Trace elements too much or too little? Susan Fairweather-Tait Department of Medicine Norwich Medical School

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1 Trace elements too much or too little? Susan Fairweather-Tait Department of Medicine Norwich Medical School

2 Outline of talk Requirements for optimal health Dietary reference values Consequences of deficiency or excess Public health policies Focus on selenium and iron

3 Optimal health

4 The evolving science of nutrition applied to dietary recommendations Prevention of Prevention of chronic disease Personalised deficiency/toxicity nutrition 1930s UK introduced IOM replaced Safe Upper Levels EU (EFSA) PRIs reference values RDAs with DRIs UK Expert Group Vits and Mins Biomarkers Biochemical measures Functional biomarkers Risk biomarkers Genetics of status Metabolomics

5 Deriving dietary reference values (DRVs) for trace elements Average requirement AR Upper level Population Reference Intake PRI Distribution reflects variability in requirements between individuals. When the coefficient of variation is unknown, DRVs are derived based on ± 2SDs of the mean AR December 4, 2014

6 Examples of differences in published average requirement values for iron Men Women (pre-/post-menopause) mg/d mg/d NNR /6 IOM (USA) /5 Australia/NZ /5 UK /6.7 *EFSA (Europe) /6 * New values will be published in 2015

7 Explanation for differences in ARs? Cannot relate dietary intake to biomarkers (status or health outcomes) so have to use the factorial approach to derive the AR Sum the obligatory losses - faecal, urinary, dermal and menstrual (women) for 50% of the population This gives the quantity of absorbed iron needed to replace losses *Select a bioavailability factor (% absorption of iron from the diet) Convert physiological quantity to dietary intake using the bioavailability factor *See Dainty et al. PLOS ONE 2014 for new approach

8 Upper levels of Fe and Se for adult men and women Expert body Iron Selenium mg/d Basis for level selected μg/d Basis for level selected Nordic Nutrition Recommendations 2012 IOM 2001 (Fe) IOM 2000 (Se) 60 Biochemical iron overload (serum ferritin concentration >300μg/L) 45 Gastrointestinal side effects 300 Threshold for inhibition of prothrombin synthesis in Chinese studies (850μg/d) with uncertainty factor of 3 (EU SCF 1993) 400 Hair and nail brittleness and loss December 4, 2014

9 Selenium Many different forms of selenium e.g. Selenomethionine (50-80% of Se in cereals and legumes), Se-enriched yeast Selenocysteine (fish) Se-methyl-L-selenocysteine Allium and Brassica families (up to 80% of total Se), yeast Good sources include Brazil nuts Red meat, offal Fish Grains Eggs Broccoli, onions, garlic and mushrooms December 4, 2014

10 Selenium intakes in Europe Finland Switzerland Netherlands Belgium Denmark Slovakia Sweden France Germany UK Poland December 4, 2014

11 Selenium intake reflects soil content Se intake (μg/person/d) < > 350 Courtesy of Prof Martin Broadley, University of Nottingham

12 Estimated prevalence of low selenium status* Low (<10%) Moderate (10-50%) High (>50%) * Based on estimated frequencies of plasma or serum Se concentrations <70 μg/l

13 Effect of form of selenium on metabolism EFSA opinion on selenium DRVs (2014)

14 Effects of chemical form on safety No observed adverse effect level (NOAEL) for clinical selenosis is 850 μg/d Applying an uncertainty factor of 3, the UL for Se is set at 300 μg/d Whole body turnover of organic Se is slower than inorganic Se, indicating that organic Se is incorporated into a long-term body pool There are safety concerns about organic forms of Se because Se can replace sulphur in S-methylcysteine

15 Selenium deficiency White muscle disease in animals where crops are grown on low Se soil (<0.1ppm Se) [1958 Oregon] In parts of China Keshan disease myocardial necrosis (associated with coxsackie virus) Kashin-Beck disease atrophy of cartilage December 4, 2014

16 Selenium and cancer prevention Lung cancer 46% Prostate cancer 63% Colon cancer 58% 200 g/day high-se yeast reduced the incidence of some cancers by 50% Clark et al 1996 JAMA 276:1957 December 4, 2014

17 Meta-analysis of data showing the relationship between toenail Se concentration and prostate cancer risk (Ghadirian et al 2000, Helzlsouer et al 2000, van den Brandt et al 2003) Lower mortality was associated with toenail selenium μg/g and serum Se concentration μg/l (Hurst et al 2012)

