Serum copper penicillamine

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). 

Copper toxicity is uncommon and is most usually due to administration of copper sulphate. solutions. Oral copper sulphate may lead to gastric perforation. Serum copper concentrations may be greatly elevated. Copper is toxic to many organs, but renal tubular damage is the major concern. Treatment is by chelation with penicillamine. 

Sato M, Yamane K, Oosawa Y, Tanaka H, Shirata A, Nagayama T, Maruyama S. Two cases of Parkinson s disease whose symptoms were markedly improved by D-penicillamine. A study widi emphasis on cases displaying a slightly low level of serum copper and ceruloplasmin. Neurol Ther Chiba (1992) 9, 555-9. 

Though in SED VIII it was stated that in patients suffering from conditions other than Wilson s disease penicillamine does not interfere with the serum copper level, it has recently been observed that the increased serum copper levels which are seen in patients with rheumatoid arthritis fall during penicillamine therapy (la ). 

A case is reported of red cell aplasia in a patient with Wilson s disease, who had been treated for 14 years with up to 2 g penicillamine daily (16 ). The erythropoiesis rapidly recovered after discontinuation of penicillamine. The serum copper concentration was 5/ug/dl (normal 80-150 jug/dl). Another case report concerns a patient who died from aplastic anaemia, which was thought to be drug-induced (17, 21 ). This patient had been treated for rheumatoid arthritis... 

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). 

Wilson s disease is a copper storage disorder that is apparently due to an inherited lesion in the copper excretion mechanism. One in 200-400 persons is a carrier of the disease. Diagnosis may be made by measuring serum ceruloplasmin levels. Whereas normal serum ceruloplasmin is 200-400 mg/L, in Wilson s disease patients it is well below 200 mg/L. Liver copper in these patients (determined by biopsy) is more than 250 /xg/g, whereas normal individuals show a value of only 20-45 /xg/g. Liver function deterioration is the most prominent symptom of Wilson s disease. Treatment includes chelation therapy with penicillamine. 

Cupruria In pronounced liver cell decay, there is not only a rise in the copper value in serum, but more particularly in the amount of copper excretion in the urine. Cupruria of < 50 pg/day rules out the presence of Wilson s disease (differential diagnosis e.g. kidney disease). The penicillamine test has proved successful after administration of 600 mg penicillamine, copper excretion increases to > 300 pg/6 hr (> 600 pg/24 hr). However, it should be noted that this test may show similar positive results in cholestatic liver diseases. 

Confirmation The diagnosis is verified by laboratory parameters (determination of the serum values of copper and ceruloplasmin as well as of copper excretion in the urine, if necessary also by means of the penicillamine test) and by demonstration of the copper content of the liver, with simultaneous differentiation of existing liver damage. 

Penicillamine-induced deficiency of both copper and iron has been held responsible for the development of anemia (139), but serum iron concentrations do not usually change in patients using penicillamine (SED-8, 535). 

Dastych M, Jezek P, Richtrova M. Der Einfluss einer PenidUamintherapie auf die Konzentration von Zink, Kupfer, Eisen, Kalzium und Magnesium in Serum und auf deren Ausscheidung in Urin. [Effect of penicillamine therapy on the concentration of zinc, copper, iron, calcium and magnesium in the serum and their excretion in urine.] Z Gastroenterol 1986 24(3) 157-60. 

Dietary. Cp deficiency is due to nutritional copper deficiency, with secondarily low levels of Cp, and is associated with neutropenia, thrombocytopenia, low serum iron, and hypochromic, normocytic, or macrocytic anemia unresponsive to iron therapy. The deficiency may be due to inadequate dietary intake, long-term parenteral nutrition without copper supplementation, malabsorption of any cause, penicillamine therapy, or combinations of these. Therapy includes dietary change or copper supplementation, plus treatment of the primary cause of malabsorption if present. 

Concerning the catalytic superoxide dismutase activity of low molecular mass copper complexes, some general comments are neccessary. Firstly, it should be emphasized, that apart from the inactive Cu-penicillamine, all complexes described above do not survive high concentrations of biological chelators in aqueous solutions. For example, bovine serum albumine is able to remove most of the copper from these complexes (Fig. 14). 

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. 

Hepatolenticular degeneration, Wilson s disease, is a severe heritable disorder of copper metabolism. The defect is caused by diminished synthesis of the copper-transporting protein ceruloplasmin and impaired excretion of copper into the bile. Copper concentration is extremely low in blood serum and high in urine furthermore, copper accumulates in liver, brain, kidney, and cornea. Chelating therapy with D-penicillamine is the medication of choice [48]. To improve copper metabolism, zinc therapy is also used [50]. 

Ten patients and 10 control patients were studied. All 10 patients had Wilson s disease based on decreased serum ceruloplasmin levels or copper turnover studies. Eight patients had been on D-penicillamine from 2.5 to 13 years. All were off drug for at least two weeks prior to study. 

Brief mention has been made earlier of the ability of penicillamine to deplete the excess copper deposits in patients vsdth Wilson s disease. There are four main lines of evidence to support this contention (1) Visible copper deposits in the corneae, the Kayser Fleischer rings, can be seen to regress and finally disappear under the influence of treatment, only to reappear if this is interrupted or reduced to an inadequate level [78, 128]. (2) The concentration of copper in the plasma falls once treatment is established, in some cases it may fall to virtually undetectable levels [66, 129, 130]. (3) The concentration of serum caeruloplasmin falls, not only in patients with Wilson s disease [130], but also in patients with other diseases treated with penicillamine [131] (see Figure 4.7). (4) There is a fall in the basal excretion of copper in the urine... 

Theoretically perhaps the most important observation which has resulted from the study of the effect of penicillamine on copper transport is the fall in caeruloplasmin concentration. In a few patients the protein has become undetectable in the serum and has remained so for many years. This iatrogenic acaeruloplasminaemia has given rise to the development of no symptoms which might be attributed to deficiency of the protein. Certainly none of the functions which have been attributed to caeruloplasmin have been affected. If the protein carried the prosthetic group of cytochrome oxidase to the cells... 

---