Liver Disease Veterinary Experts Say Too Much Copper in Commercial Dog Food

The current recommended minimum copper content in commercial dog food is too high, according to five well-known liver disease veterinarian specialists.

These veterinarians, who have two hundred years of combined experience, say that since 1997 they’ve seen an increase in the number of dogs — purebred and mixed breeds — afflicted with copper toxicosis (CT), also referred to as chronic copper hepatitis, copper associated liver disease, and copper associated hepatopathy. That’s when the Association of American Feed Control Officials (AAFCO) changed their recommendation regarding the type of copper additive to be used in commercial dog foods, according to one of the members of the vet group, Dr. Cynthia Webster, DVM. She’s a Professor and Associate Chair for Research in the Clinical Sciences department at Cummings School of Veterinary Medicine at Tufts University.

Dr. Webster; Sharon A. Center, DVM of Cornell University’s College of Veterinary Medicine; Keith P. Richter, DVM, of Veterinary Specialty Hospital of San Diego; David C. Twedt, DVM, of Colorado State University’s James L. Voss Veterinary Teaching Hospital; Joseph J. Wakshlag, DVM, PhD,  also of Cornell and clinical nutrition specialist; and Penny J. Watson, DVM, Department of Veterinary Medicine, University of Cambridge, United Kingdom, recently published their findings and opinions in the Journal of the American Veterinary Medical Association. See: https://avmajournals.avma.org/doi/full/10.2460/javma.258.4.357

All the named veterinarians also are Diplomates of the American College of Veterinary Internal Medicine (DACVIM) except Dr. Watson, who is a member of the European equivalent, and Dr. Wakshlag, who is a diplomate of the American College of Veterinary Nutrition.  Most were part of a veterinarian group that published an American College of Veterinary Internal Medicine 2019 consensus statement about the diagnosis and treatment of chronic hepatitis in dogs. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524396/

SUMMARY OF RECENT CT DEVELOPMENTS

Other recent developments on the CT front include:

• Colorado State University (CSU) is conducting a six-month trial for each participating canine that tests the effectiveness of penicillamine in canines with CT and cyclosporine in dogs with autoimmune hepatic disease;
• Dutch researchers continue their genetic CT research in Labrador Retrievers;
• Two private laboratories provide total numbers of Labradors that they tested for the ATP7B and ATP7A gene mutations, an indication that breeders are using the results as one tool in breeding decisions and owners are using results as a tool to care for their canines.
• The Facebook page, Copper Toxicosis in Labradors Retrievers, now has a list of more than 200 Labradors tested for the 7B and 7A gene mutations.

COMMERCIAL DOG FOOD

AAFCO is a voluntary association of local, state, and federal agencies that operate in a watchdog capacity to regulate the sale and distribution of animal feeds and drug remedies.

In 1997, AAFCO recommended replacing feed-grade copper oxide in commercial dog food with a more absorbable form of copper, such as copper sulfate, Dr. Webster says.  Dogs only absorb a small amount of copper oxide as opposed to 100% of copper sulfate, she adds, noting that the net result of this action was to increase the amount of copper that dogs absorbed from their diets.

The five veterinarian specialists note the AAFCO provides that the “minimum daily copper intake for maintenance adult canine diets is 1.83mg/1000kcal . . . Although it is not known how many diets exceed this minimum [AAFCO] recommendation, investigation of some commercial dog foods demonstrated alarmingly high copper contents in some brands.”

What are the acceptable minimum and maximum amounts of copper in commercial dog foods?

The veterinarian group recommends that food trials be conducted to determine those levels but is certain that AAFCO’s current minimum level can be decreased. Currently, both the AAFCO and the National Research Council (NRC) don’t recommend a maximum amount of copper, only minimum levels.

How can dog owners know how much copper is in their canines’ commercial dog food? Companies usually don’t report the amount in their premixes, where minerals are tested, and when they do, they fail to take into account the amount and absorbability of naturally occurring copper in the content of the rest of the food, such as that in salmon, organ meats or other ingredients known to be high in copper, Dr. Webster says.

She readily agrees that the way copper content is reported — often differently — is confusing. The AAFCO uses mg/km DM/d (milligram/kilogram/dry matter per day and the NRC, mg/kcal/d (milligrams per 100 kcalories as fed per day).

The AAFCO minimum copper content is 7.3mg/kg DM/d which equates to ~ .21mg/100 kcal/d and the NRC, is 7 mg/kg/DM/d which equates to ~ 0.15 mg/100kcal.  A nutritionist makes these complicated computations.

Dr. Webster’s group reports the average dog food is ~15-25 mg/kg DM/d and hepatic diets such as Hills and Royal Canin ~ 4.9 mg/kg DM/d.