18 % Incidence Biomarkers that could be used to derive DRVs for selenium Absence of benefit Risk of selenosis Input information - Benefit: Plasma GPx activity (data from dose-response studies in China and NZ) - Risk of selenosis: epidemiological data from China, and 200 g/d supplementation trial (Clark) 0.01 EAR (50% response) 45 g/d UL (50% response) 3200 g/d Selenium Daily Intake ( g/day) December 4, 2014 Adapted from Renwick et al 2008

19 % Incidence Effect of selecting different biomarkers Possible anticancer effect Possible prothrombin effect Input data Possible anti-cancer effect (Clark study and other trials) Effect used for RDA Effect used for UL Prolonged prothrombin time (data from high Se areas in China) EAR 143 g/d UL 897 g/d Selenium Daily Intake ( g/day) December 4, 2014 Adapted from Renwick et al 2008

20 Selenium recommendations from different bodies vary widely

21 Dietary iron Haem Fe Meat, fish Absorption from a Western-style diet : 25-30% Non-haem Fe Cereals, green vegetables, fortified food products Absorption from a Western-style diet : 0-15% December 4, 2014

22 Iron deficiency anaemia IRON DEFICIENCY IS THE MOST WIDESPREAD NUTRITIONAL PROBLEM IN THE WORLD Debilitated health of 500 million women >60,000 deaths/y during childbirth Lost productivity of up to 2% of GDP in the worst affected countries December 4, 2014

23 No significant relationship between iron intake and iron status (serum ferritin) NDNS ( ): data from adults who were nonsupplement users (n = 1079)

24 Dose-response relationships between iron status and health Population group Adults (19-59 years) Elderly ( 60 years) Iron status biomarkers Health outcomes Tiredness Physical performance Immune function Impaired thermoregulation Restless legs syndrome Cognitive function Infants (0-1 years) Children and adolescents (1-18 years) Pregnant women (and developing fetus) Haemoglobin Ferritin Transferrin receptor Body iron (Cook method) Growth Neurodevelopment Immunity Cognitive functions and psychomotor development Restless Legs Syndrome Fetus: Fetal growth Preterm delivery Mother: Preeclampsia Postpartum depression

25 Results of systematic reviews Relationship (outcome) Population group No of studies included Outcome Physical performance Adults and elderly 19 - Variation in outcome measures (e.g. VO2max, RER, heart rate and work rate) not possible to pool studies - Necessary to separate untrained and highly trained participants - Significant effect of iron supplementation on VO2 max in trained/athletes Tiredness Adults and elderly 3 Limited data available, different assessment questionnaires used Immune function Children and adolescents 7 For all population groups: high heterogeneity in outcome measures limited potential for meta-analysis Restless legs syndrome Cognition Adults and elderly 3 Adults 1 Iron supplemented group showed improvement compared with placebo Infants, children and adolescents 14 No meta-analysis possible (heterogeneity in population groups, outcome measures, dose etc) Growth in gestation, infancy, childhood and adolescence (Vucic et al 2013) Infants, children and adolescents Pregnant women 21 7 No significant effects observed No significant effects observed

26 Iron overload: effects of genotype Most patients with hereditary haemochromatosis (HH) are homozygous for the C282Y mutation of the HFE gene but the mutation does not accurately predict HH i.e. clinical penetrance is not high (i.e. other genes/polymorphisms must be involved) Clinical symptoms of HH usually seen in middle age as fatigue, depression, arthralgia's If untreated, death occurs from liver cancer, cirrhosis, cardiomyopathy, diabetes

27 Prevalence of HFE mutations depends on ethnicity USA C282Y homozygotes - 0.3% whites % blacks % Mexican Americans USA C282Y heterozygotes - 9.5% whites - 2.3% blacks - 2.8% Mexican Americans In the UK, the homozygote rate is higher (1 in ) In non-celtic populations (e.g. Greece) the rate is much lower (<1 in 100,000)

28 Effects of too much or too little iron Conclusions of Nordic Nutrition Recommendations 2012 Too much Chronic effects Liver damage Joint inflammation High haem iron intake and type 2 diabetes and gestational diabetes No evidence for a link with CVD No evidence for a link with cancer (apart from liver cancer in C282Y heterozygotes) Lower scores for visual-motor integration in children (in iron replete infants given high iron formula) Acute effects Mucosal erosion in stomach and intestine Nausea, vomiting, heartburn, epigastric discomfort Constipation Diarrhoea Too little Reduced work capacity Impaired cell-mediated immunological defence Altered temperature regulation Impaired children s mental development and cognitive functions Growth inhibition in children Hypertension (?)

