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Blood Loss Is a Stronger Predictor of Iron Status in Men Than C282Y Heterozygosity or Diet

Department of Human Nutrition, (A.-L.M.H.)
Department of Preventive and Social Medicine (A.R.G., S.M.W.)
University of Otago, Dunedin, NEW ZEALAND, Institute of Food Research, Norwich, UNITED KINGDOM (M.A.R., S.L.O., S.J.F.-T.)

Address correspondence to: Professor Susan Fairweather-Tait, Diet and Health Group, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, ENGLAND. E-mail: s.fairweather-tait{at}uea.ac.uk

	ABSTRACT

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Objective: To determine the relative importance of HFE gene, diet, lifestyle, and blood loss characteristics for predicting iron status in a sample of men aged 40 years or over.

Design: Iron status (serum ferritin, transferrin saturation, soluble transferrin receptor) was measured in 44 C282Y heterozygote and 85 age- and BMI-matched wildtype men aged 40 years or over. Dietary intake of iron (total, heme and non-heme), and components known to influence iron bioavailability, was determined using a validated Meal-Based Intake Assessment Tool. Information on lifestyle and blood loss was obtained by questionnaire. Height and weight were measured to determine Quetelet's body mass index. Linear mixed models were used to determine the extent to which these variables predicted iron status.

Results: C282Y heterozygosity was associated with 17% higher transferrin saturation (95% CI: 6%, 29%) but no difference in serum ferritin or soluble transferrin receptor concentrations. Blood donation was negatively associated with transferrin saturation (–13% (– 3%, –22%)) and serum ferritin (–58% (–44%, –68%)), and had a marginally significant positive association with soluble transferrin receptor concentration. Self-reported fecal blood loss was negatively associated with serum ferritin concentration (–35% (–54%, –7%)). Alcohol was the only dietary variable associated with iron status and was associated with all three of the iron status indices. Serum ferritin concentration was positively associated with body mass index (10% per unit increase (6%, 15%)).

Conclusions: Blood loss was a stronger predictor of iron status than either C282Y heterozygosity or diet in this population of men aged 40 years and over.

Key words: HFE mutations, C282Y heterozygotes, iron, transferrin saturation, ferritin, blood donor, body mass index, alcohol

	INTRODUCTION

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It is well established that 91% of people of Northern European descent diagnosed with the potentially fatal iron overload condition hereditary hemochromatosis are homozygous for the C282Y mutation of the HFE gene [1]. There is evidence that C282Y heterozygotes may be at increased risk of fatal cardiovascular and cerebrovascular disease [2], although their risk of non-fatal coronary heart disease does not appear to be elevated [3]. While these findings need to be confirmed, it is obvious that we cannot focus entirely on C282Y homozygosity, and must better characterise the phenotype of C282Y heterozygotes. This is not least because in populations of Northern European descent, although fewer than one in a hundred people are homozygous for the C282Y mutation of the HFE gene, one in eight may be heterozygous [4].

A number of studies have investigated iron status in individuals with differing C282Y genotype [5,6], and the influence of blood donation and dietary factors on iron status [7–11], however the relative importance of genotype, iron intake and iron losses in determining iron status has not yet been investigated in male C282Y heterozygotes. This is an important question because of the accepted deleterious effects of iron deficiency, and the putative, although controversial, effects of non-hemochromatotic iron overload. The aim of the present study was to determine the relative importance of HFE gene, diet, lifestyle, and blood loss characteristics for predicting iron status in a population of UK men aged 40 years and over who have a relatively high prevalence of the C282Y mutation of the HFE gene, and at least 40 years of potential iron accumulation.

	MATERIALS AND METHODS

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Participants
Five hundred and fifty-six men from the Norwich (UK) area responded to local media advertisements for men aged 40 years and over to be involved in two studies investigating links between dietary iron and health: the present study, and an iron absorption study [12]. A 10mL blood sample was taken for HFE genotype analysis [13] and identified 73 C282Y heterozygote and 326 wildtype men. Volunteers with a diagnosed medical condition likely to affect diet or digestion (e.g. diabetes, celiac disease) were excluded. Of the 59 heterozygotes invited to participate in the present study, 46 agreed to take part (78%). As each heterozygote was recruited, two wildtype (i.e. no C282Y, H63D or S65C mutations of the HFE gene) men of similar age (four age categories: 40–49.9 years, 50–59.9 years, 60–69.9 years, 70 years or older) and body mass index (four BMI categories: <20 kg/m², 20–24.9 kg/m², 25–29.9 kg/m², 30 kg/m²) were recruited. When there were more than two wildtype men of appropriate age and body mass index to choose from, the two who were screened earliest were invited to participate. Participants were not aware of their C282Y genotype, except that they knew they were not eligible to participate if they were C282Y homozygotes.