To protect your dog from too high copper levels that could adversely affect the liver, Dr. Webster recommends:

• Ask your commercial dog food company for the total copper content of its dog food in either mg/km DM/d or mg/kcal/d so you can compare the numbers with AAFCO’s or NRC’s recommended minimum numbers. Knowing the percentage of copper in the food isn’t helpful, she explains, because it isn’t easily comparable to the AAFCO or NRC numbers.
• If you give your dog supplements, check for any copper content.
• Ask your breeder about whether there is any liver disease history in your dog’s line.
• Check your well water for copper content.
• Avoid adding copper-rich ingredients to your dog’s raw diet or as snacks. Check online for high copper content foods for humans to get an idea of what foods to avoid.
• Assuming your dog doesn’t show signs of liver disease, have liver enzymes in your dog’s blood checked annually starting at age four or five. Elevated liver enzymes may be the first sign of CT. The sooner the disease is diagnosed, the better chance of survival.
• If your dog is found to have liver copper values of greater than 600 ppm, the issue should be addressed.
• The Scoop diet, a low copper food, designed by Dr. Daniel Langlois at the University of Michigan, may be an alternative to the Hills and Royal Canin foods. See: https://www.safedogfood.com/
• Dr. Webster explains: In Labradors, the 7B gene is necessary to excrete copper from the liver. The 7B gene mutation increases the amount of copper in the liver. The 7A gene is necessary for the absorption of copper in the intestine, and the 7A gene mutation decreases that absorption.
  • If your Labrador has one 7B gene mutation (i.e. heterozygous), pick a lower copper content commercial dog food or feed a diet designed by a dog food nutritionist because it’s complicated to figure out actual copper content in food. The current literature suggests that heterozygotes don’t accumulate excess copper, but more research is necessary.
  • If your Labrador has two ATP 7B gene mutations (i.e. is homozygous), put your dog on a restrictive copper diet such as Hills or Royal Canin hepatic diets because the literature shows that homozygous Labradors will accumulate excess liver copper on normal diets. The research literature suggests that only 12-13 percent of CT cases in Labradors involve homozygous gene mutations.

Dr. Webster encourages owners of CT dogs to report the condition to the U.S. Food and Drug Administration (FDA) so that the appropriate action can be taken to prevent diet from contributing to the problem. https://www.fda.gov/animal-veterinary/report-problem/how-report-pet-food-complaint

CSU RESEARCH

Dr. Sarah Shropshire, DVM, PhD, DACVIM of the CSU veterinary teaching hospital, and Dr.Tarini Ullal, DVM, DACVIN, a gastroenterology and hepatology fellow at the University of California School of Veterinary Medicine at Davis (UCD), are conducting clinical trials to determine the effectiveness of cyclosporine, a drug used to suppress the immune system to treat idiopathic chronic hepatitis (ICH), an autoimmune disease that attacks the liver. They are also studying the effectiveness of penicillamine to treat Copper Associated  Hepatopathy (CAH).

The clinical study, currently to be conducted over an eighteen-month period, is funded by a $22,500 grant from the American Kennel Club Health Foundation that was made possible by the generosity of the Bedlington Terrier Club of America. In addition, the veterinary school at Davis is contributing a small grant.

Dr. Twedt is lending his vast experience to the study.

Dr. Shropshire says the research is designed to help veterinarians treat dogs with both diseases. Currently, she says, there is no long-term study about the effectiveness of these drugs and hence, no standardized treatment for both diseases.

She says the team will evaluate the treatment effectiveness by monitoring liver parameters including, clinical signs, serum drug levels, liver values, and, in the copper study, copper levels, determined by a second biopsy at the end of six months. The study’s goal is to find “noninvasive” markers and tests to assess whether the drugs are helping the dogs. These tests include the use of ultrasound, copper staining of liver slides, and blood marker tests, all designed to potentially replace a second biopsy.

These parameters will be correlated to remission or relapse of disease to identify factors associated with treatment response, according to Dr. Shropshire. The project’s findings may significantly improve veterinarians’ ability to treat dogs with both liver diseases, she adds.

The canines enrolled in the study so far include Labradors, Lab mixes, Poodles, Poodle mixes, one Maltese, a Great Dane, and other breeds and mixed breeds. Most of the copper patients are female. All the dogs are adults, and most are seven years of age or older.

Dr. Shropshire says before being accepted into the study, all dogs must undergo a liver biopsy, at the expense of their owners, and must be diagnosed with either autoimmune or copper hepatic disease. She notes that about forty potential copper study candidates were ineligible because their liver damage was caused by congenital, vascular, or biliary disorders. Some patients were rejected because they couldn’t tolerate the medications. Others were disallowed because they had cancer or bacterial infections or required drugs other than cyclosporine or penicillamine.

Once the dogs are admitted into the study, Dr. Shropshire says the study pays for blood work, a second biopsy, drug costs, and any necessary hospitalization. The owners must be able to bring the dogs to CSU or UCD for checkups at one, three, and six-month intervals but otherwise the dogs live at home with their owners. Each dog is in the study for six months.

