Prospective evaluation of the diagnostic accuracy of hepatic copper content, as determined using the entire core of a liver biopsy sample

Abstract

Hepatic copper determination is an important test for the diagnosis of Wilson's disease (WD). However, the method has not been standardized, the diagnostic accuracy has not been evaluated prospectively, and the optimal cut-off value remains controversial. Accordingly, we aimed to prospectively evaluate the diagnostic accuracy of hepatic copper content, as determined using the entire core of a liver biopsy sample. Patients for whom a liver biopsy was indicated were consecutively enrolled. Hepatic copper content was determined with atomic absorption spectroscopy. All assays were performed using careful quality control by a single technician. WD diagnosis was based on WD score or its combination with clinical follow-up results. A total of 3,350 consecutive patients underwent liver biopsy. Six hundred ninety-one patients, including 178 with WD, underwent two passes of liver biopsy with hepatic copper determination. Mean hepatic content in WD patients was 770.6 ± 393.2 μg/g dry weight (wt). Sensitivity, specificity, and positive and negative predictive values of hepatic copper content for WD diagnosis in the absence of primary biliary cirrhosis (PBC) or primary sclerosing cholangitis at the cut-off value of 250 μg/g dry wt. were 94.4%, 96.8%, 91.8%, and 97.8%, respectively. The most useful cut-off value was 209 μg/g dry wt, with a sensitivity and specificity of 99.4% and 96.1%, respectively. A total of 23.3% of patients without WD and PBC had hepatic copper content >75 μg/g dry wt.

Conclusion: A liver biopsy sample of more than 1 mg dry wt may reliably reflect hepatic copper content and should be used for hepatic copper determination. Hepatic copper determination is a very valid procedure for the diagnosis of WD, and the most useful cut-off value is 209 μg/g dry wt.

Figure 1

Subject selection flow chart. WD, Wilson disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

Figure 2

Mean liver copper level in various liver diseases and by gender, age, phenotype, grade of imflammation, and stage of fibrosis of WD patients. WD, Wilson disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; AIH, autoimmune hepatitis; NASH, nonalcoholic steatohepatitis.

Figure 3

ROC curve of liver copper content for the diagnosis of WD. The curve was constructed with data from 178 patients with final diagnosis of WD and 465 patients without WD in the absence of PBC. SPSS automatically generated the curve and calculated the area under the curve (0.987) as well as serial data of test sensitivity and specificity at different cut‐off values (from the lowest liver copper level to the highest liver copper level). The maximum sum of sensitivity and specificity was obtained at the cut‐off value of 209 μg/g dry wt.; therefore, the optimal test cutoff value was 209 μg/g dry wt. WD, Wilson disease; ROC, receiver operating characteristic; PBC, primary biliary cirrhosis.