Title: Copper Deficiency
Key words: Menkes disease, copper enzymes, cuproenzymes, electron transporters, osteoporosis, neurotransmitter production, Cu-ATPase, Cu pump
Date: Apr 1999
Category: 3. Micronutrients
Author: Dr van Rhijn
Deficiency of copper (Cu), an essential nutrient for metabolism of numerous enzymes, electron transporters and other factors, although rare, has serious health consequences. An adults body contains between 50 120 mg of Cu and we typically consume 1-2 mg Cu per day1. The main cuproenzyme activities are discussed below.
Impaired intestinal Cu absorption in Menkes disease (X-linked disorder)2 leads to kinky hair3, osteoporosis, abnormal arterial structure (haemorrhages), failure to thrive, extensive brain damage, convulsive seizures and mental retardation. An intracellular Cu transport abnormality4, incorporates Cu into metallothionein at expense of Cu-dependent enzymes (dopamine b -monooxygenase, used as diagnostic test5) contributes to the range of tissues involved. Infant deficiency causes prematurity6, low birth weight and failure to thrive7.
Cu deficiency reduces the capacity for oxidative phosphorylation and respiration, which is followed by energy deficit (Decreased delta subunits of ATP synthetase) and slower cellular biosynthetic processes (reduced nuclear encoded subunits of cytochrome c oxidase electron transport)8. The results are mitochondrial swelling, cardiac hypertrophy and infertility due to poor sperm motility. Inefficient Cu/Zn superoxide dismutase (SOD) cytosolic antioxidant system9, enhances cell membrane fragility and reduces lifespan (erythrocytes)10, 11, secondary to oxidative damage from free radicals to unsaturated lipids12.
A reduced rate of granulopoiesis13 results in hypochromic, microcytic anaemia14, 15 and neutropenia16. The mechanism is unknown, as porphyrin and haem biosynthesis enzymes are independent of Cu. Ceruloplasmin (free oxygen scavenger17, enhanced by estrogens18, reduced by Cu deficiency) oxidises Fe2+ to the Fe3+ required for transferrin binding (cofactor for iron flux), and deficiency causes iron accumulation and reduced transferrin saturation. This can be corrected by ceruloplasmin transfusion.
Neurotransmitter production (via dopamine-b -hydroxylase) is Cu-dependent and dopamine, opiates and catecholamines (norepinephrine result in electrocardiographic changes19, 20) will be reduced along with receptor changes. Bioamines (histamine, tyramine, serotonin) are catalized by extracellular copper-dependent amine & diamine oxidases. Cu restriction in cardiomyopathy affects the basal lamina integrity of cardiac myocytes and capillaries. Alteration in expression of glutathione peroxidase and catalase in heart and liver involve both transcriptional and post transcriptional mechanisms. One of the obligatory factors contributing to cardiomyopathy may be via P-type Cu-ATPase (Cu pumps)21.
Intracellular Cu cannot be recycled22, making the enzyme lysyl oxidase23 (connective tissue) vulnerable to deficiency, leading to abnormal collagen formation24, loss of integrity of elastic and connective tissue (osteoporosis, reduced bone strength & fractures25), fragility of blood vessel walls (postcapillary venules causing macromolecular leakage, platelet-endothelial interactions & thrombogenesis), abnormal elastin with risk of arterial lesions, aneurisms, reduced vascular smooth muscle reactivity (peripheral vascular resistance)26, angiogenesis and hair depigmentation via melanin polymer (tyrosinase).
Cu deficiency is associated with hypercholesterolemia27, hypertriacylglyceridemia, glucose intolerance and increasing risk factors of cardiovascular disease28. An impaired immune response29, decreased production of IL-2 by activated human T-cells (reduced synthesis or stability of IL-2 mRNA30), antibodies, activity of natural killer cells & phagocytes, thymus weight & hormone levels and splenic T cells31. Short-lived neutrophils (Cu status tool) are reduced in number and their ability to generate superoxide anion to kill ingested microorganisms is reduced32.
Cu involvement is fundamental to life and the survival of living cells. Deficiency has deleterious consequences on various systems through numerous biochemical pathways.