Reference intervals of spot urine copper excretion in preschool children and potential application in pre-symptomatic screening of Wilson's disease

Background: With spot urine collected from a large control sample of preschool children (aged 3-7 years), reference range of spot urine copper excretion indexes and their biological variation were defined. Methods: In order to investigate their test performance in screening of Wilson disease in this age group, multiple spot urine samples from 6 WD patients diagnosed at presymptomatic stage were analysed. Cut-off values for spot urine copper concentration, copper to creatinine ratio and copper to osmolality ratio at 0.5 umol/L, 0.1 umol/mmol and 0.00085 umol/mOsmol (32 ug/L, 56 ug/g creatinine and 0.054 ug/mOsmol, respectively, in conventional units) have potential application in differentiation of WD patients. Results: The data provides a new insight that the inter-individual variation of spot urine copper indexes (CVg) were moderate with figures around 60% which was similar to other clinically useful urine tests, such as urine albumin excretion ratio. Spot urine copper excretion strongly correlated with both urine creatinine and osmolality. And more than 95% of data points in health preschool children fell within prediction regions by linear regression suggesting a good utility of normalisation by these 2 analytes. Receiver operator curve (ROC) showed that copper to osmolality ratio was the best index with an area under curve (AUC) greater than 0.98. Conclusions: Based on the data, a new WD screening time window targeting preschool children is proposed. Application of a bivariate screening strategy using spot urine copper concentration and urine osmolality may be useful in a population screening program for preschool children.