Copper excretion, urinary

The disturbance of copper excretion, primarily due to a defect in the billiary excretion, is consistent with the biochemical findings in patients with Wilson disease. Urinary copper excretion is increased owing to total body overload of copper. Renal dysfunction includes albuminuria and renal rickets. Incorporation of copper in ceruloplasmin is impaired. Thus, there is a greater proportion of copper bound to albumin and amino acid complexes in the serum. But the overall copper concentration in serum is low. Ceruloplasmin is a multicopper oxidase see Copper Proteins Oxidases) that... 

In patients with Wilson s disease, penicillamine is rapidly attached to copper and, although higher doses are used, taste disturbances develop in a lower frequency, about 4% (SED-8, 536). It has been suggested that dysgeusia is related to deficiency of copper or zinc, but a strong connection between taste impairment and urinary copper excretion has not been demonstrated (118). Serum copper concentrations remained within normal limits and copper supplements were not effective in prevention (119). 

Wilson s disease is an autosomal recessive disease of copper metabolism. It has a prevalence of 1 in 30,000 live births in most populations. The disease has a highly variable clinical presentation. It is characterized by impairment of biliary copper excretion, decreased incorporation of copper into ceruloplasmin, and accumulation of copper in the liver and, eventually, in the brain and other tissues. The biochemical findings include low serum ceruloplasmin, high urinary copper excretion, and high hepatic copper content. Some patients have normal serum cerulo-plasmia levels, and heterozygous individuals do not consistently show reduced levels of this protein. 

Very little copper is excreted in urine. Here the concentration values have little meaning the 24-hour excretion is shown in Table 4. The figures in this table were taken from the careful study of Butler and Newman (B33). Beam and Kunkel (B7) and Porter (P9) found similarly low urinary excretions. According to our own experience, the 24-hour urinary copper excretion does not exceed 40 ig in normal individuals. Others accept figures up to 60 or even 100 iig per 24 hours as normal (see references quoted in reference B33). 

It is now well established that patients with Wilson s disease have grossly abnormal amounts of copper in the liver, brain, kidney, and cornea (B19, C16, U6). The copper content of other tissues may increase, but much less than in these four organs that are the site of the pathological changes in this disease. Increased urinary copper excretion is also characteristic of the disease as evidence for this a large number of references to pertinent literature can be found in Cumings monograph (C16). 

The inherited defect in Wilson s disease is believed to be in the gene coding for an enzyme involved in copper excretion into bile and reabsorption in the kidney. Urinary copper excretion is high and serum concentrations low (Table I). Ju.st what caii.ses the low caeruloplasmin concentrations in these patients remains unclear. Confirmation is by measurement of copper in a liver biopsy which is usually greater than 250 fig/g dry weight in patients with the disease. 

Treatment is by administration of a chelating agent, penicillamine, to promote urinary copper excretion. Patients are maintained on oral penicillamine for life and require regular monitoring tt> ensure compliance and to check for side effects. Liver transplantation may also be considered, particularly in young patients with severe disease. 

The finding of a high liver copper concentration would indicate that the patient died from Wilson s disease which is an autosomal recessive disorder. The patient s sister (and brothers if any) should be screened for Wilson s disease. Serum copper, caeruloplasmin and urinary copper excretion may indicate if she also has the disease. A liver biopsy may be indicated to confirm the diagnosis and allow treatment to be initiated. DNA analysis is becoming available to assist in the diagnosis. 

Urine copper excretion is markedly increased in patients with Wilson disease however, its usefulness in clinical practice is limited. The estimation of urinary copper excretion may be misleading due to incorrect collection of 24-h urine volume or to copper contamination. In presymptomatic patients urinary copper excretion may be normal, but increase after D-penicillamine challenge (Da Costa et al., 1992). This test is valuable in the diagnosis of Wilson disease with active Uver disease, but is unreliable to exclude the diagnosis in asymptomatic siblings (Muller et al., 2007). On the other hand urinary copper excretion is also increased in any disease with extensive hepatocellular necrosis. 

Trientine is a copper chelator, acting primarily by enhancing urinary copper excretion. Trientine is licensed for treatment of Wilson disease and is now generally available. Experience with trientine is not as extensive as with penicillamine. It seems to be as effective as penicillamine, with far fewer side effects. Its efficacy was evaluated in patients with intolerance to penicillamine (Scheinberg et al 1987). Discontinuation of penicillamine resulted in death from hepatic decompensation or fulminant hepatitis in 8 of 11 patients who stopped their own treatment after an average survival of only 2.6 years. In contrast, 12 of 13 patients with intolerance to penicillamine switched to trientine (1-1.5 g/day) were alive at 2-15 years later. The remaining patient was killed accidentally. However, the efficacy of trientine was not compared with penicillamine as initial treatment of Wilson disease. Uncontrolled anecdotal reports and our own experience indicate that trientine is a satisfactory first line treatment for Wilson disease. In the early phase of treatment trientine appears to be more potent to mobilize copper than penicillamine, but cupriuresis diminishes more rapidly than with penicillamine. The cupri-uretic power of trientine may be disappointing but is sufficient to keep the patient clinically well. 

If a decoppering agent is used for treatment, the compliance can be tested by repeated measurements of the 24 h urinary copper excretion. This approach is not useful if patients are treated with zinc. The dose of d-penicillamine can be lowered if in a compliant patient urinary copper excretion decreases over time and stabilizes at < 500 p g/day. Efficacy of treatment can be monitored by the determination of free copper in serum, and depending on the presenting symptoms. Liver disease can be assessed by routine liver function tests. Repeated liver biopsies with measurement of hepatic copper content are not helpful. Improvement of neurological symptoms can be documented by clinical examination or by auditory evoked brainstem potentials. In addition, some of the MRI abnormalities are fully reversible on treatment. 

The success of D-penicillamine as an antirheumatic drug have prompted the search for other thiols with improved risk/benefit relationship. Recently 5-thio-pyridoxine f5 was shown to have therapeutical value in rheumatoid arthritis. This thiol caused no increased urinary copper excretion, had no antipyridoxin effect, had no effect on skin collagen and did not enter into SH/SS exchange with the amino acid cystine. Thus, the redox potential and reactivity of thiopyridoxine appears to be somewhat different from that of D-penicillamine. 

Yamazaki, H. et ah. Effects of the dietary snpplements, activated charcoal and copper chlorophyUin, on urinary excretion of trimethylamine in Japanese trimethylaminnria patients. Life ScL, 74, 2739, 2004. 

Treatment. Since the 1950s, the treatment of Wilson s disease has relied on chelating agents [25]. Early attempts to use BAL or EDTA for this purpose were unsuccessful, but penicillamine, triethylene tetramine dihydrochloride (trientine), and tetrathiomolybdate, all in combination with a low-copper diet, have proved to be effective, and result in the urinary excretion of large amounts of copper. The use of penicillamine is complicated by the fact that it may induce a transient worsening of neurologic function due to rapid mobilization of copper, and also has other side-effects, such as the development of nephrosis. Tetrathiomolybdate is an effective alternative with fewer side-effects [26]. In cases in which the dose was rapidly escalated, however, bone marrow suppression or liver function abnormalities have been described. 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Increased urinary excretion, normal serum Mo levels, no change in copper metabolism (11)... 

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