Nutritope

Nutrition Specialists

In an ad libitum eating test, Sysko, Walsh, Schebendach & Wilson (2005) found that AN patients improved caloric intake after weight restoration, but were still significantly restricting compared to healthy control subjects. Many weight-restored AN patients continue to struggle with urges to restrict, dramatically raising the risk of relapse. Adding a nutritionist to the treatment team helps to address these issues.

Nutritionists who specialize in ED typically work with food diaries to obtain a realistic assessment of the patient's caloric intake. To avoid redundancy, clinicians also utilizing food journals as part of their cognitive behavioral therapy (CBT) approach should coordinate this procedure with the nutritionist. The nutritionist is often a key figure in the patient's psychological life as well, and many develop a sophisticated understanding of the dynamics of these illnesses. This creates a fruitful area for therapists and nutritionists to share and enhance their mutual clinical understanding of the patient, especially if they maintain frequent contact.

Michele was a highly motivated 18-year-old college student with AN who reached a healthy and stable weight range during her residential treatment. She connected with an experienced nutritionist at home prior to returning to school in the Northeast. Once back in school, she sought intensive, twice weekly psychotherapy. From the beginning, Michele expressed her desire to maintain telephone contact with the nutritionist from home. As this seemed important to her, I agreed, although it is generally easier to utilize the local resources for nutrition therapy.

After a number of months, the patient observed that the messages from both of us were highly consistent; we were essentially "saying the same things, but in a different language." This is of particular interest, as we had rather different (although not conflicting) philosophies. My approach was primarily dynamic and interpersonal, while the nutritionist emphasized spiritual recovery and motivational factors. It is quite possible, however, that these differences in therapeutic philosophy were superficial, and that the nutritionist's discourse incorporated both dynamic and interpersonal factors, while mine also emphasized motivational and spiritual factors. The gender dynamics of male therapist/female nutritionist may also have been beneficial. Michele actually commented that although the messages were essentially the same, they were being expressed alternatively in a "male" and "female" voice. There is little question that the regular and focused communications between the two professionals ensured that we remained on the same page and greatly enhanced the patient's perception of consistency.

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TMPRSS6

Related terms:

Iron Overload

Iron-Deficiency Anemia

Hepcidin

Bone Morphogenetic Protein

Hemojuvelin

Mothers against Decapentaplegic

Nested Gene

Matriptase

Mutation

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Disorders of Iron Metabolism: Iron Deficiency and Iron Overload and Anemia of Chronic Diseases

S. Rivella, B.J. Crielaard, in Pathobiology of Human Disease, 2014

Iron Overload: Primary Hemochromatosis

The TMPRSS6 gene is a negative modulator of hepcidin expression in the liver. In fact, mutations in the TMPRSS6 gene in humans and mice are associated with a condition named IRIDA, for iron-refractory iron-deficiency anemia, characterized by high levels of hepcidin. Mutations in TMPRSS6 increased hepcidin levels in mice affected by HFE-related hemochromatosis. However, in this case, augmented hepcidin expression was associated with beneficial effects on organ iron content. These findings led to the development of pharmacological methods to target TMPRSS6 in the liver of animals affected by hemochromatosis to increase hepcidin expression. Two alternative approaches, utilizing, respectively, siRNA formulated in lipid nanoparticles and antisense oligonucleotides, reduced expression of TMPRSS6 in the liver and increased expression of hepcidin in mice affected by hemochromatosis. Both the treatments led to amelioration of iron overload. In mice affected by HAMP- and HFE-related hemochromatosis, administration of minihepcidins, small drug-like hepcidin agonists, has also showed beneficial effects on iron overload.

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Proteases in Health and Disease

Toni M. Antalis, ... Qingyu Wu, in Progress in Molecular Biology and Translational Science, 2011

2 Matriptase-2

Matriptase-2, also called TMPRSS6, was independently cloned from liver tissues by two groups in 2002 and 2003 and shown to express a membrane serine protease with homology to matriptase that displayed proteolytic activity toward various macromolecular substrates.37,195 Matriptase-2 is encoded by the TMPRSS6 gene located on human chromosome 22q12.3. Matriptase-2 is approximately 90-kDa cell surface glycoprotein with a modular structure (Fig. 1) and is synthesized as an inactive, single-chain zymogen. Cell surface matriptase-2 is efficiently shed into the conditioned medium of transfected cells in an active two-chain form by proteolytic cleavage within the second CUB domain of the noncatalytic stem region.196 Whereas matriptase is expressed in a large number of embryonic and adult epithelia, matriptase-2 expression is largely confined to adult and fetal liver in humans and mice, with minor expression in the kidney, uterus, and nasal cavity.37,195

