Diagnosing and treating canine copper-associated hepatopathies - Veterinary Medicine
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Diagnosing and treating canine copper-associated hepatopathies
Whether from inflammatory hepatic disease or an inherited metabolic defect, copper accumulation can lead to hepatocellular damage and even cirrhosis. Treatment can successfully mitigate or even reverse copper-associated changes.



Figure 2. A photomicrograph from a liver biopsy demonstrating copper staining of copper-laden lysosomes (rhodanine stain, 400X). (Photo courtesy of Dr. Mike Willard of Texas A&M University's College of Veterinary Medicine.)
Definitively diagnosing a copper-associated hepatopathy requires obtaining a liver biopsy sample surgically or laparoscopically (Figure 1) for histologic examination and copper quantification. Special stains (rubeanic acid, rhodanine, Timm's) can be used as a qualitative indicator of copper accumulation. Copper-loaded lysosomes can be identified with these stains when hepatic copper concentrations exceed 400 ppm on a dry weight basis (Figure 2).6

Table1: Laboratories That Perform Heavy Metal Atomic Absorption Analysis
Atomic absorption analysis of liver tissue is the only way to accurately assess the hepatic copper concentration. Most laboratories require fresh or freshly frozen liver samples (Table 1). Copper concentrations are reported as g/g of dry weight, which is the same as parts per million per dry weight (ppm dw).

Copper concentrations > 2,000 ppm dw are thought to be directly hepatotoxic. However, some dogs may accumulate as much as 3,500 ppm dw before liver pathology is evident.1

In non-Bedlington breeds, copper concentrations are often substantially lower; Doberman pinschers with copper concentrations as low as 750 ppm may have morphologic evidence of hepatocellular damage and show improvement with copper chelation therapy.7 This supports the suggestion that the mechanism of copper accumulation may vary with different breeds.

Interpreting the histologic findings in these cases is an essential part of patient diagnosis. Important aspects to identify are the type (suppurative vs. lymphoplasmacytic) and extent of inflammation and the severity of necrosis, fibrosis (bridging is worse than piecemeal), and cholestasis.


Table 2: Treating Canine Copper Hepatopathy*
Only treatments for copper-associated hepatopathy are discussed below. In general, provide supportive care as required on a case-by-case basis, and discontinue any drug that is known to be potentially hepatotoxic (e.g. nonsteroidal anti-inflammatory drugs, phenobarbital). See Table 2 for therapy guidelines.

Copper-restricted diet

Dogs with copper-associated hepatopathies should not be given soft water from copper pipes.6 Foodstuffs rich in copper, including shellfish, liver, kidney, heart, nuts, mushrooms, cereals, cocoa, and legumes, should also be avoided.6 In addition, these dogs should be fed a copper-restricted diet to slow—but not reverse—hepatic copper accumulation.

For growth and maintenance dog foods, the Association of American Feed Control Officials recommends 7.3 to 250 ppm per dry matter basis (DMB) of copper. Therapeutic veterinary diets designed for patients with liver dysfunction contain 3 to 5 ppm DMB of copper.6 Many of the therapeutic veterinary diets also contain high concentrations of antioxidants and adequate concentrations of high-quality proteins. Protein restriction is only required in dogs with hepatic encephalopathy, which is a rare complication.

Commercially available copper-restricted diets include Prescription Diet Canine l/d (Hill's Pet Nutrition) and Hepatic LS 14 Formula (Royal Canin). If a client prefers a homemade copper-restricted diet, consult a board-certified veterinary nutritionist.

Chelating agents

Copper chelators reduce liver copper content through chelation of copper in plasma and tissue, which is then excreted in the urine. D-penicillamine and trientine are two copper-chelating agents commonly used in veterinary medicine. D-penicillamine is associated with more side effects (e.g. vomiting, nausea, anorexia, lethargy, fever, skin problems) than trientine is, but it may also inhibit fibrosis by preventing cross-linking of collagen and by exerting an immunosuppressive effect by inhibiting T-lymphocyte function.8 Minimal, if any, side effects are associated with trientine use in dogs, but this product may be prohibitively expensive in large-breed dogs. When treating patients with D-penicillamine or trientine, it may take many months to remove excess copper from the liver (at an approximate rate of 900 g/g dw per year) and for improvement in ALT activity to be appreciated.6,9

Copper chelation is not necessarily a benign treatment. One report in the veterinary literature described iatrogenic copper deficiency associated with long-term copper chelation in a Bedlington terrier.9 Clinical signs associated with copper deficiency can include central nervous system dysfunction, anemia, and abnormal ossification.5


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