Disorders of Copper and Zinc Metabolism

Abstract

Copper and zinc are both essential trace elements and are required for the proper function of many important metalloenzymes. The uptake of both copper and zinc requires specific, but different, carriers in the intestine. Copper excretion takes place only in the liver, and its homeostasis is tightly controlled, as copper can be highly toxic. The balance between uptake and excretion of copper is disturbed in Wilson disease and Menkes disease, as well as in two milder variants of Menkes disease: the occipital horn syndrome and X-linked distal hereditary neuropathy. Both Wilson and Menkes diseases have specific pathophysiological manifestations, which are for Wilson disease mainly related to copper accumulation in the liver and brain and for Menkes disease to a systemic shortage of copper, resulting in an insufficient function of copper-containing enzymes, such as tyrosinase, lysyl oxidase and dopamine-beta hydroxylase. The absence of another copper-containing enzyme, ceruloplasmin, which is due to mutations in the corresponding gene, will result in iron overload in the liver, brain and pancreas, pointing to the role of this serum protein in iron metabolism. It is further discussed in the chapter on iron metabolism.

Zinc is a cofactor for over 100 enzymes and, as such, is involved in all major metabolic pathways. It is essential for nucleic acid metabolism and protein synthesis and its regulation through the so-called zinc-finger proteins. Zinc deficiency, either hereditary or acquired, therefore has major detrimental effects. Conversely, high serum zinc has few, probably because of its binding to albumin and α₂-macroglobulin. Acrodermatitis enteropathica, the main inborn error of zinc metabolism, is due to mutations in the intestinal carrier for zinc and will result in periorificial and acral dermatitis, diarrhoea, infections and growth retardation.