Researchers Aim to Learn More About Chronic Active Hepatitis in Poodles

Owners of Standard Poodles diagnosed with chronic active hepatitis (CAH) commonly describe early signs of the disease — poor appetite, intermittent vomiting and lethargy — that could fit several disorders. Many times, owners do not learn their dog has CAH until the disease progresses to a severe condition.

While the prevalence of the disease in Poodles is not known, clinicians and genetic researchers are finding that Standards appear to be susceptible due to the disproportionate number brought to veterinary clinics for care. Believed to be a heritable condition, veterinarians caution breeders not to breed affected dogs.

"We're still in the infancy of evaluating this disease in Standard Poodles," says David Twedt, D.V.M., DACVIM, professor of small animal medicine at Colorado State University College of Veterinary Medicine. "We believe that Standards have a higher risk than Toy or Miniature Poodles and than other breeds. We just don't know what it is." Funding support from the Poodle Club of America Foundation is helping Twedt and his research team to characterize CAH in Standards, with a goal of developing an effective treatment. As Twedt and veterinary resident Allison Bradley, D.V.M., continue to collect tissue samples from affected dogs, they are optimistic they will learn more about the disease and what causes it.

Likewise, geneticist Mark Neff, Ph.D., director of the Program for Canine Health and Performance at the Van Andel Institute in Grand Rapids, Mich., is collecting DNA samples from all varieties of affected Poodles to study the inheritance pattern. The goal of identifying a linked marker potentially could lead to identification of the causative gene mutation. This, in turn, would enable breeders to reduce the gene frequency through selective breeding. A DNA test holds promise for earlier therapeutic intervention in dogs found to be genetically at risk.

A Fatal Liver Disease

Chronic active hepatitis is ongoing inflammation of the liver that results in progressive damage to liver cells. Eventually scar tissue overtakes healthy liver tissue, leading to liver failure and death. Veterinarians may not be able to determine the source of the inflammation, although possible causes include abnormal copper accumulation in the liver, drug toxicity or infectious agents. Copper accumulation in the liver is not common in Poodles, suggesting that this disease is distinct from the CAH of other breeds, such as the Doberman Pinscher.

One of the problems clinicians have identifying dogs with CAH are the subtle signs that occur in the early stages. As the disease progresses, severe signs, including fluid buildup in the abdomen, liver encephalopathy and ulcers in the gastrointestinal tract, become apparent. Liver encephalopathy is a disorder caused by the inability of the liver to eliminate ammonia and other toxins that leads to neurological impairment.

A presumptive diagnosis is made through blood tests revealing elevated levels of the liver enzyme ALT. When liver cells are damaged, this enzyme leaks into the blood. Liver function tests, such as a bile acid test, also indicate CAH. A definitive diagnosis comes from a liver biopsy. A laparascopic biopsy is less invasive than a traditional biopsy. A needle biopsy directed by ultrasound is considered the least invasive, although sometimes the tissue from a needle biopsy is not large enough for a diagnosis.

Based on their clinical studies, Twedt and Bradley speculate that some dogs with CAH respond well to immunosuppressant therapy, or medications that reduce inflammation or suppress the immune system. "We've had some preliminary success using cyclosporine to treat dogs with CAH," Twedt says. "It is an immune-suppressing drug that has been shown to stop the ongoing inflammation. Cyclosporine has an advantage over corticosteroids as it has fewer side effects, although a disadvantage is it is more expensive."

Stem-cell therapy may provide a future treatment alternative. Researchers at the Center for Regenerative Medi­cine at Colorado State University already are experimenting with implanting new liver cells derived from stem cells in patients with liver disease or damage.

"We have harvested stem cells, and we're trying to make them into hepatocytes or hepatocyte precursors," explains Twedt. "Stem cells may actually generate new liver cells. They may also have an effect in decreasing inflammation. We are still quite a ways from clinical application in individual dogs."

Treatment for CAH is customized for individual dogs. A critical factor in the treatment plan is the amount of liver damage the dog has already suffered. If the disease is detected early before major liver damage has occurred, the prognosis is better.

Diet management plus medications suited for the signs of disease are most effective. Anti-inflammatory medications help reduce inflammation, and antioxidants and antifibrotic agents help reduce scarring of the liver tissue.

A dog should be fed a nutritious, complete and balanced dog food, particularly since the liver does not metabolize food normally. The diet should be adjusted depending on the stage of the liver condition. While years ago it was believed that feeding a low-protein diet was best, today veterinarians realize that a high-quality and biologically available protein should benefit dogs with liver disease, except for those with end-stage liver disease.

"The priority is for the dog to eat," Twedt says. "Since dogs with liver disease often suffer a loss in appetite, the most important thing is to make the diet palatable enough the dog meets his caloric need."

Seeking a Genetic Basis

CAH occurs in dogs from 3 to 10 years of age, with a mean age of 6 to 7 years. Due to the late age of onset, breeders may unknowingly breed a dog before liver disease is detected. Regular wellness screenings, which include blood work, help to pick up subclinical liver problems. They also provide baseline information for dogs that show early signs of disease.

Though it is not known definitely whether CAH is an inherited disease, the researchers at the Van Andel Institute aim to find out. Their efforts to identify the gene mutation for CAH hold promise that one day a direct DNA test may be available to identify affected dogs as well as carriers. Breeders then would be able to selectively breed healthy litters using the DNA test.

Neff, the lead researcher, thinks Standard Poodles are likely to have a genetic predisposition to CAH based on breed predilection. He is interested in collecting samples from Toy and Miniature Poodles as well. "It is possible the gene has penetrated the adjacent gene pools of these varieties, despite the fact CAH is not commonly observed in these dogs," he says.

Comparing DNA from affected Poodles with a control group of healthy dogs will enable the researchers to identify regions of the genome that are close to the mutation. The discovery of a linked marker potentially would lead to identifying the actual mutation that causes CAH. DNA samples from affected dogs are key to progress.

"With the modest cohort that we have, we're seeing what we refer to as 'trending toward significance,'" Neff says. "We haven't achieved statistical significance, but we're seeing a couple of regions in the genome that look like they are strong for the mutation. To learn whether there is a real positive association or to eliminate it as a false positive comes down to needing more samples. As few as 12 new cases could make a substantial difference in our findings."

While the research in Poodles will help breeders, the information about canine liver disease may also one day help researchers studying human liver disease. "In the next decade, because of the power of canine genomics, findings in veterinary medicine are likely to benefit human patients," Neff says. "This hasn't always been the case. Over the last 100 years, all the best practices, best diagnostics and best medicines came from human medicine to veterinary medicine. The time is right to reverse this flow of biomedical knowledge."

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