tests on samples to ensure that there would be no false positive or negative results and that the results could be replicated. Once the tests were developed and validated for accuracy, PPG tested DNA samples submitted to its laboratory from ten Labradors diagnosed with CT by elevated copper scores from liver biopsies. In addition, about forty other Labradors that were related to these ten canines also were tested with the newly developed CT tests. Unfortunately, a sample of Patron’s liver was lost in transit to PPG and his blood was mistakenly thrown out by the lab technician at Jacobson’s vet’s office, so his DNA was never tested.

Ballif says of the CT-diagnosed Labradors tested by PPG, 40% had one or two copies of the 7B gene mutation, and 50% had one or two copies of the protective 7A gene mutation. Many of the related dogs had the 7A and 7B gene mutations. He also notes that the number of CT-diagnosed Labradors was small primarily due to the difficulty in obtaining DNA samples on CT-diagnosed dogs who also had increased copper scores identified by liver biopsy.  He adds that the results on these validation samples suggested that the 7A and 7B gene mutations can clearly be identified by genetic testing but do not account for all causes of CT in CT-diagnosed Labradors.

Dogs that inherit the 7B gene mutation are at risk for increased copper storage in the liver, Dr. Carl says. Dogs with two 7B gene mutations are at a greater risk than those with only one 7B mutation. Females with the 7B gene mutation are at greater risk for the disease than males, according to studies. Dr. Carl notes that although males can only inherit one copy of the 7A gene protectant mutation, they appear to have more protection than females who inherit only one 7A gene mutation and one normal gene.

As of mid-September, PPG had tested more than 500 Labradors. Of those tested, about 36% had one copy of the 7B mutation, and 3.5%, two copies, according to Dr. Carl. He cautions that the percentages probably aren’t representative of the frequency of the gene mutation in Labradors because the samples were from litters and other related dogs.

Although research so far reveals that most dogs with CT show symptoms in middle age, there were a couple of Labradors in the two-three-year age range with CT in the PPG study, according to Ballif. These symptoms may include weight loss, diarrhea, lethargy, vomiting, weakness and abdominal pain, Dr. Carl says. Late stage signs of the disease may include abdominal swelling, jaundice and neurologic problems.

A group of geneticists from the University of Michigan’s Department of Human Genetics and Michigan State University’s School of Veterinary Medicine developed a CT test for Bedlington Terriers decades ago and later formed VetGen in Ann Arbor, Michigan. The company now tests Labradors’ DNA for CT. As of late July, it had tested twenty Labradors for CT, and half tested clear for the 7B gene mutation, according to a VetGen geneticist. Of the ten other dogs, eight had one copy of the 7B gene mutation but only two of these dogs had the 7A gene mutation. One of the two dogs with two 7B gene mutations had the 7A protectant gene mutation but the other didn’t.

Although genes other than the 7B gene mutation probably contribute to CT in Labradors, Ballif and Carl urge breeders to use the CT DNA test as one tool to reduce the incidence of this very complex disease. Dr. Carl suggests breeding dogs clear of the 7B mutation gene to each other OR dogs with one or two 7B gene mutation(s) to clear dogs to limit the number of offspring with the gene mutation. A single parent may pass on the 7B gene mutation to his/her pups.

According to Dr. Twedt, the environment, such as water and diet, plus “maybe” genetic factors, causes CT in dogs. He recalls that in the 1990s, the type of copper used in commercial dog foods changed to a type that was more biologically available. That’s when he saw an increase in cases of CT. He doesn’t recommend a certain level of copper in commercial kibble for dogs but notes diets low in copper, such as homemade meals or prescription diets including Royal Canin prescription Hepatic Diet (7 mg/kg per manufacturer’s website) or Hills prescription L/D Diet (4.5 ppm of copper per Hill’s website) worked well for Bedlingtons after they received treatment for CT. He says human foods to stay away from include shellfish, liver, certain grains and some nuts.

Dr. Twedt notes that some well water also may have high copper levels. He’s less concerned about city water because it’s treated and individuals can call their city to find out copper levels in the water.

Can CT be caused solely by diet and water? Dr. Roberts says that would be “extremely rare” that a dog could ingest that much copper. “It is much more common that there is a genetic makeup component of the disease.”

TIPS TO PROTECT LABRADORS FROM CT

How can Labrador owners protect their dogs from the disease? Dr. Twedt recommends an annual blood workup.

Here are some other ideas:

• Become educated about CT in Labradors. Dr. Carl welcomes questions from both breeders and owners. Email pawprintgenetics.com or call 509-483-5950.
• Realize that your breeder probably didn’t test the parents of your current Lab for CT because they didn’t know about the disease and/or the CT DNA test for Labradors wasn’t available.

  

• Submit a DNA swab from your Labrador to a laboratory that tests for CT gene mutations, such as PPG or VetGen. Excluding discounts, standard prices for CT tests are $80 at PPG and $98 at VetGen. Both companies now test for the 7B and 7A gene mutations even if the dog is clear of the 7B gene mutation.
• Consider authorizing your vet to take a liver biopsy of your dog when you have him or her neutered or spayed, so the sample can be checked for CT and perhaps become part of a database.
• Before buying a puppy from a breeder, ask if the parents have been tested for CT and if so, request the results. Here’s Dr. Carl’s breakdown of the probability, based on parentage, that a Labrador pup will have the 7B gene mutation:
  • Both parents clear of the 7B gene mutation (clear): pups all will be clear.
  • One parent with one copy of the 7B gene mutation and the other parent, clear: 50% of the pups will have one copy, and 50%, clear.
  • Both parents with one copy of 7B gene mutation: 25% of the pups will have two copies; 50%, one copy, and 25%, clear.
  • One parent with one 7B gene mutation and the other with two copies: 50% of pups will have two copies, and 50%, one copy.
  • Both parents with two copies of 7B gene mutation: all puppies will have two copies of 7B gene mutation.
• If your dog has one or two copies of the 7B mutation, consult your veterinarian to decide what steps to take to try to prevent/curtail the disease. Those steps may include:
  • feeding a lower copper content dog kibble,
  • scheduling regular blood tests to determine if the liver appears to be working correctly, and
  • feeding over the counter zinc supplements.