29 Combatting trace element deficiencies Dietary advice - selecting nutrient-rich foods - avoiding high energy, nutrient-poor foods - improving bioavailability by increasing enhancers and reducing inhibitors (iron) Food fortification - mandatory or voluntary - staple foods e.g. cereals - manufactured food products tailored for vulnerable groups Food supplements Biofortification

30 Iron fortification development of new more effective fortificants Nano iron (1 to 100 nm particle size): 12 entries listed in the EFSA Nano inventory (EFSA 2014)

31 How well is nano iron absorbed? Iron solubility in gastric juice depends on surface area and chemical structure The smaller the particle size, the greater the solubility and hence the better absorbed the iron should be

32 Absorption of nano iron DMT1 Iron solubility in gastric juice depends on surface area and chemical structure The smaller the particle size, the greater the solubility and hence the better absorbed the iron should be However, iron uptake by DMT1 in Caco-2 cells was inversely related to gastric solubility Is nano iron absorbed by endocytosis? Is it under the same homeostatic control as other forms of iron (safety issues)? Pereira et al 2014

33 Biofortification Selection and breeding of crop varieties with higher iron and/or lower phytate/tannin content (inhibitors of iron absorption) Genetically modified crops Fertilisation - applied to soil or as foliar feed (Se) Courtesy of University of Nottingham (Prof Martin Broadley)

34 Selenium fertiliser programme in Finland Mean Se concentration of spring wheat Changes in plasma selenium Se content of fertilizers: 16 mg/kg in mg/kg in mg/kg in mg/kg in 2007

35 Conclusions of the Finnish experience Supplementation of fertilisers with Se has increased the Se concentration of all major food groups Plasma Se concentrations have increased by 70% Toenail Se increased from a pre-supplementation level of 0.45 mg/kg to 0.72 mg/kg in 1995 Mean current Se intake is higher than dietary recommendations Alfthan et al 2014

36 Effects of changes in Se intake on human health Age-standardised incidence of cancers Age-adjusted CHD mortality has continuously declined since the 1960s (probably due to a reduction in risk factors such as smoking, BP, cholesterol). No apparent change resulting from Se fertilisation. Increased rate in prostate cancer since the 1990s is probably due to enhanced diagnosis. Difficult to draw conclusion about the effects of Se on human health because there is no reference or Se-deficient populations for comparison.

37 Effects of Se intake on individuals: potential consequences of SNPs Gene/SNP Biomarker Health outcome GPx1 Pro198Leu Serum Se Decreased risk of prostate cancer with increasing serum Se SEP G/A (3 UTR) Plasma Se Positive association with lung cancer risk SEP15 (rs561104) Plasma Se Inverse association with prostate cancer mortality SOD2 rs4880 (C/T position 47) Plasma Se VV or VA allele and high plasma Se increases risk of prostate cancer; AA genotype and high plasma Se decreases risk MnSOD (Val/Ala codon 16) Plasma Se AA genotype and low plasma Se at increased risk of prostate cancer compared with VA/VV genotype HbSS and Hb AA haplotypes GPx activity Sickle cell anaemia (HbSS) associated with lower mean GPx activity compared with HbAA controls Hurst et al 2013

38 Biofortification programme led by HarvestPlus

39 Biofortification increasing the ferritin content of plant foods Ferritin is as well absorbed as ferrous sulphate Davila-Hicks et al 2004 Lonnerdal et al 2006

40 Breeding programmes in practice

41 Summary Public health policies aimed at preventing trace element deficiencies should take into account the consequences of chronic high intakes Chemical form may be important Further data are needed on the effects of low and high intakes of trace elements on health endpoints in population groups Adaptive (physiological) responses designed to maintain homeostasis should be taken into consideration DRVs and public health policies are designed for populations - vulnerable individuals will only be considered if the group they belong to makes a significant contribution to the population as a whole The needs of individuals can only be addressed through personalised nutrition

42 Thank you for your attention Any questions?