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Background and Purpose: The severity of Wilson's disease (WD) is linked to free copper accumulating in the liver and brain. Exchangeable copper (CuEXC) is a new technique to determine plasmatic copper and is useful in the diagnosis of WD. It is hypothesized that it may also enable a good evaluation of extra-hepatic involvement and its severity., Methods: Forty-eight newly diagnosed WD patients were prospectively evaluated using hepatic, neurological, ophthalmological and brain magnetic resonance imaging (MRI) scores. Three phenotypic presentations were distinguished: pre-symptomatic, hepatic and extra-hepatic. CuEXC was determined in addition to standard copper assays before decoppering therapy. Correlations between biological parameters and the different scores were determined and compared in the hepatic and extra-hepatic groups., Results: Extra-hepatic patients had significantly higher CuEXC values than those with the hepatic form (P < 0.0001). The overall ability of CuEXC to separate the two forms was satisfactory, with an area under the curve of 0.883 (95% confidence interval 0.771-0.996) and an optimal threshold for extra-hepatic diagnosis of 2.08 μmol/l (sensitivity 85.7%; specificity 94.1%). In extra-hepatic patients, CuEXC was the only biological marker to be positively correlated with the Unified Wilson Disease Rating Score (r = 0.45, P = 0.016), the Kayser-Fleischer ring score (r = 0.46, P = 0.014) and the brain MRI score (r = 0.38, P = 0.048), but it was not correlated with the hepatic score., Conclusions: Exchangeable copper determination is useful when diagnosing WD as a value >2.08 μmol/l is indicative of the severity of the extra-hepatic involvement. In the case of purely hepatic presentation, atypical or mild neurological signs, it should encourage physicians to search for lesions in the brain and eyes., (© 2016 EAN.)

Background: Family screening is a main step for the diagnosis in Wilson disease. This study was undertaken to evaluate the value of relative exchangeable copper for family screening., Methods: Data from family screening were collected from the French National Center of Reference for Wilson disease. Subjects who were first- or second-degree relatives of the index case underwent clinical examination and biological parameters., Results: Of 127 subjects examined, copper abnormalities or low ceruloplasminemia were detected in 21 subjects, corresponding to 5 patients with Wilson disease, 14 heterozygous ATP7B carriers and 2 subjects with no ATP7B mutations. Relative exchangeable copper determination significantly discriminates heterozygous ATP7B carriers and subjects with no ATP7B mutations from WD patients with a cutoff of 15%., Conclusions: Exchangeable copper appears to be a promising tool for family screening in Wilson disease., (© 2013 International Parkinson and Movement Disorder Society.)

Background: Wilson's disease (WD) is an inherited disorder of copper metabolism leading to liver failure and/or neurological impairment. Its diagnosis often remains difficult even with genetic testing. Relative exchangeable copper (REC) has recently been described as a reliable serum diagnostic marker for WD., Methodology/principal Findings: The aim of this study was to validate the use of REC in the Long Evans Cinnamon (LEC) rat, an animal model for WD, and to study its relevance under different conditions in comparison with conventional markers. Two groups of LEC rats and one group of Long-Evans (LE) rats were clinically and biologically monitored from 6 to 28 weeks of age. One group of LEC rats was given copper-free food. The other groups had normal food. Blood samples were collected each month and different serum markers for WD (namely ceruloplasmin oxidase activity, exchangeable copper (CuEXC), total serum copper and REC) and acute liver failure (serum transaminases and bilirubinemia) were tested. Every LEC rat under normal food developed acute liver failure (ALF), with 40% global mortality. Serum transaminases and bilirubinemia along with total serum copper and exchangeable copper levels increased with the onset of acute liver failure. A correlation was observed between CuEXC values and the severity of ALF. Cut-off values were different between young and adult rats and evolved because of age and/or liver failure. Only REC, with values >19%, was able to discriminate LEC groups from the LE control group at every time point in the study. REC sensitivity and specificity reached 100% in adults rats., Conclusions/significance: REC appears to be independent of demographic or clinical data in LEC rats. It is a very simple and reliable blood test for the diagnosis of copper toxicosis owing to a lack of ATP7B function. CuEXC can be used as an accurate biomarker of copper overload.

Iron and copper are essential trace metals, actively absorbed from the proximal gut in a regulated fashion. Depletion of either metal can lead to anemia. In the gut, copper deficiency can affect iron absorption through modulating the activity of hephaestin - a multi-copper oxidase required for optimal iron export from enterocytes. How systemic copper status regulates iron absorption is unknown. Mice were subjected to a nutritional copper deficiency-induced anemia regime from birth and injected with copper sulphate intraperitoneally to correct the anemia. Copper deficiency resulted in anemia, increased duodenal hypoxia and Hypoxia inducible factor 2α (HIF-2α) levels, a regulator of iron absorption. HIF-2α upregulation in copper deficiency appeared to be independent of duodenal iron or copper levels and correlated with the expression of iron transporters (Ferroportin - Fpn, Divalent Metal transporter - Dmt1) and ferric reductase - Dcytb. Alleviation of copper-dependent anemia with intraperitoneal copper injection resulted in down regulation of HIF-2α-regulated iron absorption genes in the gut. Our work identifies HIF-2α as an important regulator of iron transport machinery in copper deficiency.

