LAUSR

Copper is an essential redox cofactor and enabler of protein function through electron transfer. The daily requirement is 1 mg; most diets supply 1–5 mg/day with drinking water contributing 6%–13%. 2 Regulatory limits for drinking water range from 1 mg/L to 3 mg/L. Other sources include contaminated drinking water, copper cookware, intrauterine devices, dietary supplements, fungicides and pesticides. Occupational exposure occurs in plumbers and industrial workers (welders, machinists, smelters, steel production, municipal incinerators). Free copper causes oxidative damage to cellular organelles, lipids, proteins, carbohydrates and nucleic acids. 3 Copper homeostasis is tightly regulated to prevent toxicity; plasma copper is extensively ceruloplasmin bound (95%) and intracellular copper is sequestered by cuproproteins and chaperones. Copperbinding ATPases facilitate biliary copper excretion. Wilson’s disease is an archetypal example of chronic copper toxicity, caused by defective ATP7Bmediated copper excretion at normal intakes. Systemic copper dissemination leads to neurological disease, commonly the first manifestation. Molecular testing, dietary copper restriction and chelation therapy underpins management. Indian Childhood Cirrhosis (ICC) is a rapidly fatal copperassociated paediatric cirrhosis. Absence of Wilsonian features, elevated serum/urine copper and normal ceruloplasmin distinguish it from Wilson’s disease. ICC has been linked to storage and heating of milk in copper cookware, producing copper intakes of 6–63 mg/L. 8 Genetic susceptibility contributes since cirrhosis frequently runs in affected families, and asymptomatic siblings often demonstrate subclinical defects in copper handling. Excess copper exposure is not consistently present, and populationbased studies do not support liver injury in normal people at water copper levels of 2–8 mg/L. 10 In the Tyrolean epidemic, affected and unaffected children consumed the same milk with copper content of 10.5–63.3 mg/L. ICC livers have greater copper content and oxidative injury than Wilsonian livers, yet less severe cases frequently remit after the age of 5 years, and preicteric cases benefit from copper avoidance and penicillamine. Familial occurrence, a spectrum of severity and inconsistent copper exposure support an underlying genetic trait, but molecular evidence is lacking while ICC diagnoses are declining, possibly due to socioenvironmental change. The worldwide prevalence of both nonWilsonian copper overload and heterozygous Wilson’s disease is unknown, due to a paucity of reliable biomarkers. These patients are at risk in regions with high copper intake. Available biomarkers do not detect subclinical changes in body copper status and perform better in deficiency than excess. Direct quantification of liver copper is essential. Serum/urine copper and ceruloplasmin do not reflect copper status; they are influenced by age, gender, seasonal variation, acute phase response, hormonal status, malnutrition, hepatitis, cholestasis and congenital aceruloplasminaemia. Ceruloplasmin immunoassays lack standardisation and crossreact with apoceruloplasmin. Normal ceruloplasmin levels are occasionally found in severe Wilson’s disease. Deficiency is in reality much more common than excess, and a noninvasive biomarker is needed that reliably predicts both. Calculated nonceruloplasmin copper and relative exchangeable copper (ultrafiltration method) show variable accuracy and cannot be used in isolation. A promising new biomarker under evaluation is erythrocyte levels of the copper chaperone of superoxide dismutase.