Title: Minerals

Key words: enzyme systems, muscle contraction, nerve transmission, blood clotting, chromium, copper, iodine, manganese, selenium, zinc, dietary sources, optimal intake, functions, deficiency, excess

Date: June 2000

Category: Micronutrients

Type: Article

Author: DJE Candlish

Minerals

• the major elements – including calcium, iron, magnesium, phosphorus and potassium
• the trace elements – including chromium, copper, iodine, manganese, selenium and zinc

Class: Trace Elements

Chromium levels in water are low ( 2 m g/L)¹ and food appears to be the main source of intake. Yeast is a particularly good source. Recent reports suggest that, with a typical Western diet, intakes are around 50m g/day. A 70kg man contains approx 5mgs of chromium².

1000m g/day has been suggested in a recent study³.

Chromium is essential for proper carbohydrate and lipid metabolism in mammals. The mechanism of action proved elusive until the identification of low-molecular-weight chromium-binding substance. This appears to be an oligopeptide and was found to activate insulin receptor kinase activity up to 7 fold with a dissociation constant of 250 picomolar in the presence of 100 nanomolar insulin⁴. LMWCr has been partially characterised in terms of structural and spectroscopic properties. It appears that LMWCr may function in a manner similiar to the calcium-binding signal protein calmodulin.

LMWCr is maintained in its active apo-oligopeptide form and in response to a chromium flux can bind 4 chromic ions.The holoprotein is then capable of binding to an insulin receptor (and perhaps other enzymes) and activation of a membrane phosphotyrosine phosphatase⁵. It appears that LMWCr may exert its effects in the post receptor role inside the insulin dependent cell and enable glucose to be converted into lipid in adipocytes. The binding of GTF chromium to insulin may disrupt the binding of insulin to the receptor. GTF chromium may, however, be acting more as a nutrient, providing organic chromium. This is especially important if the recipient is chromium deficient⁶.

Mertz first provided evidence that chromium influences glucose metabolism via its effects on cell transport⁷. The first clues about the existence of GTF may have appeared in 1929 when Glaser and Halpern⁸ noticed that yeast extracts potentiated the action of insulin. These researchers showed that incubating yeast extracts with insulin resulted in a substantially greater ability of the hormone to lower blood sugar levels.

Mertz and Schwarz postulated the existence of a new dietary agent (GTF) and proceded to identify the major components⁹ and then by 1969 reorganised the part it plays in facilitating the reaction of insulin with receptor sites on the cell membrane¹⁰. It now appears that humans can make GTF chromium and that it consists of trivalent chromium, the vitamin niacin or tryptophan and 3 amino acids glycine, glutamic acid and cysteine. This is analagous to the relationship of cobalt and vitamin B₁₂.

In a chromium deficient person about 4 hours after taking GTF chromium there is an improvement in glucose tolerance. Chromium deficiency has been implicated in diabetes, heart disease and impaired lipid metabolism and it appears that chromium in the form of synthetic complexes or high chromium yeasts are more biologically active than inorganic chromium¹¹.

Tissue chromium levels do not apparently equilibrate with blood (Trace elements) but levels much lower than normal values (serum O.14-0.15 ng/ml or plasma 0.26-0.28ng/ml) may indicate severe chromium deficiency.

Elevated serum levels and high chromium urinary excretion, as found in affected tannery workers, may be good indicators of excessive exposure.

The high intakes of chromium reported before 1980 may have been due to contamination and analytical problems. Sample collection and storage methods are critical because contamination from needles, anticoagulant and plastics can introduce errors¹².

Chromium is widely distributed in the earth's crust and can exist in valencies from +2 to +6. chromium IV is more readily absorbed from the gastrointestinal tract than chromium lll. Chromium IV compounds are active in a wide range of in vitro and in vivo genotoxicity tests. The mutagenic activity of chromium IV is decreased or abolished by reducing agents eg gastric acid.

1. 'Guidelines for drinking-water quality' WHO ISBN 92-4-154460-0

2. Taylor DM Williams DR 'Trace element medicine and chelation therapy'Royal Society of Chemistry ISBN 0-85404-503-l.

'Trace elements in human nutrition and health' WHO ISBN 92-4-156173-4.