A breakthrough in the understanding of the physiological function of matriptase-2 was enabled by the generation of matriptase-2 knockout mice and by the identification of loss of function mutations in the TMPRSS6 gene as a cause of the human autosomal recessive disorder, iron-refractory iron deficiency anemia (IRIDA). Both mice and humans with matriptase-2 deficiency suffer from very low iron levels and severe microcytic anemia.197–199 Matriptase-2 expressed by liver cells functions as a suppressor of the hepatic hormone, hepcidin, which in turn internalizes the iron export protein, ferroportin, on enterocytes and macrophages to reduce iron uptake. Thus, matriptase-2 is a key regulator of systemic iron hemostasis. Hepcidin suppression by matriptase-2 appears to occur at the transcriptional level, as hepcidin mRNA levels are elevated in both matriptase-2-deficient humans and mice.197–199 This suppression of hepcidin gene transcription has been linked to matriptase-2-mediated degradation of hemojuvelin, a cofactor for bone morphogenetic protein, and a key regulator of hepcidin gene activation.200,201

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Matriptase-2

Andrew J. Ramsay, ... Gloria Velasco, in Handbook of Proteolytic Enzymes (Third Edition), 2013

Conclusions and Perspectives

The TTSP matriptase-2 (also known as TMPRSS6), has rapidly become acknowledged as an integral member of the mammalian iron homeostasis axis. As iron is not efficiently excreted in mammals, body iron stores are constrained within narrow limits via the regulation of dietary iron absorption and recycling by the hepatic peptide hormone, hepcidin. Hepcidin itself is under the control of numerous stimuli associated with iron homeostasis, including the recently described transcriptional suppression by matriptase-2. Unraveling the role played by matriptase-2 in iron physiology was an important milestone in hematological research. Not only has it provided new insights on hepcidin regulation, it has also provided information on the etiology of a significant but previously poorly characterized genetic disease (IRIDA). Indeed, modulation of matriptase-2 may be a feasible approach for the treatment of iron overload disorders and some forms of anemia.

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Iron Metabolism: Hepcidin

Laura Silvestri, ... Alessia Pagani, in Vitamins and Hormones, 2019

6.1 BMP-SMAD pathway activators

Promising results have been obtained by targeting the hepcidin inhibitor TMPRSS6 (matriptase-2) through antisense oligonucleotides (ASO) (Guo et al., 2013) or small interfering RNAs (siRNAs) (Schmidt et al., 2013). Although inactivation of TMPRSS6 to increase hepcidin expression in hemochromatosis is a promising approach only for HFE and TFR2 forms, it could also be a therapeutic opportunity for the more common thalassemia, in which iron overload occurs through erythropoiesis-mediated chronic hepcidin inhibition (Table 2). In this case, inducing iron restriction through hepcidin upregulation may ameliorate also anemia as demonstrated in preclinical studies (Guo et al., 2013; Nai et al., 2012; Schmidt et al., 2013).

Table 2. Pharmacologic targeting of the BMP-SMAD pathway for hepcidin regulation in preclinical models.

DrugTargetEffect on hepcidinDiseaseASO-Tmprss6TMPRSS6↑HH, beta thalassemiasiRNA-Tmprss6TMPRSS6↑HH, beta thalassemiaRAPA, FK506FKBP12 (ALK2)↑HH, beta thalassemiaLDN193189BMPRI↓IRIDA, AISoluble HJVBMP-SMAD pathway↓IRIDA, AIHeparinsBMP-SMAD pathway↓IRIDA, AIMomelotinibALK2↓IRIDA, AI

RAPA = rapamycin; FK506 = tacrolimus; AI, anemia of inflammation; BMPRI, BMP type I receptors; HH, hereditary hemochromatosis; IRIDA, iron refractory iron deficiency anemia.

