Zinc and copper

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Zinc and copper

Zinc

Zinc is an essential element present in over 200 metalloproteins with a wide range of functions, such as carbonic anhydrase, alcohol dehydrogenase, alkaline phosphatase and steroid hormone receptors.

Zinc deficiency is a major health problem in the poorer nations of the world. The daily requirement, which varies with age, sex and during pregnancy is about 150 µmol (10 mg) per day (Fig 58.1). Zinc is present in all protein-rich foods and approximately 30% is absorbed. Phytates are indigestible in man, bind calcium, iron and zinc, and reduce their absorption. In the liver, zinc is incorporated into metalloenzymes, while in blood the majority of the zinc is contained in the erythrocytes. In plasma, 90% of zinc is bound to albumin and 10% to α₂-macroglobulin. Zinc reserves in the body are small and are located mainly in muscle and bone. Zinc is excreted in urine, in bile, in pancreatic fluid and in milk in lactating mothers.

Fig 58.1 Zinc balance.

Zinc deficiency

In children, the rate of growth during rehabilitation from famine has been clearly related to the dietary supply of bioavailable zinc. Zinc deficiency is known to occur in patients on intraveneous nutrition and causes a characteristic skin rash (Fig 58.2) and hair loss. Wound breakdown and delayed healing are other complications. Acrodermatitis enteropathica, a rare inherited disorder of zinc metabolism, manifests itself in infancy as skin rash. Untreated, the prognosis is poor, but oral zinc therapy leads to complete remission. Cadmium displaces zinc from metalloproteins, and zinc deficiency can be a consequence of chronic cadmium poisoning.

Fig 58.2 Skin lesions in zinc deficiency.

Zinc toxicity

Zinc toxicity is uncommon. It is usually due to exposure to high levels of zinc fumes. It is difficult to induce toxicity by dietary means. However, in cases of self poisoning with zinc salts, the symptoms are fever, vomiting, stomach cramps and diarrhoea.

Laboratory assessment

The concentration of zinc in plasma decreases as part of the metabolic response in inflammation such that when the CRP concentration is >20 mg/L it is an unreliable indicator of zinc status. The repeated finding of a plasma zinc <5 µmol/L is suggestive of impending zinc deficiency and warrants investigation.

Marginal zinc deficiency is best demonstrated by a positive clinical response to supplementation. Oral or intravenous zinc reverses the signs and symptoms of zinc deficiency within weeks.

Copper

Copper is an essential trace metal that is a component of a wide range of intracellular metalloenzymes, including cytochrome oxidase, superoxide dismutase, tyrosinase, dopamine hydroxylase and lysyl oxidase.

Copper physiology

About 50% of the average daily dietary copper of around 25 µmol (1.5 mg) is absorbed from the stomach and the small intestine (Fig 58.3). There is evidence that not all modern diets contain sufficient copper, especially when large amounts of refined carbohydrate are consumed. Copper absorption is facilitated by cation transport enzymes in the mucosal cells. A high zinc intake will block the absorption of copper by inducing metallothionine in the mucosal cells. Copper has high affinity for metallothionine and is lost when the mucosal cells are shed in the faeces. Absorbed copper is transported to the liver bound to albumin where it is incorporated into caeruloplasmin, that contains 6 copper atoms per molecule, and exported into the circulation. (Fig 58.4).

Fig 58.3 Copper balance.

Fig 58.4 Cu⁶⁵ uptake test. The most abundant stable isotope of copper is Cu⁶³. A standard dose of Cu⁶⁵, another naturally occurring stable isotope, is given orally. The initial increase in enrichment is followed by a decrease at 6 hours representing liver uptake. The later increase represents the export of caeruloplasmin from the liver. In Wilson’s disease the initial increase is exaggerated – typically 5 times normal with subsequent diminished export from the liver. In Cu malabsorption, due to disease or Zn induced mucosal block, the initial increase is blunted but the subsequent export from the liver is normal.

Copper is present in all metabolically active tissue. The highest concentrations are found in liver and in kidney, with significant amounts in cardiac and skeletal muscle and in bone. The liver contains 10% of the total body content of 1200 µmol (80 mg). Excess copper is excreted in bile into the gut.

The oral Cu⁶⁵ absorption test (Fig 58.4) is a powerful tool in the investigation of patients found to have a low plasma copper.

Inborn errors of copper metabolism

Wilson’s disease and the much rarer Menke’s syndrome are the main inborn errors of copper metabolism.

Wilson’s disease

All adolescents or young adults with otherwise unexplained neurological or hepatic disease should be investigated for Wilson’s disease. Symptoms are a result of copper deposition in liver, brain and kidney. Copper deposits in the eye can sometimes be seen as a brown pigment around the iris (the Kayser–Fleischer ring).

Wilson’s disease is caused by a mutation in the gene ATP7B that codes for a cation transporting enzyme involved in copper transport. Urinary free copper excretion is high and total serum concentrations low (Table 58.1). Confirmation is by measurement of copper in a liver biopsy, which is usually greater than 250 µg/g dry weight in patients with the disease. A non invasive 65Cu-oral uptake test is a reliable test for the diagnosis of Wilson’s disease and available in some specialist laboratories.

Table 58.1

Biochemistry determinations in patients with Wilson’s disease

Investigation	Normal adult	Wilson’s disease
Serum copper µmol/L	10–22	<10
Caeruloplasmin g/L	0.15–0.6	<0.15
Urinary copper µmol/24h	<1	5–15
Liver copper µg/g dry weight	20–50	>250