Participants were sent an Information Sheet on the study to read before their first appointment. The study was then explained in detail during a visit to the Human Nutrition Unit at the Institute of Food Research (Norwich, UK) when participants were given an opportunity to have any questions answered, and written informed consent was obtained. The study was approved by the Norwich District Ethics Committee.

Study Design
Participants visited the Human Nutrition Unit at the Institute of Food Research (UK) four times: three blood samples were taken over the course of one week, and a dietary assessment was completed at the fourth appointment, approximately one week later. Participants also completed a questionnaire designed to collect information on blood donation, other sources of blood loss (fecal blood loss, nose bleeds, diagnosed stomach ulcer), dietary patterns, supplement use, medication, recent illness, physical activity [14], cigarette smoking, and socio-demographic status. Height and weight measurements were made in duplicate using standardized procedures, with participants standing erect in bare feet, and wearing light clothing. A portable stadiometer (Seca, Birmingham, United Kingdom) was used to measure height to the nearest 0.5cm. Body weight was recorded to the nearest 0.1kg using digital scales (Seca, Birmingham, United Kingdom) from which Quetelet's body mass index (BMI) was calculated.

Assessment of Iron Status
The three morning fasting venipuncture blood samples were collected for biochemical analyses (25mL on day 1, 10mL on each of days 2 and 3). Serum ferritin (SF), serum iron, total iron binding capacity, transferrin saturation (TS), C-reactive protein and soluble transferrin receptor (sTfR) were determined on each of the three days. Hemoglobin (5mL blood) and HFE genotype (10mL blood) were determined on Day 1 only. All analyses, except sTfR and HFE genotype, were undertaken at the Chemical Pathology Department of the Norfolk and Norwich University Hospital, UK. Soluble transferrin receptor concentration was measured in EDTA plasma, stored at –80°C, using a commercially available ELISA kit (Quantikine IVD Soluble Transferrin Receptor ELISA, R&D Systems Europe Ltd, Oxon, United Kingdom). HFE genotype was determined according to the method described by Willis et al. [13].

Measurement of Dietary Intake
The Meal-Based Intake Assessment Tool (MBIAT) [15] was used to estimate intake of dietary iron, non-heme iron, meat iron, heme iron and the modifiers of iron absorption: vitamin C, meat/fish/poultry, phytate, calcium, and black tea equivalents, at the dietary assessment appointment. The MBIAT is a quantitative computer-based questionnaire that asks participants to describe the meals and snacks they have eaten during the past month using 630 foods sorted into sixteen food groups. Serving sizes are estimated using multiples and proportions of common standard measures (e.g. cups of coffee, slices of bread), and three-dimensional food models for meats, cheese, pizza, slices of cake, and potato chips. Dried beans and plates were used to assist in volume estimation. In this study, the MBIAT was administered by an interviewer.

The food list for the MBIAT was based on the 5^th edition of the UK Food Composition Tables [16], and supplements to the 4^th and 5^th editions [17–25] with the following deletions: (a) culturally specific foods unlikely to be consumed by men aged 45 years and over living in Norfolk, (b) specific varieties when a generic food was available, (c) foods with a negligible content of the food components of interest (e.g. butter, margarine, sugar).

The food composition data for total iron, vitamin C and calcium nutrient intakes were calculated using the UK Food Composition Tables, and its supplements. Meat/fish/poultry values were calculated as grams of animal tissue in 100g edible portion of food. Heme iron was calculated as the product of meat iron and the proportion of heme iron in the specific meat using values from the literature [26,27]. Non-heme iron was the difference between heme iron and total iron. Meat iron was calculated as the product of the total iron content per 100g of the specific meat(s) in the food, and the meat/fish/poultry value of the food expressed as a proportion. Therefore, meat iron was equal to total iron both for foods with a meat/fish/poultry value of 100g/100g and for foods with all their iron coming from meat. Phytate values were based on published data [21,23–25,28,29]. When phytate values could not be found in the literature, values for foods of similar composition were used. Black tea equivalents were calculated as follows: a value of 100 was assigned to 100g of black tea infusion. Other beverages with an appreciable content of tannins were assigned a proportion of this figure according to their inhibitory effect on iron absorption compared to black tea [30–32]. For composite dishes, phytate and MFP content was estimated using recipes published with the UK Food Composition Tables and its supplements, online recipe books (primarily www.recipesource.com), or manufacturer's information (primarily via www.tesco.com).