5. Davis CM et al. 'A biological active form of chromium may activate a membrane phosphotyrosine phosphatase (PTP).' Biochemistry 1996; Oct 1:35(39):12963-9.

6. Vincent JB ' Relationship between Glucose Tolerance Factor and LMWCr binding substance ' J Nutr. 1994; 124:117-118.

7. Mertz W & Roginski EE ' The effect of trivalent chromium on galactose entry in rat epididymal fat tissue' J Biol. Chem. 1963; 238:868-872.

8. Glaser E and Halpern G Biochemistry 1929; Z 207, 377-383.

9. Schwarz K & Mertz W Archives of Biochemistry & Biophysics. 1959, 85: 292-295

10. Mertz W Physiological review. 1969, 49:163-239.

11. Vinson JA & Hsiao KH. 'Comparative effect of various forms of chromium on serum glucose: an assay for biologically active chromium' Nutritional Reports International, 1985; 32(1).

12. Taylor A. 'Detection and monitoring of essential trace elements' Ann Clin Biochem 1996; 33:486-510.

Good dietary sources (>2 microgms/gm ) include seafood, organ meats, legumes and nuts. Refined cereals, sugar, milk and dairy products are low (<2microgms/gm). The contribution from water through copper pipes is often overlooked. This can vary from 0.1mg/day in hard water to 1mg in extremely acidic soft waters.

Safe and adequate adult daily copper intakes were set at 2-3 mg in 1980¹ however more recent studies analysing duplicate diets suggest actual intakes in the USA may be 1-1.5mg/day.

Copper is involved in a wide range of body processes, including:

• enzyme activity
• transmission of nerve impulses
• energy production
• fatty acid metabolism

The copper dependent enzymes include Cytochrome oxidase, Dopamine-B monooxygenase, lysl oxidase, Petidylglycine alpha-amidating monooxygenase (PAM), Superoxide dismutase, ceruloplasmin and amine oxidase.

Some people with arthritis may be helped by copper. Wearing copper bracelets is believed by many to provide the extra copper required, by absorption through the skin.

Copper deficiency causes pale skin and diarrhoea in babies, anaemia in adults and reduced white blood cell counts. People taking zinc supplements may also need extra copper intake, as zinc can reduce copper levels.

Dietary copper deficiency may impair cardiovascular function and contribute to high blood pressure, enhance inflammation, anaemia, reduced blood clotting and arteriosclerosis. The alterations include weakened structural integrity of the heart and blood vessels, impairment of the use of energy by the heart, reduced ability of the heart to contract (cardiomyopathy), altered ability of the blood vessels to control their diameter and to grow, and altered structure and function of circulating blood cells. There may be links between these effects and diabetes.

Those at particular risk of copper deficiency include premature infants, hospital in-patients receiving total parenteral nutrition and those on special diets or unmodified cow’s milk formulae².

Harmful effects are not usually seen with doses up to 10mg daily, but higher doses should be avoided

Various factors can influence the bioavailability of copper. These include protein sources, amino acids, phytates, ascorbic acid, Zinc and Iron cations. Absorption from breast milk is higher than from infant feeds ( 80% have Fe/Cu ratios <20:1, higher than the recommended 10 to 17:1). Copper intake may be particularly important to premature infants who are born with low stores³.

The most promising functional indices of copper status include enzyme activity of PAM and diamine oxidase, and biochemical indicators include urinary pyridinium cross links, immune measures, mitochondrial DNA damage, DNA damage and bone density⁴.

Menkes Disease⁵ is a rare genetic disorder. It is X-linked, manifests from early pregnancy due to failure of copper transport via the placenta and results in steely hair, cutis laxa, atonia, cardiomyopathy and mental retardation with death in early childhood.

1. Trace elements in human nutrition and health
WHO 1996; ISBN 92-4-156173-4. 2. Cordano A, Clinical manifestations of nutritional copper deficiency in infants and children Am J Clin Nutri, 1998; May , 67:5 Suppl, 1012S-1016S.3. Lonnerdal B, Copper nutrition during infancy and childhood
Am J Clin Nutri, 1998; May, 67:5 Suppl, 1046S-1053S.

