Trace Minerals: Zinc, Copper, Selenium & Others
Tiny doses, landmark enzymes: what each trace element does and how its lack or excess shows
Zinc
Roles. Zinc is a cofactor for hundreds of enzymes, including alkaline phosphatase, carbonic anhydrase, alcohol dehydrogenase, Cu/Zn superoxide dismutase and the matrix metalloproteinases. It also holds together the zinc-finger DNA-binding domains of many transcription factors, such as steroid hormone receptors. A low alkaline phosphatase can be a clue to deficiency, which is confirmed by a low plasma zinc level.
Acquired deficiency. Common settings are alcoholism (increased urinary loss), malabsorption (Crohn disease, celiac disease), chronic diarrhea, TPN without added zinc and diets high in phytate, which binds zinc. Features:
- Periorificial and acral dermatitis (red, scaly or crusted plaques around the mouth, eyes, anus and on the hands and feet)
- Alopecia and diarrhea
- Dysgeusia and anosmia
- Delayed wound healing and frequent infections (impaired T-cell function)
- Hypogonadism with growth delay in children
Acrodermatitis enteropathica. An autosomal recessive defect of SLC39A4 (ZIP4), the intestinal zinc uptake transporter. Zinc in human milk is more bioavailable than in formula or cow's milk, so the triad of periorificial/acral dermatitis, alopecia and diarrhea typically appears once the infant is weaned, often with irritability and infections. Lifelong oral zinc produces rapid improvement.
A periorificial rash with alopecia in an infant has other mimics: biotinidase deficiency (with seizures and lactic acidosis) and essential fatty acid deficiency. Zinc supplementation also shortens acute diarrhea in children in low-income settings.
Copper
Handling. Copper is absorbed in the proximal small intestine and exported from enterocytes into the blood by the ATPase ATP7A. In hepatocytes, ATP7B loads copper onto ceruloplasmin and excretes the excess into bile, the main route of elimination.
| Enzyme | Normal job | Effect of deficiency |
|---|---|---|
| Cytochrome c oxidase | Complex IV of the electron transport chain | Energy failure, neurodegeneration |
| Lysyl oxidase | Cross-links collagen and elastin | Weak connective tissue, tortuous arteries, aneurysms |
| Cu/Zn superoxide dismutase | Converts superoxide to H2O2 | Oxidative injury |
| Ceruloplasmin (and hephaestin) | Ferroxidase: Fe2+ → Fe3+ so iron can bind transferrin | Anemia from impaired iron export |
| Dopamine β-hydroxylase | Dopamine → norepinephrine | Low norepinephrine |
| Tyrosinase | Tyrosine → melanin | Hypopigmented skin and hair |
Acquired copper deficiency. Causes include bariatric surgery that bypasses the duodenum, malabsorption, copper-free TPN and excess zinc. Zinc (supplements or zinc-rich denture creams) induces enterocyte metallothionein, which binds copper more avidly than zinc; the copper is lost when the enterocytes are shed into the lumen. Zinc acetate treats Wilson disease by this same mechanism.
Features. Anemia (normocytic, macrocytic or microcytic; ring sideroblasts and vacuolated precursors can mimic myelodysplasia) and neutropenia, plus a myeloneuropathy that copies B12 deficiency: dorsal-column sensory ataxia with lost vibration and position sense, spastic gait and peripheral neuropathy, sometimes with T2 hyperintensity of the dorsal columns on MRI. B12 and methylmalonic acid are normal; serum copper and ceruloplasmin are low, and zinc is high when zinc excess is the cause.
