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COPPER TOXICOSIS/ CHRONIC ACTIVE HEPATITIS

W. Jean Dodds, DVM

Hemopet

938 Stanford Street

Santa Monica, CA 90403

310-828-4804; Fax 310-828-8251

 

 

Abnormal accumulation of copper in the liver leads to chronic liver failure, and is an heritable or familial trait recognized in an increasing number of dog breeds, including the West Highland White Terrier, Bedlington Terrier, Skye Terrier, Doberman Pinscher, Labrador Retriever, Keeshond, and American Cocker Spaniel. Other breeds may also be affected. Certain diseases of the liver, especially those that cause blockage of the bile duct or bile flow (cholestasis), also can result in excessive hepatic copper accumulation.

 

While the level of copper and other metals stored in the body generally tends to be higher in newborns, levels in the dog remain fairly constant throughout life, and are higher than those normally seen in humans. The mean copper concentration in the liver of normal dogs of any breed is 200-400 ppm on a dry weight basis. Dogs with copper toxicosis (also known as chronic active hepatitis) may exhibit concentrations of copper up to 10,000 ppm, while levels of 2000 or greater ppm are excepted to be toxic.

 

Copper toxicosis, a copper storage disease, is known as Wilson's disease in people. A similar disease was first recognized in the Bedlington Terrier breed, and there is now a specific genetic DNA screening test for this trait. Investigators at the University of Utrecht in Holland have recently identified the specific gene locus associated with copper toxicosis in the Bedlington Terrier. Unfortunately, with the exception of the West Highland White Terrier, current North American research efforts are not directed at the other affected breeds, such as the American Cocker Spaniel, in order to have a breed-specific DNA screening test. Hopefully, research in this field will allow development of a specific test, once a sufficient number of samples from affected animals are available for study. We hope to work with the Dutch group in order begin a project to identify the affected gene in Cocker Spaniels. To accomplish this goal, we need the cooperation of American Cocker Spaniel breeders so that a sufficient number of tissue DNA samples can be obtained for genetic analysis from affected dogs and/or their relatives.

 

Clinical and Pathological Findings

 

In affected dog breeds, whether the defect is an heritable trait involving the metabolism of copper itself or is a copper storage disorder --- such as might be involved with the Doberman pinscher --- does not affect the outcome. There are three progressive stages of copper toxicosis. In the first stage, the dog is young and not clinically ill, copper levels are beginning to accumulate in the liver, and values are reported to be as high as 1500 ppm. Regardless of the breed, this accumulation begins very early in life, and the rate of accumulation will vary among different breeds and also within individual animals. Wedge biopsy of the liver at this stage will look normal, although special copper stains of biopsy tissue will reveal the excess copper. Stage two of copper toxicosis occurs when the copper level in the liver reaches 2000 ppm. The dog is typically not ill at this point but wedge biopsy of the liver will show hepatitis and is the definitive test to make a diagnosis. Laboratory findings at that time may include an increase in ALT and alkaline phosphatase enzyme levels, but these are nonspecific findings, not necessarily indicative of copper toxicosis. As an elevated ALT enzyme concentration reflects specific hepatocellular disease, it signifies a toxic or other form of injury to the liver cell. There are other pathological changes in blood profiles which can include: low platelet counts, thyroid dysfunction, increase bilirubin in the blood and/or urine, hypoalbuminemia, and anemia. Finally, in stage three disease the dog becomes clinically ill, may have a poor appetite (anorexia), depression, abdominal pain, vomiting, excessive drinking (polydipsia) and urination (polyuria), icterus or jaundice, ascites, high amylase and lipase concentrations, and weight loss, the latter is commonly seen and may be the only clinical sign. These clinical signs usually result from liver necrosis, which is triggered by copper concentrations above 2000 ppm.

 

In the end stages of copper toxicosis, the concentration of copper in the liver may actually decrease, as the cells that die during the necrotic process are those that have accumulated copper. Because of the progressive nature of the disease, most affected animals are not presented for diagnosis and treatment until the late stages, when clinical symptoms are present, or after some significant body stress event such as a pregnancy. In fact, most of the severely affected, fatal cases in American Cocker Spaniels have occurred in females within a few weeks to months after a pregnancy. An intriguing possibility is the potential relationship between the high incidence of autoimmune hemolytic anemia in American Cocker Spaniels [the breed with highest risk worldwide] and copper toxicosis due to the free radicals produced by copper accumulation. Such a relationship has been suggested in the Bedlington Terrier.

 

Management and Treatment

 

Treatment of copper toxicosis can include dietary, medical, or a combination of these methods. Please see the accompanying two-page handout, which discuss dietary modification to reduce copper accumulation. When copper accumulation is detected early on and the dog is asymptomatic, initiating treatment at that time may slow down the accumulation of copper before irreversible damage to the liver has occurred. In addition to the dietary changes mentioned in the accompanying handout, chelating agents can be used which bind or chelate copper, thereby enhancing its excretion in the urine or bile. The most commonly used chelating agent is d-penicillamine given at 10-15 mg/kg. However, the use of this copper-chelating drug is somewhat controversial because it also binds zinc, which made deplete tissue levels of zinc and have undesirable side effects. Also, d- penicillamine has other side effects such as anorexia, nausea, and vomiting. In treating some canine cases, the adverse effects of d-penicillamine were counteracted by using a homemade low copper-low protein diet with additional zinc supplementation. Other drugs that have been used in chronic active hepatitis are corticosteroids, such as prednisone, and colchicine. Of the two drugs, prednisone would be preferred as it helps the body excrete excess copper while fighting the inflammation and fibrosis of the liver. Side effects of both these drugs include inducing liver enzyme levels, and colchicine often produces nausea.

 

Selected References

 

Dodds W J. Pet food preservatives and other additives, Chapter 5. In: Complementary and Alternative Veterinary Medicine. Mosby, St. Louis, 1997; pp 73-79.

 

Dill-Mackey E. Chronic hepatitis in dogs. Vet Clinics N. Amer, 25(2): 387-397, 1995.

 

Dodds W J, Donoghue S. Interactions of clinical nutrition with genetics, Chapter 8. In: The Waltham Book of Clinical Nutrition of the Dog and Cat. Pergamon Press Ltd., Oxford, 1994, p.105-117.

 

Schilsky M L , Sternlieb I. Animal models of copper toxicosis. Adv Vet Sci Comp Med, 37:357-373, 1993.

 

Thornburg L P. A study of canine hepatobiliary diseases, Part 4: copper and liver disease. Comp An Pract, 2(7): 3-6, 1988.

 

Hardy R M. Chronic Hepatitis in dogs: a syndrome. Comp Cont Edu Pract Vet, 8: 904-914, 1986.

 

Thornburg L P, Polley D, Dimmitt R. The diagnosis and treatment of copper toxicosis in dogs, Can Pract, 11(5): 36-39, 1984.

 

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