Relevance of dietary iron intake and bioavailability in the ...

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10 of 12 MORETTI ET ALFIGURE 1. IQRs (lines) and medians (dots) of serum ferritin, hepcidin,and estimated iron bioavailability in HH patients with high or normal ferritinvalues compared with those of their WT counterparts. The estimated ironbioavailability was based on the extrapolation of hepcidin concentrations inHH patients as published by van Dijk et al (20) with the following regressionformula: iron absorption (%) = 23.9656 ln[hepcidin (nmol/L)] + 13.238(26), relating hepcidin concentrations with iron bioavailability in healthysubjects. HH, hereditary hemochromatosis; WT, wild-type.iron) can affect the iron absorption and balance in HH patients.In addition, the modulation of the amount of dietary iron intake(36) or iron bioavailability (34) may decrease the rate of ironaccumulation in patients with HH. It has also been shown thatthe presence of a food matrix per se (31) influences iron bioavailabilityin HH patients. The factors that would elicit an effecton iron bioavailability are similar to enhancers and inhibitors ofiron absorption for non-HH subjects (58). The prospective,longitudinal studies discussed in this review also suggested aneffect by dietary modulation on iron balance in HH patients (34,36). However, the overall (nonsignificant) effect reported in thestudy that investigated the effect of tea on long-term body ironstatus may have been a result of other dietary and lifestylefactors associated with frequent tea drinking because subjectswere not randomly assigned to treatment. Furthermore, the latterstudy had a small sample size (n = 19) (34). Although the resultsseen may not have been solely because of tea drinking, theeffect size suggested a decrease in absorbed iron over thecourse of 1 y of w400 mg, one-third in iron accumulation (34),and would correspond to a yearly decrease in phlebotomy needof 0.7 L blood.Despite this suggestive evidence, limited direct evidence wasshown to support the hypothesis that dietary modulation caninfluence iron accumulation in HH patients in a clinically relevantmanner. This was a result of several important limitations.First, the evidence from cross-sectional studies was difficult tointerpret because of the potential confounding effect of chronicsubclinical inflammation (ie, diabetes, the metabolic syndrome,and cardiovascular disease), which influences iron-statusmarkers, which was likely to confound the relation betweendietary iron intake and iron status. In one of the cross-sectionalstudies (42), low fruit intake was associated with higher risk ofhaving an iron-overload phenotype in first-degree relatives of HHpatients. This result was somewhat surprising because an oppositeeffect may be expected because of the vitamin C content offruit. However, it is possible that fruit intake was a proxy for thedietary quality and a healthier lifestyle. This limitation may alsoapply to studies that investigate the bioavailability of iron inrelation with SF, in which SF may not always reflect iron storesin the presence of subclinical inflammation.A second limitation was that fully penetrant HH is a raredisease, which makes it difficult to conduct large prospectivestudies with iron status as the primary outcome. Therefore,studies have thus far been mostly conducted in small groups ofsubjects (n = 16–18), which has limited the statistical powerof inference (59, 60). New approaches to study design such asthe use of population pharmacokinetics to describe changes iniron status in longitudinal studies may allow studies to beconducted with smaller populations of HH patients and moreclosely describe the development of iron status over time followingspecific dietary or lifestyle patterns (61). With the use ofthe quantity of iron removed by a phlebotomy as an outcomemeasure may be promising because it would be less affected byshort-term changes in iron-status markers because of subclinicalinflammation.Third, as noted by Tao et al (55), the calculation of the SF toiron bioavailability regression equation assumes that all subjectswith clinically penetrant HH have a similar impairment of ironabsorption regulation, which may not be the case (51) becausea small proportion of homozygotes develop iron overload, andiron stores may plateau before reaching the critical level (52). Arange of genetic and environmental factors, including dietaryfactors (15), may influence iron intake and bodily iron distributionand, thus, may influence disease penetrance. The predictionof the bioavailability in HH patients by using the serumhepcidin concentration may provide indications about the rate ofiron loading in individual subjects at any given time but wouldrequire reference data that link the hepcidin concentration to ironbioavailability in clinically confirmed HH subjects. Studies thatexplicitly link genetic mutations and environmental and epigeneticfactors to iron bioavailability in clinically confirmed HHsubjects may provide additional leads.Fourth, in only one of the studies that directly assessed ironbioavailability, the HFE genotype was assessed. The remainingstudies in idiopathic HH patients, although conducted in clinicallyconfirmed HH patients, may not have been entirely representativeof the population of HFE-related HH patients andbecause isotopic studies have typically been conducted in a limitednumber of subjects. However, the likelihood of including
DIETARY IRON AND HFE HEMOCHROMATOSIS 11 of 12a subject with a rare genotype other than homozygosity for the p.Cys282Tyr mutation in the HFE gene or in other HH-relatedgenes is low because of the high prevalence of p.Cys282Tyrhomozygosity in clinically affected HH patients (25).In HH patients with low to normal iron status who consumea typical Western diet that contains 16–18 mg/d Fe (62), a dietaryiron absorption of 20–40% for heme and nonheme iron combinedas shown in the studied literature would imply a long-termpositive iron balance of w3–7 mg/d. It is very unlikely that sucha positive balance could be reduced to zero with an exclusivedietary intervention. However, a dietary modulation may bea useful accessory measure to reduce the rapid reaccumulationof iron in clinically diagnosed HH patients who are undergoinga phlebotomy, especially in the maintenance phase. Depletionthrough a phlebotomy of HH patients until a very low SF concentration(50 mg/L) is reached (63) will upregulate the ironabsorption in HH patients. Therefore, the inhibition or reductionof absorbed iron by dietary modulation could help to avoidexacerbating the excess release of iron into the circulation,which results in a vicious circle of more-frequent maintenancephlebotomies in HH patients (20, 64)In conclusion, dietary modification may provide an auxiliarymeasure to inhibit iron accumulation and reduce the number ofrequired phlebotomies in clinically confirmed HH patients. Thisresult could increase the patient’s active involvement in treatmentand, as such, may be beneficial for prospective diseaseoutcomes (65). However, additional longitudinal research wouldbe required to formulate and test an effective dietary strategy forthis patient group and quantify the clinical benefit in the numberof phlebotomies avoided as well as patient wellbeing. Sucha dietary strategy would comprise lowering dietary iron intakeand reducing iron bioavailability while maintaining adequateintakes of other essential nutrients that are typically consumed aspart of an iron-rich diet (ie, zinc, vitamin C, and vitamin B-12).We thank Hans Verhoef, Cell Biology and Immunology, Wageningen University,Netherlands, for in-depth advice and Irene Gosselink, Science Shop,Wageningen University, Netherlands, for logistical support. We are grateful tothe Dutch Hemochromatosis Society (Nederlandse Hemochromatose Vereiniging)for the interest in dietary factors that affect patients with HH.The authors’ responsibilities were as follows—GMvD, DM, and AM-B:conducted the literature research; DM: wrote the first draft of the manuscript;GMvD, AM-B, and DWS: edited the manuscript; DM and AM-B: hadprimary responsibility for the final content of the manuscript; and all authors:designed the study and read and approved the final manuscript. 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