Copper-associated liver disease (Proceedings)


Copper-associated liver disease (Proceedings)

Nov 01, 2010

Copper is an essential trace element in diets and is required for a number of physiologically important enzymes. Cells have highly specialized and complex systems for maintaining intracellular copper concentrations. At toxic concentrations, free intracellular copper initiates oxidative damage causing hepatocellular necrosis and inflammation. Copper accumulation in the liver can be associated with significant hepatic injury resulting in acute hepatitis, chronic hepatitis, and cirrhosis. It is one of the few well-documented causes of canine chronic hepatitis. In one study, copper-associated hepatitis (acute and chronic) accounted for 1/3 of all dogs with primary hepatitis. Hepatic copper accumulation and hepatopathy have been described in cats but appears to be rare. The severity of hepatic injury correlates with the amount of hepatic copper, but subcellular localization of molecules and the molecular association also plays a role. Serum copper levels do not accurately reflect hepatic copper content and quantitative analysis of copper in the liver is required. Hepatic copper concentration in normal dogs is between 150 - 400 ugm/gm dry weight (ppm). Inflammatory hepatic injury does not consistently occur until copper concentrations exceed 2,000 ugm/gm dry weight. However, there may be breed variations; for example, in Doberman pinschers hepatic inflammation is present with lower copper concentrations. Transient acquired Fanconi's syndrome has been described in dogs with excess hepatic copper accumulation. Copper granules were demonstrated on renal biopsy in some but not all dogs.

Potential mechanisms for hepatic copper accumulation include primary metabolic defects in hepatic copper metabolism, cholestasis causing impaired biliary excretion of copper, and excess copper absorption. A primary defect in hepatic copper metabolism occurs in Bedlington terriers with a genetic mutation in the gene encoding the copper transport protein, COMMD1 (formerly MURR1), resulting in a defect in biliary copper excretion. In the early stages, copper is sequestered in hepatic lysosomes and hepatic damage is minimal. However, with progressive accumulation of copper, hepatic injury becomes significant. The average copper concentration in Bedlington terriers with chronic hepatitis is approximately 6,000 ugm/gm dry weight and values up to 12,000 ugm/gm dry weight have been reported. Inherited copper-associated liver disease is also described in the West Highland white terrier, Skye terrier, Doberman pinscher, Dalmatian, and Labrador retriever, but with the possible exception of Dalmatians, the hepatic copper levels are much lower than in Bedlington terriers. The pathogenesis of copper accumulation and the relationship to chronic liver disease in these breeds is poorly understood. It seems likely that these breeds have a hereditary disorder of copper handling, but it is unlikely to be the same as described for the Bedlington terrier. Breed related disorders are discussed in more detail in a subsequent section of this chapter.

Hepatic copper accumulation in the liver may also be a consequence rather than the cause of chronic hepatitis. Since copper is normally excreted in the bile, chronic cholestasis and impaired bile flow can result in secondary copper accumulation. Secondary copper accumulation is predominantly periportal and is usually less than 2000 ugm/gm dry weight. The effect of cholestasis on hepatic copper content was evaluated in three groups of dogs: Bedlington terriers with copper toxicity, dogs with extrahepatic biliary obstruction (the prototype example of a cholestatic disorder) and chronic hepatitis in breeds not known to be at risk for copper-associated liver disease. Hepatic copper content was evaluated by a semi-quantitative method based on copper staining of liver tissue with rubeanic acid, using a scale of 0 (no copper) to five. Copper staining revealed absent to mild increases (scores of 0-2+) in dogs with biliary obstruction and chronic hepatitis when compared to Bedlington Terriers (scores of 5+). It was concluded that copper scores of 3+ or higher were suggestive of a primary copper storage disease. Unfortunately, quantitative copper analysis was not evaluated. Markers of oxidative injury and altered defense mechanisms were similar in the 3 groups, consistent with the concept that copper, inflammation, and cholestasis can all contribute to oxidative injury.

Many other breeds of dogs (including mixed breeds) have been identified with increased hepatic copper and chronic hepatic disease but a hereditary mechanism has not been proven. When liver disease and copper accumulation are identified in a breed of dog not previously described with familial copper-associated disorder, it can be difficult to determine whether copper accumulation is primary or secondary. Findings that would support a primary metabolic defect in copper metabolism include copper accumulation that precedes cholestasis or inflammation, centrolobular (zone 3) distribution of copper, histochemical score for copper of 3+ or greater, or quantitative copper measurements that exceed 2000 ugm/gm dry weight.

High dietary copper intake appears to be an uncommon cause of hepatic copper accumulation, although it was suspected in two farm dogs chronically eating commercial calf food supplemented with copper. The copper content of commercial dog foods range from 12-16 mg/kg dry matter, which is relatively high compared to recommended minimum daily copper requirements in dogs. Commercial dog food alone does not appear to explain hepatic copper accumulation and liver disease in dogs. However, it has been speculated that the recent increase in pathologically elevated hepatic copper concentrations (specifically evaluated in Labrador retrievers), may coincide with a pet food industry recommendation to replace cupric/cuprous oxide in feed formulations because of its low bioavailability.