Iron overload due to low hepcidin may be corrected also by targeting FKBP12 that allows an increase of BMP pathway through ALK2 activation (Colucci et al., 2017). This approach, if proven to be effective in HH and thalassemia mouse models, can be easily translated in clinics since FDA-approved drugs that sequester FKBP12 are already available, as FK506 and RAPA (Table 2). This drug repurposing approach has been successfully proposed for Pulmonary Arterial Hypertension, a disease due to BMPR2 mutations in which FKBP12 sequestration by FK506 efficiently ameliorates the phenotype in preclinical models (Spiekerkoetter et al., 2015, 2017, 2013). In this case, hepatocytes selective targeting is mandatory to avoid toxic effects due to the ubiquitous body distribution of FKBP12.

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Iron Metabolism in Aging

Laura Silvestri, in Molecular Basis of Nutrition and Aging, 2016

Hepcidin Regulation by Iron

Iron activates hepcidin with different mechanisms: (i) increased liver iron transcriptionally activates BMP6 [22]; (ii) increased iron bound to TF stabilizes TFR2 on the cell surface [23]; and (iii) binding of iron loaded TF to its receptor TFR1 displaces it from the binding to HFE that likely becomes able to interact with TFR2 and activates hepcidin [18].

The sole hepcidin inhibitor whose role has been clearly demonstrated in vivo is TMPRSS6, encoding matriptase-2, a type II transmembrane serine protease expressed exclusively in the liver. Genetic inactivation of TMPRSS6 in humans [24] and mice [25,26] causes IRIDA, a rare genetic disorder characterized by iron deficiency anemia due to high hepcidin levels. It was demonstrated that TMPRSS6 downregulates hepcidin by cleaving HJV [27–30] (Fig. 37.3). Although the formal proof on the role of TMPRSS6 in HJV cleavage in vivo is still lacking, inactivation of Hjv [31] and Bmp6 [32] in Tmprss6 KO mice reverts the IRIDA phenotype, indicating that Tmprss6 is functionally upstream of Hjv and Bmp6 and negatively modulates the BMP-SMAD pathway, in accordance with HJV being the physiologic TMPRSS6 substrate.

TMPRSS6 is supposed to be active in iron deficiency, since inactivation of the protease causes the inability to downregulate hepcidin even if the patients are severely ID, and inactive in iron overload (Fig. 37.3). However, genetic inactivation of the protease in the hemochromatosis Hfe [33] and Tfr2 [34] KO animals reverts the iron overload phenotype because of low hepcidin levels, suggesting a function role of Tmprss6 even in iron overload. Hypoxia responsive elements have been identified in the TMPRSS6 promoter region and in vitro chemical hypoxia transcriptionally activates TMPRSS6 [35,36]. However, in vivo this transcriptional regulation seems not to be relevant [37], suggesting that TMPRSS6 is regulated mainly with posttranslational mechanisms. Indeed acute iron deficiency stabilizes Tmprss6 in rats [38] through a mechanism than reduces the iron-mediated decrease of the protease [39].

Hepcidin is efficiently suppressed in iron deficiency through several mechanisms: (i) BMP6 downregulation [39]; (ii) destabilization of the HFE-TFR2 complex [18]; (iii) increased stability of TMPRSS6 [38]; and (iv) increased EPO-mediated erythropoiesis [40] (Fig. 37.3).

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Iron-Deficiency Anemia

Philip Lanzkowsky, in Lanzkowsky's Manual of Pediatric Hematology and Oncology (Sixth Edition), 2016

Iron-Refractory Iron-Deficiency Anemia

This is a rare autosomal recessive disorder (OMIM number 206200). Iron-deficiency anemia is defined as "refractory" when there is absence of hematologic response (an increase of <1 g/dl, of hemoglobin) after 4–6 weeks of treatment with oral iron. Iron-refractory iron-deficiency anemia (IRIDA) is caused by a mutation of TMPRSS6, the gene encoding transmembrane protease, serine 6, also known as matriptase-2, which inhibits the signaling pathway which activates hepcidin. This type of anemia is variable, more severe in children, and unresponsive to treatment with oral iron. It is characterized by striking microcytosis, extremely low transferrin saturation, normal or borderline-low ferritin levels, and high hepcidin levels. The diagnosis is confirmed by sequencing of TMPRSS6. IRIDA occurs in less than 1% of cases of iron-deficiency anemia seen in medical practice. Most cases of iron resistance are due to disorders in the GI tract (see Table 6.1).