The MBIAT was validated using data provided by the first 48 participants. These participants completed the MBIAT on two occasions, and collected 12 days of weighed food records [15]. The questionnaire was able to clearly differentiate between low and high intakes for total iron, heme iron, non-heme iron and all the iron absorption modifiers of interest except calcium (it was decided to include the calcium data because although the MBIAT performance for this nutrient was poorer, it was able to classify individuals’ calcium intake correctly to within one quartile for 77% of the time). For instance, cross-classification demonstrated that 54% and 56% of alcohol and heme iron intakes respectively were classified in the same quartile by both methods, and for both nutrients, only 2% (n=1 participant) of intakes were misclassified by the questionnaire into the opposite quartile of weighed diet record intake. The MBIAT was readministered 6 months after the first administration. There were no significant differences between the results for the two administrations in "opposite" seasons (e.g. winter versus summer) suggesting that the method was able to capture "habitual" intake.

Statistical Analysis
The data analysis for this paper was generated using SAS software Version 9.1.2 of the SAS system for Microsoft Windows (SAS Institute Inc, Cary NC, USA). Matching had been performed based on age and BMI because these were expected to influence the outcomes. These variables were controlled for where possible, as indicated in the tables.

In order to compensate for skewed residuals, the following variables were log-transformed when used as dependent variables: BMI, mean transferrin saturation, mean serum ferritin concentration, mean soluble transferrin receptor concentration, and intake of total iron, heme iron, non-heme iron, meat/fish/poultry, vitamin C and phytate. The following variables were log-transformed after adding 1 to allow for zero values: intake of black tea equivalents and alcohol. Therefore, as indicated in the tables, the results showing differences in means are ratios for these transformed variables, and actual differences for all other variables.

Table 1a was constructed using SAS's proc mixed to specify a model containing a random effect for the "match identifier" to account for the similarity between matched cases and controls. Fixed effects were included for HFE genotype, BMI and age. A Satterthwaite approximation for the denominator degrees of freedom was used. Differences in least squares means were used to assess the effects of genotype, BMI and age.

	RESULTS

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The C282Y heterozygotes had a slightly, but significantly, higher mean transferrin saturation than the wildtype participants (32% vs 27% (ratio (95% CI): 1.2 (1.1, 1.3))) (Table 1a). There was no significant difference between the two different genotypes for any of the other measures of iron status, blood loss, or diet indices, except aspirin use (Table 1b). A significantly higher proportion of heterozygotes were taking 7 or more aspirin per week (a level of aspirin use that may be associated with lower serum ferritin concentrations [33]). Exclusion of these high aspirin users did not raise the serum ferritin concentrations of either the C282Y heterozygotes or wildtype controls, nor alter the "Genotype" or "Lifestyle" serum ferritin models reported below, so these individuals were included in the analyses.

C282Y heterozygosity was associated with 17% (95% CI: 6%, 29%) higher transferrin saturation after controlling for age, BMI and blood donation (Table 2) but there was no significant association between C282Y heterozygosity and either serum ferritin concentration (Table 3) or soluble transferrin receptor concentration (Table 4) after controlling for age, BMI and blood donation.

Serum ferritin concentration was, however, significantly associated with a number of blood loss variables, alcohol intake and BMI (Table 3). Blood donation in the past four months was associated with a 72% lower (CI: –81%, –58%) serum ferritin concentration, while past blood donation was associated with a 52% lower serum ferritin concentration (CI: –64%, –35%). In addition, self-reported fecal blood loss was associated with a 35% (CI: – 54%, –7%) decrease in serum ferritin concentration. Only one dietary variable was associated with iron status. Each unit of alcohol was associated with a 7% (CI: 2%, 12%) increase in serum ferritin. In addition, each BMI point was associated with a 9% (CI: 5%, 14%) increase in serum ferritin concentration. Neither heme iron nor non-heme iron intake was significant in the serum ferritin model.