Replacing copper (and stopping excess zinc) corrects the blood counts, but neurologic deficits often persist, so early recognition matters.
| Feature | Menkes disease | Wilson disease |
|---|---|---|
| Gene / inheritance | ATP7A; X-linked recessive | ATP7B; autosomal recessive |
| Defect | Enterocytes cannot export copper | Liver cannot excrete copper into bile or load ceruloplasmin |
| Copper status | Systemic deficiency | Overload in liver, basal ganglia, cornea |
| Clinical picture | Infant boys: kinky, brittle, hypopigmented hair; hypotonia, seizures, tortuous arteries, bladder diverticula | Liver disease, movement disorder, psychiatric change; Kayser-Fleischer rings |
| Labs | Low copper and ceruloplasmin | Low ceruloplasmin, high urinary copper |
| Treatment | Early copper histidinate injections | Chelation (penicillamine, trientine) or zinc |
Selenium
Selenoproteins. Selenium is built into proteins as selenocysteine, inserted at a UGA codon (normally a stop signal) with the help of an mRNA hairpin, the SECIS element. Key selenoproteins are glutathione peroxidase (reduces hydrogen peroxide and lipid peroxides using glutathione), thioredoxin reductase and the iodothyronine deiodinases that convert T4 to active T3.
Deficiency. Keshan disease is an endemic dilated cardiomyopathy of children and young women in selenium-poor regions of China, in which coxsackievirus may act as a cofactor. Kashin-Beck disease is a childhood osteoarthropathy of growing cartilage in similar regions, with enlarged, stiff joints and short stature. Long-term TPN without selenium produces skeletal myopathy with muscle pain and raised creatine kinase, and cardiomyopathy.
Excess (selenosis). Overdosed supplements or industrial exposure cause a garlic odor on the breath, hair loss, brittle or shed nails, skin rash, GI upset, fatigue and peripheral neuropathy.
Other trace elements
| Element | Role | Deficiency | Excess |
|---|---|---|---|
| Chromium | Enhances insulin action (trivalent form) | Glucose intolerance, weight loss, neuropathy on long-term TPN | Hexavalent industrial chromium: lung carcinogen |
| Manganese | Mitochondrial superoxide dismutase, arginase | Rarely seen | Parkinsonism (welders, miners, TPN, cirrhosis) |
| Molybdenum | Xanthine oxidase, sulfite oxidase, aldehyde oxidase | Cofactor deficiency: neonatal seizures, lens dislocation, very low uric acid | Rarely seen |
| Fluoride | Forms acid-resistant fluorapatite in enamel | Dental caries | Dental and skeletal fluorosis |
| Iodine | Thyroid hormone synthesis | Goiter, hypothyroidism, cretinism | Iodine-induced thyroid dysfunction |
Chromium. Deficiency has been described mainly in long-term TPN without added chromium, producing hyperglycemia or glucose intolerance, weight loss and peripheral neuropathy that reverse with chromium.
Manganese. Manganese leaves the body in bile. Welders and miners who inhale it, patients on long-term TPN (especially with cholestasis) and people with cirrhosis accumulate it in the globus pallidus, which appears bright on T1-weighted MRI. The result is parkinsonism with dystonia, gait disturbance and psychiatric change that responds poorly to levodopa.
Molybdenum. The molybdenum cofactor is needed by xanthine oxidase (hypoxanthine → xanthine → uric acid), sulfite oxidase and aldehyde oxidase. Inherited molybdenum cofactor deficiency presents with intractable neonatal seizures and encephalopathy, later lens dislocation, very low uric acid and sulfites in the urine.
Fluoride. Fluoride converts enamel hydroxyapatite into acid-resistant fluorapatite. Community water fluoridation, fluoride varnish applied from first tooth eruption through age 5, and oral supplements for children whose water supply is low in fluoride all reduce caries. Too much fluoride while teeth are forming causes dental fluorosis (white streaks to brown mottling of enamel); chronic heavy intake causes skeletal fluorosis with osteosclerosis and stiff joints.
Iodine. Iodine deficiency is the leading cause of goiter worldwide. During pregnancy it causes congenital hypothyroidism (cretinism) with intellectual disability, short stature and deafness, making it the most common preventable cause of intellectual disability worldwide. Iodized salt is the preventive measure.