Copper deficiency and Wilson s disease

Menkes disease (associated with copper deficiency) and Wilson s disease (associated with copper excess) (1,2), and its possible role in Alzheimer s disease (3), prion disease (4), and familial amyotrophic lateral sclerosis... 

Many metals, as positive ions, are essential nutrients in biological systems. A Medical Perspective Copper Deficiency and Wilson s Disease gives but one example. 

If iron mobilization is dependent on Cp, shouldn t there be a disturbance in iron metabolism, perhaps resembling copper deficiency, in Wilson s disease This is a disorder characterized by low plasma Cp and the accumulation of copper in the liver and brain. It is treated by eliminating copper from the diet and/or removing copper by administering penicillamine. However, the evidence to support a concomitant upset in iron utilization is tenuous. There is one recent paper by O Reilly et al. (51) in which eight patients with Wilson s disease were reported to have iron deficiency or low plasma iron or both, sometimes associated with anemia. Most of these subjects had low or low-normal levels of transferrin. One mitigating factor is that the size of the spleen in Wilson s disease is almost doubled and this may permit a more rapid turnover of plasma iron despite the low plasma ferroxidase activity. 

Copper appears as the a2-globulin ceruloplasmin in the human body (Sarkar 1994). Deficiency of this protein in serum is characteristic of both Menkes and Wilson s diseases. Wilson s disease is an abnormal storage of Cu(II) in body tissues. Cu(II) in biological material can be determined by spectrophotometry or by FAAS, ceruloplasmin in serum by a spectrophotometric method. 

Two inherited human diseases that represent abnormal copper metabolism are Menkes syndrome and Wilson s disease. Menkes syndrome, with symptoms similar to those of copper deficiency, is characterized by a progressive brain disease, abnormally low copper concentrations in liver and other tissues, and diminished ability to transfer copper across the absorptive cells of the intestinal mucosa (USEPA 1980 Aaseth and Norseth 1986). Wilson s disease (hepatolenticular degeneration) is the only significant example of copper toxicity in humans. Wilson s disease is an autosomal recessive disorder that affects normal copper homeostasis and is characterized by excessive... 

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). 

With the exception of genetically impaired individuals with Menkes disease and Wilson s disease, individuals who suffer from various grossly inadequate diets, diarrhea and severe malnutrition, and the patients who suffer from primary biliary cirrhosis, and cholestatic syndromes of Indian childhood cirrhosis, the development of copper deficiency and toxicity is not a significant risk for man. 

As demonstrated with "Cu in rats, (Cu,Zn)-SOD receives its copper from ceruloplasmin after 2-3 days The (Cu,Zn)-SOD activity in erythrocytes is reduced in Cu deficiency, as shown with several species With rats e.g. during Cu depletion, plasma Cu and ceruloplasmin were decreased by 78 and 75% respectively against 72 % and only 56 % for the blood cell Cu and (Cu,Zn)-SOD respectively In three patients with Wilson s disease the SOD level of erythrocytes was normal, although the disease is characterized by an accumulation of Cu in the liver e.g. and usually by low concentrations and sometimes the absence of ceruloplasmin... 

Monugasiric animals, including humans, are less sensitive than ruminants to either copper deficiency or toxicity. Copper deficiency in people has been round only when other complications, such as excessive bleeding, general starvation, and iron deficiency, arc also present. Wilson s disease, an inherited disease ol humans, prevents the loss of excess copper tram the body and brings on copper toxicity. No direct relationships have been found between levels of avaitable copper in the soil and the copper status of humans. 

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. 

Excessive levels of essential metal ions can be undesirable and chelation therapy may be needed for adequate control to be achieved. The treatment of patients suffering from Wilson s disease (hepatolenticular degeneration in which there is intracellular deposition of copper in the liver and brain, accompanied by a deficiency of the copper-containing protein, caeruloplasmin) is an example45. ... 

Several metal ions are essential or beneficial to life while others, such as lead, cadmium or mercury, are highly detrimental. Many diseases have been associated in a way or another to altered metal ion concentrations in the body. Deficiencies can be as damaging as overloads. Copper deficiency has been associated to anemia while excess copper can lead to Wilson s disease (liver cirrhosis). Anemia may also be caused by a lack of iron and overload of this same metal ion is connected to thalassemia and siderosis [122]. In vivo determination of metal ion distribution is thus highly desirable and progresses have been made towards the design of MRI contrast agents sensitive to the concentration of metal ions. 

Only Wilson s disease is associated with copper metabolism. Sickle cell anemia and acrodermatitis enteropathica are associated with Zn metabolism, and geriatric diabetes, with Cr deficiency. 

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. 

Elevation of serum copper is found in cholestasis, obstructive jaundice, primary biliary cholangitis, malignant tumours, kwashiorkor, exocrine pancreatic insufficiency, during the last trimenon of pregnancy and after administration of oestrogens. A decrease in serum copper is typical of Wilson s disease. In some rare cases, it is caused by familial benign hypocupraemia and nutritional deficiency in neonates. 

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