Alcohol intake was the only significant predictor of soluble transferrin receptor concentration and was associated with a 2% lower concentration for each unit consumed per day (CI: –4%, 0%). Recent blood donation was marginally statistically significant (Table 4).

	DISCUSSION

 
These results confirm that C282Y heterozygosity is associated with slightly higher transferrin saturation but not higher serum ferritin concentration in men [6]. Our data suggest there was also no effect of C282Y heterozygosity on tissue iron status, as measured by soluble transferrin receptor concentration. In conjunction with the recent observation that C282Y heterozygotes do not have higher absorption of either non-heme [12,34] or heme iron [34], these findings suggest that C282Y heterozygotes do not have higher iron stores than their wildtype counterparts. Transferrin saturation has been described as "the earliest phenotypic marker of hereditary hemochromatosis" because it may be elevated in young homozygote individuals who have a normal ferritin level [35]. The consistent finding of slight elevation in transferrin saturation, in the absence of elevated iron stores in C282Y heterozygote populations suggests a partial expression of the homozygote phenotype. It is unclear whether this difference in transferrin saturation reflects an increase in iron absorption that is too small to be detectable in typical iron absorption studies [12,34], or alterations in iron distribution. The lack of difference in serum ferritin and soluble transferrin receptor concentrations suggest that transferrin saturation is unlikely to reflect differences in body iron stores.

In this population, blood loss was a stronger predictor of iron status than either C282Y heterozygosity or the dietary variables measured. Recent blood donation was associated with 24% lower transferrin saturation, and recent and past blood donation with 72% and 52% lower serum ferritin concentration respectively. There was a marginally statistically significant 15% increase in soluble transferrin receptor concentration in men who had recently donated blood. The finding that transferrin saturation was lower and soluble transferrin receptor concentration higher amongst those who had donated blood in the past four months, but not in those who had donated blood in the more distant past, suggests that caution should be exercised when interpreting these indices within four months of blood donation. The geometric mean serum ferritin concentration in this study was lower than that reported in other studies of adult men –60µg/L compared to, for example, 111 µg/L [5] and 177µg/L [6]. It is likely that this is due, at least in part, to the high number of participants (41%) who had been a blood donor at some time in the past. Self-reported fecal blood loss was also associated with lower serum ferritin concentration. This blood loss probably reflected haemorrhoidal bleeding. Because tests for occult bleeding were not carried out, we were unable to investigate any association between total gastrointestinal blood loss and iron status, however the existence of a substantially lower iron status amongst participants reporting fecal blood loss suggests that haemorrhoidal blood loss may in itself be an important predictor of iron status. It would be interesting in subsequent studies to quantify fecal blood loss and determine when rectal bleeding becomes a risk factor for iron deficiency. It should be noted, however, that the association reported here is particularly useful because it refers to bleeding that can be identified by the patient themselves. In this study of middle-aged men, 10% of whom reported having nosebleeds, there was no association between nosebleeds and iron status, in contrast to the twofold increased risk of iron deficiency in a younger population of adult women, 20% of whom experienced nose bleeds [36]. Although it is well known that blood donation is associated with lower iron status [7–11], previous studies in adult males have not investigated other types of blood loss as possible predictors of iron status.

Each unit of alcohol (10mL or 8g ethanol) consumed per day was associated with a 7% increase in serum ferritin concentration, a 3% increase in transferrin saturation, and a 2% decrease in soluble transferrin receptor concentration. Thirty-five percent of this population of UK men reported consuming an average of 20g ethanol or more a day. In the study of Australian men by Leggett et al. [9] in which a similar proportion were drinking heavily (32%), alcohol intake accounted for 7.3% of the variability in serum ferritin concentration, controlling for serum levels of the liver enzyme -glutamyltransferase (GGT) which was used as an indicator of liver disease. Other researchers have reported a dose-dependent increase in serum ferritin with increasing alcohol intake [37], and elevated transferrin saturation in individuals with high alcohol intakes [38], however the mechanism for these effects remains unknown. It is probable, although not certain, that the higher serum ferritin concentrations seen in those consuming alcohol do not reflect higher iron status. Although some studies have suggested that alcohol may enhance absorption of at least some forms of non-heme iron [39–41], others have found little or no effect [30,42], and alcoholic drinks often contain iron absorption inhibitors such as the polyphenols in wines [30]. In vitro studies suggest that chronic high alcohol intakes may increase serum ferritin concentration by increasing ferritin synthesis independently of iron levels [43], and evidence that serum ferritin concentration and GGT are both considerably elevated in alcoholics, and fall in parallel during a period of abstinence [44], are consistent with high alcohol consumption elevating serum ferritin concentration independently of iron status. However, the report by Leggett et al. [9] of an association between alcohol intake and serum ferritin concentration, even among men with normal serum concentrations of GGT, would require that alcohol has an effect on serum ferritin concentration either in the absence of liver damage, or in response to very low levels of damage. It is also interesting to note in this context that the present study has demonstrated a small but statistically significant 2% decrease in soluble transferrin receptor concentration per unit of alcohol suggesting that intracellular iron status may in fact be increased to a small degree by alcohol intake.