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism. Failure to diagnose WD can be dramatic leading to irreversible damages. The molecular genetic analysis of ATP7B gene is the reference test for diagnosis but the number of reported mutations of the ATP7B gene is on the rise. The analysis is cumbersome and requires tedious work. Other clinical and biological tests are proposed but it is often difficult to interpret some patients' results. A rapid and reliable biological test for WD diagnosis is still needed. Analytical reliability of Exchangeable copper (CuEXC) determination procedure is examined by studying the repeatability, the short term stability and stability in frozen serum. Relative exchangeable copper (REC=CuEXC/total copper%) is proposed and evaluated as a new diagnostic test and compared to classic tests used for WD diagnosis. Sixteen new Wilson disease patients were diagnosed in our institution between January 2009 and May 2011. The different biological tests used for WD diagnosis yielded lower sensitivity and specificity compared to our new biomarker, the REC. We show that REC is an excellent discriminatory tool for the diagnosis of WD offering 100% sensitivity and 100% specificity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We report two patients with myelopathy associated with copper deficiency and pancytopenia. Excessive intake of zinc can lead to a severe deficiency of copper reducing the absorption of ingested copper. The patients had in common consumption of denture adhesive paste containing zinc. In both patients, laboratory tests showed a combination of copper deficiency, hyperzincemia and increased urinary zinc level. The use of a denture cream was stopped. Copper supplementation, initially subcutaneously then oral corrected the copper deficiency and pancytopenia. Clinically, the pain faded but the gait disturbance persisted. Copper deficiency associated with the use of denture cream rich in zinc is an unrecognized cause of myelopathy associated with pancytopenia which should be diagnosed early to establish appropriate therapeutic measures to minimize neurological complications., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Copper is essential for many enzymatic reactions and in neurotransmitter biosynthesis. Its deficiency or its excess has consequences on many organs, especially the liver and the brain. The biochemical tests performed in case of suspicion of copper metabolism disorder are difficult to analyse. They include the measurement of serum ceruloplasmin, serum copper and 24h urinary copper excretion. The interpretation must take into account the clinical features. We distinguish mainly: (1) copper deficiency, acquired in malabsorption or in copper diet deficiency, or related to a genetic disease (Menkes disease); (2) copper overload, acquired or from a genetic origin (Wilson disease); (3) aceruloplasminemia, reducing ferroxidase activity leading to iron overload. It is important to diagnose these diseases as some of them have an effective treatment if it is started early enough., (Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

The knowledge of copper (Cu) distribution in blood contributes to a better understanding of copper metabolism and to a better approach and follow up of related diseases such as Wilson's disease (WD). Many tests can be used to investigate patients who may have WD but they show many drawbacks and do not allow real patient monitoring. Knowing that the Cu overload can result from the free and easily exchangeable form of copper in plasma, a two-step method (ultrafiltration-determination by ETAAS) was carried out to determine these two fractions. The ultrafiltration procedure and the instrumental determination showed good repeatability, and a very low limit of detection was obtained (0.7 nmol/L). In vitro stability of both ultrafiltrable copper (CuUF) and exchangeable copper (CuEXC) was studied. Plasma was ultrafiltered in 44 presumably healthy subjects to determine CuUF and CuEXC and to set reference values ranges. The method was applied on a few patients showing good correlation between both parameters and the clinical and biological features of the patients.

A sequential method of measuring zinc, copper and aluminium in serum by inductively coupled plasma (ICP) spectrometry is described. It involves a 1/5 dilution of serum with a potassium chloride solution which enhances aluminium signal intensity and reduces variations between different matrix compositions. The method is as sensitive as atomic absorption for zinc (sensitivity: 0.11 mumol/l) and copper (sensitivity: 0.020 mumol/l) and can also be applied to monitor aluminium (sensitivity: 0.12 mumol/l) for patients receiving total nutrition therapy or hemodialysis. Its linearity extends at least to 200 mumol/l for copper and zinc and to 20 mumol/l for aluminium. The correlations with atomic absorption are satisfactory for the 3 parameters, as assessed by the correlation coefficients established for both methods. A reference interval was established with 34 sera of control subjects (19 men, 15 women) which showed an average zinc, copper and aluminium of 14.5 (S.D. 2.6), 17.3 (S.D. 2.1) and 0.32 (S.D. 0.12) mumol/l, respectively. This method does not require a simultaneous ICP spectrometer and can be performed with 1 ml of serum in a single tube, using a routine sequential ICP spectrometer.