Dr. Roberts immediately recommended bloodwork for Ranger when he learned that our boy has one copy each of the 7B and 7A gene mutations. Ranger’s liver enzymes tested normal but will be retested annually. Dr. Roberts cautions that if there is even a small elevation in Ranger’s liver enzymes, then aggressive action must be taken. Once a dog is symptomatic, the dog can be helped but not saved, he says. If Ranger had two copies of the 7B gene mutation, he’d recommend semiannual blood testing.

Based on Dr. Robert’s recommendation, we checked the copper content of Ranger’s kibble because he said low-end commercial dog food often has between 25 to 30 mg/kg as fed basis of copper. The manufacturer of Ranger’s Taste of the Wild Sierra Mountain kibble reported a 15 mg/kg as fed basis of copper content which Dr. Roberts thinks is acceptable for Ranger. He notes that the Association of American Feed Operators recommends only a minimum 7.3 mg/kg copper content but no maximum.

How can breeders reduce the incidence of CT in Labradors?

• Acknowledge that CT exists in Labradors.
• Share information about the disease with each other. This is being done on a closed Facebook page called Copper Toxicosis in Labradors. Ask to join if interested.
• Test dogs for the 7B and 7A gene mutations. Butler and Jacobson, who have each bred Labradors for more than twenty-five years, now test their dogs for CT.

  

• Follow Dr. Carl’s recommendation to breed only dogs clear of the 7B gene mutation to one another, OR clear dogs to dogs with one or two 7B gene mutation(s), with one of the dogs possibly having the 7A gene mutation. Vet Gen also recommends breeding dogs with the 7B gene mutation(s) to only clear dogs.
• Educate your puppy buyers about the disease. Butler emailed an informational letter to all of her buyers of puppies from the litters that included Patron and also his mother, Naughty. Like Ranger, Naughty (Patron’s dam) has one 7B and one 7A gene mutation but Patron’s sire, has two 7B gene mutations and no 7A gene mutations. Missy, Patron’s granddam and Naughty’s and Ranger’s dam, is clear. In her letter, Butler explained that she hadn’t known about the disease when she bred both litters but has since tested not only both dams but also other dogs that she hopes to include in her breeding program. Butler also provided information about the disease and recommended that their dogs be tested and their veterinarian be consulted.
• Urge the Labrador Retriever Club, Inc. (LRC), the parent club of local Labrador clubs, to explore possibility of additional research of CT in Labradors. Ask that the LRC or your local club search for a public or private research facility willing to store DNA and liver biopsy results which could be used for additional research.

THE BEDLINGTON EXPERIENCE

Can the CT be reduced in Labradors? Absolutely, if Labrador breeders learn from Bedlington Terrier breeders even though the genetic inheritance of the disease is different. (Bedlington pups must inherit their deletion of the Commdt 1gene from both parents to become CT symptomatic.)

In 1977, Lucy Heyman learned of the breed’s genetic propensity for CT when she bought her first two Bedlingtons. She had both of her dogs’ livers biopsied and never looked back in her decades-long fight against the disease. She’s currently the Health and Wellness chair of the Bedlington Terrier Club of America, and still breeds and shows Bedlingtons. She recalls being told about forty years ago, that about 75% of her breed had the disease. That percentage has been dramatically reduced to about 10%, she estimates, thanks to careful breeding and care of Bedlingtons.

Over the forty years that she’s bred Bedlingtons, she’s had less than ten dogs with CT and lived with one. She always biopsied her dogs before breeding prior to when geneticists at the University of Michigan developed a blood test to identify the Bedlington CT gene. A DNA test was developed which she uses except when breeding to a line that may have the CT gene, and then she has a liver biopsy done of her dog to make sure it is clear of CT.

Heyman recommends feeding dogs, especially with the CT gene:

• a very high-quality dog food;
• no junk food;
• no liver or shellfish such as shrimp;
• and foods without wheat, an ingredient of many dog treats.

She also suggests testing the water in your home to see if it has a high copper content and if so, provide only bottled or filtered water to your dogs. In addition, she says, don’t stress your dogs with the CT gene and that may mean not competing with your dog in the show ring, depending on the individual canine.

Heyman also notes that breeders and breed clubs can help fight CT by not being accusatory or defensive. “Transparency is essential to try to eradicate or at least control the disease in one’s breed. Don’t breed affected dogs or carriers to one another.” And, the hardest part, she says, is to have a necropsy performed on the dogs with CT so that they leave a legacy of information.

Experts agree that more research about the genetic component(s) of CT in Labradors is necessary. VetGen is open to more studies depending on outside interest.

If followed, Dr. Robert’s suggestion to establish a database of liver biopsies and/or laboratory results of liver biopsies collected from dogs at the time they are spayed or neutered just might be another huge step towards reducing the incidence or even eliminating this heartbreaking disease in Labradors.

Additional information:  https://www.pawprintgenetics.com/blog/2017/08/01/labrador-retriever-copper-toxicosis-test-interpretation-breeding-strategy-and-monitoring/