The results of this study showed no association between dietary variables, other than alcohol, and serum ferritin concentration, transferrin saturation and soluble transferrin receptor concentration. In contrast, Cade et al. [45] have reported a positive association between heme iron intake and serum ferritin concentration in the UK Women's Cohort Study of women aged 35 to 69 years. However subgroup analysis suggests that heme iron was positively associated with serum ferritin concentration only in postmenopausal C282Y homozygotes, and not in C282Y heterozygotes, wildtypes or premenopausal C282Y homozygotes. This subgroup analysis is in agreement with our finding of no association between heme iron intake and serum ferritin concentration in our C282Y heterozygote and wildtype participants. Fleming et al. [46] reported an association between heme iron intake and serum ferritin of a similar magnitude in the Framingham Heart Study population of men and women aged 67–93 years to that found by Cade et al. [45]. This may be explained at least partially by the presence of postmenopausal and male C282Y homozygotes in their cohort because participants were excluded on the basis of the presence of elevated iron indices rather than C282Y genotype.

A positive association between serum ferritin concentration and body mass index has been observed in a number of previous studies [10,46–48]. In the current study each unit increase in body mass index was associated with a 9% increase in serum ferritin concentration, after controlling for variables including age and alcohol intake. The positive relationship between body mass index and serum ferritin concentration may at least partially explain reports of increased risk of coronary heart disease amongst individuals with higher serum ferritin concentration [49] because obesity increases risk of coronary heart disease [50]. This effect may be mediated via increased central adiposity because waist circumference or waist-to-hip ratio are positively associated with both serum ferritin concentration [51] and risk of coronary heart disease [52].

Serum ferritin concentration is widely used clinically and in a research setting as a measure of iron stores, however because serum ferritin is an acute phase reactant influenced by many factors, including inflammation and infection, it is necessary to carry out quantitative phlebotomy to determine iron stores directly [53]. In the present study, a considerable proportion of the variability in serum ferritin concentration was explained by variables with a biologically plausible association with iron status, in particular the negative associations with blood loss, suggesting that in this population serum ferritin concentration was a useful qualitative, if not quantitative, measure of iron stores. However, Hallberg et al. [54] argue, on the basis of iron absorption studies, that once iron stores reach a level reflected by a serum ferritin concentration of approximately 60ug/L, iron absorption decreases so that it is sufficient to cover basal losses only. If this were the case, then serum ferritin concentrations greater than 60ug/L would not be a reflection of increased iron stores. Although it seems unlikely that the 32% of participants in the present study who had a serum ferritin concentration greater than 60ug/L had serum ferritin concentrations artificially elevated by liver disease, infection, inflammatory conditions, renal failure, cardiovascular disease or high alcohol consumption [53], we investigated whether excluding these participants altered our results. When we excluded participants with a serum ferritin concentration greater than 60ug/L (and 15 controls who were matched with excluded cases), the ratios for the Genotype model were attenuated because of the smaller number of participants (n=73, 57% of full sample), but the positive association with BMI, and negative association with blood donation, remained. Similarly, the Lifestyle model continued to report positive associations between serum ferritin concentration and BMI, and negative associations with recent blood donation, and marginally statistically significant negative associations with past blood donation and self-reported fecal blood loss. Interestingly, the association with alcohol intake was no longer significant. This could be because the sample size was too small for so many predictor variables, or because this variable is associated with an artificially elevated serum ferritin concentration, i.e. one above 60ug/L, rather than with iron stores.