The copper dogs must be fed a liver disease diet — either Hills or Royal Canin — because of the difficulty of determining the total content of copper in commercial-grade diets. Or they can be fed a home-cooked diet designed by a veterinary nutritionist. However, they can’t take any supplements or drugs, including milk thistle, zinc, and denamarin, but must be given their clinical trial medications twice a day.

Dr. Shropshire says she’d like to have twenty dogs in each study for six months at a time. Currently, fourteen dogs are in the autoimmune study, and six to seven in the copper study.

“We are always looking for more dogs to join the study. The current dogs have been referred by veterinarians and word of mouth. Most live in Colorado, Wyoming, and California but two are from Montana and one, from South Dakota.

Contact Dr. Shropshire at Sarah.Shropshire@colostate.edu if interested in applying to have your dog participate in this study.

DUTCH RESEARCH OF COPPER DISEASE IN LABRADORS

Dutch researchers are continuing to study the relationship among the 7B gene mutation, the ATP7A gene protectant mutation, and CT, with biopsies and DNA taken from about 400 “to better predict the value of the DNA test.” They also are trying to find a blood marker for CT in Labradors. The researchers haven’t said when the studies may be completed.

However, they have finished a study of 239 Labradors, of which they had liver biopsies and DNA for 176 of those dogs. They were trying to discover gene variants or modifiers, in addition to ATP7B and ATP7A, that could affect copper levels and influence the development of CT in Labradors.

The researchers discovered one gene, RETN, that produces the protein resistin, which might act as a protectant for copper toxicosis much like the 7A gene, according to Dr. Hille Fieten. More research is needed to confirm this possibility. The study also ruled out the gene COMMD1 as contributing to CT in Labradors. See: Investigation of Genetic Modifiers of Copper Toxicosis in Labrador Retrievers  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693796/

CONTINUED TESTING FOR THE 7B and 7A GENE MUTATIONS IN LABRADORS

As of early April, PawPrints Genetics (PPG) of Spokane Washington, had tested 4,739 Labradors for the 7B gene mutation, and reports that 64.87% tested clear; another 30.96 % had one copy of the 7B gene mutation, and only 3.97% were found to have two copies of the 7B gene mutation. However, PPG notes these figures may be skewed when compared to the entire Labrador population because many of the tested dogs are related.

PPG didn’t provide statistics about the number of dogs that had 7A gene mutations because those figures weren’t readily accessible.

Gen Sol of Clayton, GA only began testing for the CT gene mutations a couple of years ago. So far, it’s tested 162 dogs for the 7B gene mutation and 80 dogs for the 7A gene mutation. According to Dr. Mica Halpern, not all customers’ dogs are tested for both mutations. Her company’s reporting system is unable to currently provide information about the 7B and 7A gene mutations tested in the same dog. Of the 162 dogs tested for the 7B gene mutation, 67% were clear, 29 % had one 7B gene mutation and just 4% had two 7B gene mutations.

She says, of the 80 dogs tested for the 7A gene mutation, 46 % didn’t have the gene mutation, 30% had one 7A gene mutation, and 24% had two 7A gene mutations.

Veterinary Genetic Services of Ann Arbor, MI, which tests for both gene mutations, was unable to provide any statistics because of a lack of clerical staff.

One other lab refused to provide any information, saying their clients had privacy interests.

PUBLIC RESULTS OF 7B & 7A GENE MUTATION TESTING OF LABRADORS

More than 950 individuals belong to the Facebook private group, Copper Toxicosis in Labrador Retrievers. Some breeders and individual owners post the results of their dogs that are tested for the 7B and 7A gene mutations. The group keeps a file that lists the dogs by registered name, sex, if they are symptomatic of CT, their dams and sires,  the test results, and their owner names. As of late May, the results of about 200 dogs were listed.

Members of this Facebook group also share experiences with CT issues and their opinions about testing for the 7B and 7A gene mutations. Some breeders report they use the test as one tool when they make breeding decisions.

Casey Carl, DVM of PPG says that the 7B gene mutation “is only one genetic factor of potentially many factors contributing to the risk of CT.” He adds that dogs that are clear of the 7B gene mutation may still develop CT, and dogs with the 7B gene mutation may never develop the disease.

That’s why, he says, “it’s important to consider genetic diversity of the breed rather than eliminating every dog with the ATP7B mutation from breeding. Instead, if breeders want to eliminate the 7B mutation from their line, it’s preferable from a genetic diversity standpoint to breed these dogs to clear dogs.”

He explains: “In the case of a dog with two copies of the ATP7B mutation being bred to a clear dog, 100% of the litter would carry one copy of ATP7B and would have a lower risk than the parent with the two copies.” Dr. Carl adds that he’s happy to take calls at 509-483-5950 or emails at ccarl@pawpringenetics.com) to discuss the gene mutation and how it’s associated with CT.

RELATED ARTICLES:

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

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