4. Strain JJ 2000 Defining optimal copper status in humans
Proceedings of 10th International Symposium on Trace Elements in Man and Animals. New York: Plenum Press, in print

5. Kaler SG, 'Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency' Am J Clin Nutr, 1998 May, 67:5 Suppl, 1029S-1034S.

Uauy R et al., Essentiality of copper in humans
Am J Clin Nutri, 1998; May, 67:5 Suppl, 952S-959S.Nath R , Copper deficiency and heart disease : molecular basis, recent advances and current concepts. Int J Biochem Cell Biol , 1997 Nov, 29:11, 1245-54.Saari JT & Schuschke DA , Cardiovascular effects of dietary copper deficiency Biofactors, 1999, 10:4, 359-75.

The main food sources are milk, meat, fish, cod liver oil, iodized salt drinking water and coastal air. Marine fish and some seaweeds are excellent sources of iodine¹. Iodine is readily absorbed from the gut and skin and normal level excess intake is excreted in the urine. Cooking can reduce the iodine content of foods (frying 20%, grilling 23% and boiling up to 58%). Due to the low iodine content of typical diets in the mountainous areas of developing countries in Asia, Africa and South America and also in many parts of Europe, iodine is added to salt and edible oils to prevent iodine deficiency disorders (IDD)².

The body contains 15 – 20 mg iodine (70 – 90 % in the thyroid gland).

Endemic goitre occurs with daily intake below 70 m g and fetal iodine deficiency disorder (FIDD) in off-spring (1-5% of babies) below 20 m g.

Iodine is an essential requirement for hormone synthesis (iodoproteins: active tri-iodo-thyronine = T₃ & thyroxine = T₄) and thyroid function under the main regulator, Thyroid Stimulating Hormone (TSH). These hormones are vital to growth, development & maintenance and contribute to the control of body weight, cellular metabolism and integrity of connective tissue.

Dietary iodine deficiency is a major cause of thyroid dysfunction. Patients may be euthyroid or hypothyroid depending on the severity of iodine deficiency.

Iodine deficiency can cause a range of functional and developmental abnormalities, including thyroid function abnormalities. These can be compounded by coexistent Selenium deficiency as occurs in Zaire⁴. In severe deficiency, endemic goitre, cretinism, endemic mental retardation, decreased fertility, increased perinatal and infant mortality can develop. Those most at risk include pregnant mothers, foetuses, neonates and young infants because of the irreversible mental retardation (cretinism) that iodine deficiency can cause².

Exposure to excessive iodine through foods, dietary supplements, topical medications and/or iodinated contrast media has resulted in thyroiditis, goitre, hyperthyroidism, hypersensitivity reactions and acute responses for some individuals⁵. Fatal iatrogenic iodine toxicity has occurred when used in skin or bowel povidone-iodine treatments⁶.

Four degrees of iodide excess in humans have been defined⁷:

1. A relatively modest excess promoting temporary increase in the absolute uptake of iodine by the thyroid and the formation of organic iodine without inhibiting the capacity to release iodine in response to physiological demand.

2. A large excess, which can inhibit iodine release from the thyrotoxic human thyroid or from thyroids in which iodine release has been accelerated by TSH.

3. A slightly greater intake which inhibits organic iodine formation and which probably causes iodide goitre ( Wolff- Chaikoff effect ) .

4. Very high levels which saturate the active transport mechanisms. The acute pharmacological effects of iodide can usually be demonstrated before saturation becomes significant.

Wolffe has suggested that 2000m g/day should be considered as excesssive or potentially harmful. Normal diets are less than 1000m g/day but very high marine fish or seaweed consumption, as is common in Japan, can lead to intakes as high as 50,000-80,000m g/day¹. In Japan, the incidence of non toxic diffuse goitre and toxic nodular goitre are markedly decreased by high dietary iodine. The high iodine intake can induce hypothryroidism in autoimmune thyroiditis. In areas which previously had low iodine intake levels, supplementation programs with iodised salts or oils can cause a mild increase in the incidence of hyperthyroidism and in general should be avoided by people aged over 40. The issues involved in confronting endemic iodine shortage have been reviewed⁸. Such conditions may resolve spontaneously with or without antithyroid drugs.