Interestingly, a significant (p=0.004) thirteen-fold higher proportion of heterozygotes had a level of aspirin use that may be associated with lower serum ferritin concentrations [33]. This excess of high aspirin users amongst the heterozygotes did not explain the lack of association between heterozygosity and serum ferritin concentration, however, in future studies it would be interesting to see whether this finding is repeated, and whether C282Y heterozygosity is associated with more inflammation or illness.

In conclusion, in this population of UK men aged 40 years and over, C282Y heterozygosity was associated with slightly higher transferrin saturation but there was no evidence of higher levels of total body iron as assessed by serum ferritin or soluble transferrin receptor concentration. Blood loss, in particular due to blood donation and self-reported fecal blood loss, was a stronger predictor of all three iron indices than either the measured dietary variables or C282Y heterozygosity.

This study was funded by the Food Standards Agency UK, (project number NO5022), the Biotechnology and Biological Sciences Research Council, and an Overseas Postdoctoral Fellowship from the Health Research Council of New Zealand (ALMH).

The authors would like to thank the volunteers for participating in the study. They would also like to thank Catherine Macrow (Institute of Food Research, UK) for assistance with participant recruitment, and Aliceon Blair, Linda Oram and Lesley Maloney (Human Nutrition Unit, Institute of Food Research, UK) for clinical assistance.

Received July 27, 2006. Accepted December 21, 2006.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS REFERENCES

 