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Erythropoietin

Ilona Rybinska, Gaetano Cairo, in Vitamins and Hormones, 2017

3.1 Hepcidin Regulation by Iron Availability

Increased iron levels activate the bone morphogenic proteins 6 (BMP6)–BMPR–SMAD1/5/8 transduction pathway which triggers hepcidin transcription. At the molecular level, in response to increased liver iron stores, BMP6, predominantly produced by liver nonparenchymal cells, binds to the coreceptor hemojuvelin and BMP type I and type II receptors (BMPR) to induce phosphorylation of SMAD1/5/8 proteins, which form heterodimers with SMAD4 and reach the nucleus to bind the hepcidin promoter (reviewed by Core, Canali, & Babitt, 2014; Ganz & Nemeth, 2012; Gozzelino & Arosio, 2016; Zhao, Zhang, & Enns, 2013). High levels of serum iron activate SMAD1/5/8 phosphorylation downstream or independent of BMP6. BMP6-dependent activation of hepcidin transcription is modulated by a complex comprising HJV, a BMP coreceptor, human hemochromatosis protein (HFE), and transferrin receptor 2 (TfR2), three proteins which are mutated in patients with distinct types of hemochromatosis (Zhang, West, Wyman, Bjorkman, & Enns, 2005). Conversely, in response to iron deficiency, hepcidin is controlled in a negative way by matriptase-2 (TMPRSS6), a hepatocyte serine protease which cleaves HJV from the plasma membrane. In vitro studies have shown that TMPRSS6 determines the levels of membrane-bound HJV (m-HJV) by cleaving the protein into an inactive soluble fragment (s-HJV) which is released and acts as a decoy molecule for BMPs, thus inhibiting hepcidin (Du et al., 2008; Folgueras et al., 2008; Silvestri, Pagani, Nai, et al., 2008). The role of TMPRSS6 was shown by studies demonstrating that its inactivation in mice leads to hepcidin increase, block of iron absorption, and anemia (Core et al., 2014; Ganz & Nemeth, 2012; Gozzelino & Arosio, 2016; Zhao et al., 2013). Moreover, a rare form of anemia (refractory iron deficiency anemia, IRIDA) can be caused by mutations in the gene encoding TMPRSS6/matriptase-2 (De Falco et al., 2013).

Furin (Silvestri, Pagani, & Camaschella, 2008) and neogenin, an HJV-interacting protein which assists in the proper assembly of BMPs/BMPR complexes (Lee et al., 2010), are other factors coexpressed in hepatocytes which influence hepcidin regulation (Zhao et al., 2013). HJV complexed with neogenin is much more susceptible for cleavage by the proprotein convertase furin, and the cleaved HJV is rapidly released from cells. This action of furin is enhanced in iron deficiency and hypoxia and results in generation of s-HJV, which antagonizes BMP-dependent activation of hepcidin (Silvestri, Pagani, Nai, et al., 2008). Since furin participates also in processing of prohepcidin into the mature protein (Valore & Ganz, 2008), the effect of furin on hepcidin expression may be complex, resulting in activation or inhibition depending on the conditions (Poli et al., 2010). The precise molecular mechanisms underlying the interaction of these pathways and proteins remain incompletely understood. Since the detailed discussion of the control of hepcidin transcription is outside the scope of this chapter, readers are referred to recent reviews (Core et al., 2014; Ganz & Nemeth, 2012; Gozzelino & Arosio, 2016; Zhao et al., 2013).

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Iron deficiency anemia, anemia of chronic disorders and iron overload

MJ Pippard, in Blood and Bone Marrow Pathology (Second Edition), 2011

Role of hepcidin

In 2001 it was reported that expression of hepcidin was increased in iron loaded mice,54 and that mice in which HAMP, coding for hepcidin, had been knocked out developed hepatic but not macrophage iron overload.55 This pattern of disturbed iron metabolism in hepcidin deficient mice mirrors that seen in human hemochromatosis56 and it became clear that the various types of hemochromatosis (see Table 11.3, below) are associated with inappropriately low production of hepcidin except in rare cases with a ferroportin mutation that prevents a response to hepcidin. Conversely, hepcidin over-expression in mice led to iron deficiency,57 including in mice with inactivation of TMPRSS6 (coding for matriptase-2, a liver transmembrane serine protease).58,59 A human inherited iron-refractory iron deficiency anemia (IRIDA) was then shown to be associated with over-expression of hepcidin resulting from recessive inheritance of inactivating mutations of TMPRSS6.60,61