Although endemic goitre is rare in developed countries (due to iodine fortification), altered dietary habits have awakened new health concerns about a trend of iodine deficiency among young women, putting their unborn children at risk of reduced mental intellect.

(1) National Research Council. Recommended dietary allowances, 10th ed., Washington, DC, National Academy of Sciences, 1989.

(2) Freeland-Graves JH et Al. ' Metabolic balance of manganese in young men consuming diets containing five levels of manganese'. Journal of nutrition, 1988, 118: 764-773.

(3) Garcia-Aranda JA et al. 'In vivo intestinal absorption of manganese in the rat '.

(4) Ikeda S etal. 'Manganese deposits in patients with biliary atresia after hepatic enterostomy.' J Paediatr Surg, 2000 Mar, 35:3, 450-3.

(5) Wilson DC et al. ' Plasma manganese levels in the very low birth weight infant are very high in early life ' Biol Neonate 1992, 61(1): 42-46.

(6) Fell JME et al. ' Manganese toxicity in children receiving long-term parenteral nutrition '

Lancet 1996; 347: 1218-21.

Liver and kidney, meat, fish and shellfish, wholegrain cereals and dairy products are all good sources of selenium.

Normally, about 80% of the selenium in the diet is absorbed across the intestine but this process does not appear to be under homoeostatic control. Dietary selenium intake, therefore, determines tissue selenium levels. Reductions in intake tend to be followed by a proportional reduction in blood levels.

Selenium is an antioxidant, which helps to remove potentially harmful free radicals. It also helps maintain the normal functioning of the immune system, heart and liver.

The biological activity of selenium is due to selenoproteins. Selenium is first incorporated into body tissues as selenocysteine, produced by messenger RNA, part of every cell’s genetic mechanism. The selenocysteine is then incorporated into proteins, forming selenoproteins. There are around 35 selenoproteins, of which three appear to be particularly important.

i) the antioxidant Glutathione Peroxidases.

These enzymes stop lipid peroxidation and convert hydrogen peroxide to water. This protects the phospholipids in cell membranes and also appears to protect cells against mutagenic peroxides formed from DNA and nucleotides. The enzymes help to maintain the integrity of red blood cells and also help white cells to kill bacteria. The mitochondria of macrophages are particularily subject to free radical damage and these enzymes appear to protect them. Macrophages play an important role in the immune response.

A daily dietary supplement of at least 30m g of DL-selenomethionine is necessary to fully saturate plasma glutathione peroxidase activity (equivalent to 41m g selenium per day for a 65 kg man).¹ However, at higher intakes, cells produce more of the saturated enzyme. This may explain the protective value of higher selenium intakes.

ii) the Iodothryonine Deiodinases.

These enzymes are responsible for the conversion of thyroxine (T4) to trioiodothyronine (T3) which is six times more metabolically active. Low selenium could therefore contribute to hypothyroidism. Borderline thyroid function can return to normal after appropriate selenium supplementation (2m g/kg/day).

iii) Mark: name of this one?

The third key selenoprotein is found in the sperm mitochondrial capsule that makes up the mid section of the sperm tail. Early in the development of sperm (spermatogenesis) this protects the developing sperm from oxidative damage. Later, it polymerises into a structural protein that is essential for the stability and motility of sperm.

Selenium deficiency syndrome was first identified in the Keshan region of China² where many mothers gave birth to children who died from a cardiomyopathy. At post mortem their heart muscle was found to be white and wasted. A similiar condition affected domesticated animals in this region. The average daily intake of local people at the time was estimated at only 11m g. Fortunately, the condition could be prevented by giving pregnant women selenium supplementation. Keshan disease did not exist in areas where the mean intake for a 60 kg man was 19.1m g or more per day.

A selenium deficient person may:

• have a lower resistance to infections (especially viral)
• be more susceptible to the harmful effects of toxins
• have reproductive difficulties (low sperm count and motility in men, miscarriage, unexplained infertility and perhaps malpresentations in labour in women)
• have an increased risk of cancer, heart disease, endocrine dysfunction and post-viral fatigue syndromes.