1. The UK Haemochromatosis Consortium: A simple genetic test identifies 90% of UK patients with haemochromatosis.Gut41 :841 –844,1997 .[Abstract/Free Full Text]
2. Roest M, van der Schouw Y, de Valk B, Marx J, Tempelman M, de Groot P, Sixma J, Banga J: Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women.Circulation100 :1268 –1273,1999 .[Abstract/Free Full Text]
3. van der A D, Peeters P, Grobbee D, Roest M, Marx J, Voorbij H, van der Schouw Y: HFE mutations and risk of coronary heart disease in middle-aged women.European J Clin Invest36 :682 –690,2006 .[Medline]
4. Jackson H, Carter K, Darke C, Guttridge M, Ravine D, Hutton R, Napier J, Worwood M: HFE mutations, iron deficiency and overload in 10 500 blood donors.Br J Haematol114 :474 –484,2001 .[Medline]
5. Distante S, Berg J, Lande K, Haug E, Bell H: High prevalence of the hemochromatosis-associated Cys282Tyr HFE gene mutation in a healthy Norwegian population in the city of Oslo, and its phenotypic expression.Scand J Gastroenterol34 :529 –534,1999 .[Medline]
6. Rossi E, Bulsara M, Olynyk J, Cullen D, Summerville L, Powell L: Effect of hemochromatosis genotype and lifestyle factors on iron and red cell indices in a community population.Clin Chem47 :202 –208,2001 .[Abstract/Free Full Text]
7. Boulton F, Collis D, Inskip H, Paes H, Garlick M: A study of the iron and HFE status of blood donors, including a group who failed the initial screen for anaemia.Br J Haematol108 :434 –439,2000 .[Medline]
8. Brussaard J, Brants H, Bouman M, Löwick M: Iron intake and iron status among adults in the Netherlands.Eur J Clin Nutr51 :S51 –S58,1997 .[Medline]
9. Leggett B, Brown N, Bryant S, Duplock L, Powell L, Halliday J: Factors affecting the concentrations of ferritin in serum in a healthy Australian population.Clin Chem36 :1350 –1355,1990 .[Abstract/Free Full Text]
10. Milman N, Ovesen L, Byg K-E, Graudal N: Iron status in Danes updated 1994. I: Prevalence of iron deficiency and iron overload in 1332 men aged 40–70 years. Influence of blood donation, alcohol intake, and iron supplementation.Ann Hematol78 :393 –400,1999 .[Medline]
11. Osler M, Milman N, Heitmann B: Dietary and non-dietary factors associated with iron status in a cohort of Danish adults followed for six years.Eur J Clin Nutr52 :459 –463,1998 .[Medline]
12. Roe M, Heath A-L, Oyston S, Macrow C, Hoogewerff J, Foxall R, Dainty J, Majsak-Newman G, Willis G, Fairweather-Tait S: Iron absorption in male C282Y heterozygotes.Am J Clin Nutr81 :814 –821,2005 .[Abstract/Free Full Text]
13. Willis G, Scott D, Jennings B, Smith K, Bukhari M, Wimperis J: HFE mutations in an inflammatory arthritis population.Rheumatology41 :176 –179,2002 .[Abstract/Free Full Text]
14. Baecke J, Burema J, Frijters J: A short questionnaire for the measurement of habitual physical activity in epidemiological studies.Am J Clin Nutr36 :936 –942,1982 .[Abstract/Free Full Text]
15. Heath A-L, Roe M, Oyston S, Fairweather-Tait S: Meal-based intake assessment tool: relative validity when determining dietary intake of Fe and Zn and selected absorption modifiers in UK men.Br J Nutr93 :403 –416,2005 .[Medline]
16. Holland B, Welch A, Unwin I, Buss D, Paul A, Southgate D: "McCance and Widdowson's The Composition of Foods," 5th rev exten ed. Cambridge: The Royal Society of Chemistry,1991 .
17. Chan W, Brown J, Buss D: "Miscellaneous Foods: Fourth Supplement to the 5th Edition of McCance and Widdowson's The Composition of Foods." Cambridge: The Royal Society of Chemistry,1994 .
18. Chan W, Brown J, Church S, Buss D: "Meat Products and Dishes: Sixth Supplement to the 5th Edition of McCance and Widdowson's The Composition of Foods." Cambridge: The Royal Society of Chemistry,1996 .
19. Chan W, Brown J, Lee S, Buss D: "Meat, Poultry and Game: Fifth Supplement to the 5th Edition of McCance and Widdowson's The Composition of Foods." Cambridge: The Royal Society of Chemistry,1995 .
20. Holland B, Brown J, Buss D: "Fish and Fish Products: Third Supplement to McCance and Widdowson's The Composition of Foods" 5th ed. Cambridge: The Royal Society of Chemistry,1993 .
21. Holland B, Unwin I, Buss D: "Cereals and Cereal Products: Third Supplement to McCance and Widdowson's The Composition of Foods," 4th ed. Nottingham: The Royal Society of Chemistry,1988 .
22. Holland B, Unwin I, Buss D: "Milk Products and Eggs: Fourth Supplement to McCance and Widdowson's The Composition of Foods," 4th ed. Cambridge: The Royal Society of Chemistry,1989 .
23. Holland B, Unwin I, Buss D: "Vegetables, Herbs and Spices: Fifth Supplement to McCance and Widdowson's The Composition of Foods," 4th ed. Cambridge: The Royal Society of Chemistry,1991 .
24. Holland B, Unwin I, Buss D: "Fruits and Nuts: First Supplement to McCance and Widdowson's The Composition of Foods," 5th ed. Cambridge: The Royal Society of Chemistry,1992 .
25. Holland B, Welch A, Buss D: "Vegetable Dishes: Second Supplement to McCance and Widdowson's The Composition of Foods," 5th ed. Cambridge: The Royal Society of Chemistry,1992 .
