Liver Disease in a Rat Model of Wilson's Disease

The purpose of this study was to establish whether 99m Tcmebrofenin could noninvasively assess liver function in Wilson’s disease. Methods: Long–Evans Cinnamon (LEC) rats, which reproduce Wilson’s disease with copper toxicosis, and their normal counterparts, Long–Evans Agouti (LEA) rats, were studied. Scintigraphic findings were correlated with biliary mebrofenin excretion and residual organ counts and with hepatic copper content, histology, copper excretion capacity, and liver test results. Results: Serum alanine aminotransferase (ALT) levels were elevated in some LEC rats, whereas serum bilirubin levels were normal. Liver histology was normal in LEA rats, whereas LEC rats showed multiple abnormalities. Mebrofenin was incorporated rapidly in LEA rats, with a mean time to peak liver activity of 80 30 s, followed by prompt biliary excretion of the tracer. In LEC rats, the mean time to peak activity, 283 190 s, was significantly longer (P 0.001). The time to half of peak activity, indicating tracer clearance, was significantly greater in LEC rats than in LEA rats (1,825 1,642 s vs. 524 82 s, P 0.002). Hepatic mebrofenin handling correlated with hepatic copper content, histologic grade, copper excretion capacity, and serum ALT. Conclusion: Correlation of 99m Tc-mebrofenin handling with liver morphology, function, and copper accumulation in LEC rats suggests that mebrofenin scintigraphy can be useful for noninvasively monitoring disease progression and therapeutic response in Wilson’s disease. Although the data were obtained in an animal model of Wilson’ disease, these biochemical parameters likely reflect liver damage in general, suggesting that there may be a role for mebrofenin scintigraphy in other chronic liver diseases as well. Although liver tests such as serum bilirubin, aminotransferase levels, and prothrombin activity estimate global liver function, structure–function correlation in disease states often requires liver biopsy. Noninvasive evaluation of hepatocellular function in chronic conditions such as Wilson’s disease, in which extensive fibrosis develops, has generally been difficult. Sonography, CT, and MRI provide useful morphologic information but are of limited value for assessing hepatocellular function. Because Wilson’s disease, and chronic liver disease in general, are associated with progressive parenchymal injury, our objective was to identify a noninvasive test that would correlate with hepatic structure and function. We selected hepatobiliary scintigraphy with 99m Tc-N-(3-bromo