Selenium supplements are rarely associated with adverse effects. Toxicity can occur when dietary intakes are high (well above 500 microgms per day). This can cause hair loss, diarrhoea, nausea, fatigue and irritability.

People likely to benefit from selenium supplementation include:

• vegetarians, vegans and the elderly, as their diets may not supply enough
• smokers, as selenium may help to reduce the damaging effects of smoking
• pregnant and lactating women, as developing babies need a good supply of selenium

In Finland, when all grain was home produced, people had average daily intakes of 25m g selenium. This was found to increase to 40-50m g when the harvest was bad and imported wheat had to be used instead. In 1984 the addition of selenium to fertilisers was made compulsory - at 6mg/kg to all grassland fertilisers and at 16mg/kg (reduced to 6mg/kg in 1994) to all grain phosphate fertilisers³. The aim was to increase the selenium content of grain from 10 to 100 m g/kg. The levels in beef subsequently rose ten fold to 600m g /kg and levels in dairy products rose from 30 to 175-225m g /kg. The high mortality from coronary heart disease in Finland has now decreased, at least partly because of this increase in dietary selenium.

In the U.K. the estimated daily intake of selenium fell from 60m g (in year?) to 43m g in 1988 and 34m g in 1994 ( range of 29-39m g) primarily due to reduction in the import of Canadian flour (high selenium or ‘hard’ wheat ). More recently, the fall in intake may have been due to soil depletion. A daily intake of 29-39m g for selenium now appears to be suboptimal.

Live stock farmers generally attempt to improve trace element intake by treating animals directly with injections, drenches or mineral licks. A more effective and enduring method of correcting the balance of trace elements is to apply them directly to soils and pastures, as shown in Finland.This technique ensures the soil microflora, plants and ruminants feeding on them are all treated.

Good dietary sources of zinc include dairy products, red meat, eggs, fish and wholemeal bread

Zinc is involved in a wide range of body processes as it is an essential component of a wide range of enzymes. It also contributes to the body’s immune defences and is needed for healthy skin, nails and hair.

Zinc functions as a stabiliser of the molecular structure of subcellular constituents and membranes.Zinc is also required for normal foetal development.

Zinc deficiency results in skin disorders, including acne, eczema and psoriasis. It may also cause mental lethargy and impaired immune defences to infection. Zinc deficiency, as found in the Middle East, for example, causes growth retardation and lack of development of secondary sexual characteristics.

Vegetarians and vegans are at risk of zinc deficiency, as their dietary intake may be too low.

Zinc compounds can cause acute renal tubular necrosis and interstitial nepritis and inhalation of zinc chloride causes chemical pneumonitis and adult respiratory distress syndrome¹.

Very high doses of zinc can reduce red and white blood cell counts, as well as causing vomiting and gastrointestinal disturbances. At doses below 15mg/day there are few side effects, but higher doses should only be taken under medical supervision.

In the UK, average daily intakes of 10 mg ( MAFF) fall below the RDA of 15mg. Zinc supplementation of between 1.3 to 15 mg per day is therefore becoming fashionable. Some preparations have added Copper 0.3-1mg. However, there is evidence that even low levels of Zinc supplementation (close to 15 mg ) may interfere with the utilisation of copper and iron and to adversely affect HDL cholesterol. Higher levels (100-300mg Zinc/day) induced copper deficiency with anaemia, neutropaenia, impaired immune function and adverse effects on LDL/HDL cholesterol².

In Turkey asymptomatic deficiency has been corrected by zinc-supplemented bread with no manifestations of zinc toxicity³.

1. Barceloux DG 'Zinc' J Toxicol Clin Toxicol, 1999; 37:2, 279-92
2. Fosmire GJ 'Zinc Toxicity' Am J Clin Nutr, 1990; Feb, 51:2, 225-7
3. Kilic I et al. 'The effect of zinc-supplemented bread consumption on school children with asymptomatic zinc deficiency '. J Paedtr Gastroenterol Nutri, 1998 Feb, 26:2, 167-71.