26. Hallberg L, Hulthén L: Prediction of dietary iron absorption: an algorithm for calculating absorption and bioavailability of dietary iron.Am J Clin Nutr71 :1147 –1160,2000 .[Abstract/Free Full Text]
27. Rangan A, Ho R, Blight G, Binns C: Haem iron content of Australian meats and fish.Food Aust49 :508 –511,1997 .
28. Bunch S, Murphy S: World Food Dietary Assessment System. Version 2.0. Food and Agriculture Organization of the United Nations (FAO). Internet: http://www.fao.org/infoods/software_worldfood_en.stm (accessed 4 November 2003).1996 .
29. Harland B, Oberleas D: Phytate in foods.World Rev Nutr Diet52 :235 –259,1987 .[Medline]
30. Cook J, Reddy M, Hurrell R: The effect of red and white wines on nonheme-iron absorption in humans.Am J Clin Nutr61 :800 –804,1995 .[Abstract/Free Full Text]
31. Hurrell R, Reddy M, Cook J: Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages.Br J Nutr81 :289 –295,1999 .[Medline]
32. Morck T, Lynch S, Cook J: Inhibition of food iron absorption by coffee.Am J Clin Nutr37 :416 –420,1983 .[Abstract/Free Full Text]
33. Fleming D, Jacques P, Massaro J, D'Agostino R, Wilson P, Wood R: Aspirin intake and the use of serum ferritin as a measure of iron status.Am J Clin Nutr74 :219 –226,2001 .[Abstract/Free Full Text]
34. Hunt J, Zeng H: Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis.Am J Clin Nutr80 :924 –931,2004 .[Abstract/Free Full Text]
35. Bacon B: Hemochromatosis: diagnosis and management.Gastroenterology120 :718 –725,2001 .[Medline]
36. Heath A-L, Skeaff C, Williams S, Gibson R: The role of blood loss and diet in the aetiology of mild iron deficiency in premenopausal adult New Zealand women.Public Health Nutr4 :197 –206,2001 .[Medline]
37. Jacques P, Sulsky S, Hartz S, Russell R: Moderate alcohol intake and nutritional status in nonalcoholic elderly subjects.Am J Clin Nutr50 :875 –883,1989 .[Abstract/Free Full Text]
38. Ballot D, MacPhail A, Bothwell T, Gillooly M, Mayet F: Fortification of curry powder with NaFe(111)EDTA in an iron-deficient population: initial survey of iron status.Am J Clin Nutr49 :156 –161,1989 .[Abstract/Free Full Text]
39. Charlton R, Jacobs P, Seftel H, Bothwell T: Effect of alcohol on iron absorption.Br Med J2 :1427 –1429,1964 .[Free Full Text]
40. Hallberg L, Rossander L: Effect of different drinks on the absorption of non-heme iron from composite meals.Hum Nutr Appl Nutr36A :116 –123,1982 .[Medline]
41. Sörensen E: Studies on iron absorption. V. The effect of ascorbic acid and ethyl alcohol on the absorption of iron in iron-deficient subjects.Acta Med Scand180 :241 –244,1966 .[Medline]
42. Celeda A, Rudolf H, Donath A: Effect of a single ingestion of alcohol on iron absorption.Am J Hematol5 :225 –237,1978 .[Medline]
43. Moirand R, Kerdavid F, Loréal O, Hubert N, Leroyer P, Brissot P, Lescoat G: Regulation of ferritin expression by alcohol in a human hepatoblastoma cell line and in rat hepatocyte cultures.J Hepatol23 :431 –439,1995 .[Medline]
44. Meyer T, Kassianides C, Bothwell T, Green A: Effects of heavy alcohol consumption on serum ferritin concentrations.S A Med J66 :573 –575,1984 .
45. Cade J, Moreton J, O'Hara B, Greenwood D, Moor J, Burley V, Kukalizch K, DT B, Worwood M: Diet and genetic factors associated with iron status in middle-aged women.Am J Clin Nutr82 :813 –820,2005 .[Abstract/Free Full Text]
46. Fleming D, Jacques P, Dallal G, Tucker K, Wilson P, Wood R: Dietary determinants of iron stores in a free-living elderly population: The Framingham Heart Study.Am J Clin Nutr67 :722 –733,1998 .[Abstract]
47. Iribarren C, Sempos C, Eckfeldt J, Folsom A: Lack of association between ferritin level and measures of LDL oxidation: The ARIC Study.Atherosclerosis139 :189 –195,1998 .[Medline]
48. Oshaug A, Bugge K, Bjønnes C, Borch-Iohnsen B, Neslein I-L: Associations between serum ferritin and cardiovascular risk factors in healthy young men. A cross-sectional study.Eur J Clin Nutr49 :430 –438,1995 .[Medline]
49. Heath A-L, Fairweather-Tait S: Health implications of iron overload: The role of diet and genotype.Nutr Rev61 :45 –62,2003 .[Medline]
50. Pi-Sunyer F: The obesity epidemic: pathophysiology and consequences of obesity.Obes Res10 :97S –104S,2002 .[Medline]
51. Williams M, Poulton R, Williams S: Relationship of serum ferritin with cardiovascular risk factors and inflammation in young men and women.Atherosclerosis165 :179 –184,2002 .[Medline]
52. Lakka H-M, Lakka T, Tuomilehto J, Salonen J: Abdominal obesity is associated with increased risk of acute coronary events in men.Eur Heart J23 :706 –713,2002 .[Abstract/Free Full Text]
53. Hallberg L, Hulthén L: High serum ferritin is not identical to high iron stores [letter].Am J Clin Nutr78 :1225 –1226,2003 .[Free Full Text]
54. Hallberg L, Hultén L, Gramatkovski E: Iron absorption from the whole diet in men: how effective is the regulation of iron absorption?Am J Clin Nutr66 :347 –356,1997 .[Abstract/Free Full Text]

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