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Evolution of Exchangeable Copper and Relative Exchangeable Copper through the Course of Wilson's Disease in the Long Evans Cinnamon Rat

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This animal study followed Long Evans Cinnamon rats, which lack working ATP7B copper transport like people with Wilson’s disease, from 6 to 28 weeks of age. Every rat in this strain fed a normal diet developed acute liver failure, while rats of the same strain fed a diet with almost no copper did not. Relative exchangeable copper, the share of serum copper that is loosely bound, separated the affected strain from controls at every time point.

Key numbers

  • Diets: normal diet with 13 ppm copper; copper-deficient diet with less than 1 ppm copper (0.367 mg/kg) (Methods 2.1, p. 2).
  • All 15 normally fed Long Evans Cinnamon rats showed acute liver failure, at a median age of 13 weeks (range 9 to 18); mortality in this group reached 40% by the end of the study (Results 3.1, p. 3).
  • None of the 9 rats of the same strain on the copper-deficient diet showed acute liver failure or died during 28 weeks (Results 3.1, p. 3).
  • Relative exchangeable copper, mean ± SD: 49.5% ± 16.6% in normally fed affected rats, 36.5% ± 3.8% in affected rats on the low-copper diet, 8.9% ± 1.2% in controls; a 19.0% cutoff gave 97.3% sensitivity and 100% specificity across ages (Results 3.2, p. 4).

Methods (brief)

Rats were bled every four weeks or at signs of liver failure. Serum exchangeable copper was isolated by EDTA incubation and 30 kDa ultrafiltration; exchangeable and total serum copper were measured by electrothermal atomic absorption spectrometry at a hospital toxicology laboratory. Liver failure was graded on a clinical scale, and markers were evaluated with ROC analysis.

Evidence fitness

Supports toxicological context on inherited copper overload: loss of ATP7B function plus a normal copper diet produced liver failure in this model, and dietary copper restriction prevented it during the study. It does not describe human dietary exposure or the general population.

Limitations

Small groups of a rodent model, a single laboratory, and 28 weeks of follow-up. Long Evans Cinnamon rats do not show the neurological signs seen in some people with Wilson’s disease.

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