Copper in Wilson’s disease

Ammonium tetrathiomolybdate can be used as a chelator of copper in Wilson s disease. 

By January 1991, 50 orphan products had been approved for the treatment of 58 rare conditions. Companies had received 12 million in tax credits for orphan research. The classic orphan drug cases had been sorted out. For example, trientine hydrochloride, H2N(CH2)2-NH(CH2)2NH(CH2)2NH2.HC1, a chelating agent used to remove excess copper in Wilson s disease for patients who... 

There is a high level of copper in urine in patients with this disease. Patients with symptomatic Wilson s disease usually excrete more than 100 pg copper per 24-hr urine compared to less than 50 pg per 24-hr urine in normal individuals. Fecal and serum copper levels are found to be below normal level in most patients with Wilson s disease. The blood level of copper in Wilson s disease is low. The direct-reacting, exchangeable form of copper fraction that is not bound to ceruloplasmin is increased. However, a low total serum copper is not a reliable feature of Wilson s disease. With an increased direct-reacting copper fraction combined with a moderately low ceruloplasmin level, it can produce a normal serum copper level in Wilson s disease patients. 

Penicillamine also undergoes reactions with copper(ii) peptide complexes which might act as models for the therapeutic effect of penicillamine in the removal of copper in Wilson s disease. A number of species could be identified by e.p.r. and visible absorption techniques, including 1 1 and 1 2 penicillamine-copper(n) complexes, in the binary system although in the ternary systems there was no e.p.r.-detectable ternary complex. The results are consistent with the scheme shown, in... 

The somewhat paradoxical situation of having enhanced copper levels in advanced arthritis, and the moderate advantages of using copper complexes in treatment, is mirrored by the apparent contradiction of D-penicillamine efficacy, despite its clinical use for treatment and excretion of excess copper in Wilson s disease [46]. There is little evidence that penicillamine copper complexes have any relevance in vivo. Ceruloplasmin copper is unavailable for chelation and, indeed, D-penicillamine is not particularly effective at scavenging Cu(II) from BSA [84]. 

A generalized aminoaciduria that results from proximal renal tubular damage. Failure to reabsorb phosphate and glucose also occurs. The syndrome can be caused by endogenous poisons (e.g. copper in Wilson s disease) or exogenous poisons (e.g. cadmium) damaging the renal tubule. 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

The amino acid histidine is used for the treatment of copper overload in Wilson s disease and forms a strong 1 2 complex (Fig. 27) (553). Copper-histidine therapy is also an efficient treatment for copper deficiency in Menkes disease (554). 

D-penidllamine can promote the elimination of copper (e.g., in Wilson s disease) and of lead ions. It can be given orally. Two additional uses are cystinu-ria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In the latter, penicillamine can be used as a basal regimen (p. 320). The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances. 

Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson s disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (see Chapter 36). Its ability to increase urinary excretion of lead and mercury had occasioned its use in outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower adverse-effect profile, has generally replaced penicillamine for these purposes. 

Copper 80 mg 2-3 mg Metal storage/transport (ceruloplasmin) enzymes in synthesis of cartilage, bone, myelin interaction with iron Occurs in malnutrition, TPN anemia, neutropenia, skeletal and neurological defects Danger in Wilson s disease... 

Two genetic disorders of copper metabolism, Wilson s disease (see Section 62.2.3.3) and Menkes disease, are known. The latter involves impaired intestinal absorption of copper56,57 as well as probably subcellular metabolic defects which result in copper deficiency with respect to metal-loenzyme activity. The characteristic steely hair in Menkes disease results from free SH bonds in hair protein because of failure of lysyl oxidase to produce the disulfide links. Depigmentation of hair and skin, hypothermia, cerebral degeneration, central nervous system retardation, skeletal demineralization and arterial degeneration are all seen. Copper supplements may benefit hypothermia and increase pigmentation but the disease is not generally cured. 

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. 

Copper in plasma can be estimated following twenty-fold dilution with 0.1 normal HC1. Although few metals cause interference when using flame AAS [31] standards containing 6/xgCu per 100 ml should be made up in the plasma or mine equivalent [32]. Only very small amounts of copper are excreted in the urine of normal subjects and specimens are best aspirated undiluted. However, in Wilson s disease and especially during treatment urine copper may be high and appropriate dilution will be needed. 

Ceruloplasmin is synthesized in the hver as a precursor with a signal peptide directing it to the endoplasmic reticulum. It incorporates Cu provided by the Wilsons disease-associated Cu-ATPase, ATP7B, and is secreted into the bloodstream. The copper-deficient ceruloplasmin in Wilson s disease patients has been found to rapidly degrade. A GPI-anchored form of ceruloplasmin has been recently identified as the product of an alternately spliced ceruloplasmin transcript that generates a hydrophobic C-terminal GPI-anchoring signal, similar to those found in phytocyanins (Patel and David, 1997). The GPI-anchored form of ceruloplasmin is preferentially expressed in brain. 

Caeruloplasmin Copper-incorporating a glycoprotein true function remains unclear but acts as a copper donor and oxidative enzyme Low caeruloplasmin levels may be seen in cirrhosis (especially primary biliary cirrhosis) as caeruloplasmin is excreted hepatically Levels increased in infection, injury or inflammation. Low levels are found in Wilson s disease, which is an autosomal recessive disorder of copper metabolism it results in copper deposition in the liver, basal ganglia and eyes, and culminates in cirrhosis and neurological impairment... 

Wilson s disease, and therefore they suggested that it be contraindicated in such patients. The Nova T 380 device, which is a copper-based lUD licensed in the UK, is now contraindicated in Wilson s disease [7]. 

Excess— results in liver disease, various neurologic disturbances, dementia, copper cataracts. These occur in Wilson s Disease, where there is excess coj r deposition in the brain, liver, cornea, lens, and kidney. 

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