It is now clear that hepcidin is the major physiological regulator of iron absorption and internal iron exchange (Fig. 11.5), and that inappropriate hepcidin production underlies much iron pathophysiology.11 Hepcidin binds to ferroportin at the 'donor' cell surface and promotes the transporter's internalization followed by ubiquitin-mediated lysosomal degradation.62,63,64 Hepcidin-induced degradation of ferroportin prevents iron release to circulating plasma transferrin and leads to reduced iron absorption, a block on the release of iron derived from senescent red cells within macrophages, and reduced serum iron concentration. It is therefore a negative regulator of iron release from cells. Hepcidin is excreted rapidly into the urine consistent with its regulation at the level of production. Decreased hepcidin production is seen with hypoxia65 and in association with ineffective erythropoiesis,66 as well as in iron deficiency. Conversely increased hepcidin production, occurs with inflammation65 as well as with increased iron stores.

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How Nutrients are Affected by Genetics

Martin Kohlmeier, in Nutrigenetics, 2013

4.8.1.4 Abnormal Iron Retention

Healthy, iron-replete individuals usually absorb about 1 mg of iron from a varied diet. Some individuals tend to absorb much more of the available iron in foods, largely due to a genetic predisposition. The extra iron tends to accumulate slowly, eventually causing harm. Hemochromatosis is an inherited condition with a greatly relaxed control of iron excess and an increased tendency to retain excess iron in storage. By definition, more than 45% of the iron-binding capacity of their circulating transferrin is saturated, which is much more than the 25% to 30% in people without the condition. Their blood concentration of free iron (not bound to transferrin) is increased above average by several orders of magnitude.

Genetic variants of HAMP, HFE, HJV, and TFR2 all diminish hepcidin release and thereby increase iron absorption from the intestine and promote its storage in liver and other tissues. Such proabsorption variants probably represent adaptions to nutritopes with low iron availability because they shift the balance toward retaining more iron and safeguarding less against iron overload. This should be expected in light of the great risks of maternal iron deficiency for the fetus. The HFE gene, in particular, has common variants that promote iron absorption and retention. One of them has a tyrosine instead of the regular cysteine in position 282 (Cys282Tyr; rs1800562). This variant goes back to a mutation about 6000 years ago in an early ancestor of the Celtic population [154]. His63Asp (rs1799945) is a second iron-retaining variant, which probably arose several thousand years ago in today's Basque region in the north of Spain. A third one is Ser65Cys (rs1800730). These variants promote less iron retention than the allele encoding HFE 282Tyr and have much lower penetrance in terms of clinically relevant hemochromatosis.

Ferroportin disease is a more recently discovered condition, which also confers a tendency for iron accumulation. It is caused by variants in the HAMP gene (encoding hepcidin) that alter ferroportin responsiveness to hepcidin-mediated inactivation. The defining characteristic is iron overload in liver and macrophages as reflected by the ferritin concentrations, which tend to be massively in excess of 300 μg/L [155]. Transferrin saturation is increased in some patients but not in others, probably depending on the nature of the gene variant. Figure 4.26 summarizes average ferritin concentrations in patients with the same variant. The size of the dots corresponds to the number of reported patients with the same variant. As can be seen, the most common variants occur in a cluster between amino acids 64 and 181 and a few more at the tail end of the protein. Basically, all of these variants are associated with a significant loss of function, almost regardless of the position in the protein sequence where the change occurs. Lists of average observed effects for each known variant will eventually help with the prediction of clinical outcomes based on whole-genome information.



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FIGURE 4.26. Several variants have been linked to ferroportin disease. Shown here is the median ferritin concentration for people with variants at the indicated amino acid positions in the mature ferroportin protein [155]. All of them are significantly over the upper ferritin reference limit of 300 μg/L for men (dashed line). The area of each spot corresponds to the number of observed cases.

We still have to ask about the biological relevance of polymorphisms that promote iron retention. As we have seen in Chapter 1, hemochromatosis is not a harmless condition. The main dangers are inflammation, cirrhosis, and eventually cancer of the liver, heart disease, cognitive decline, and increased vulnerability to some bacterial infectious agents. The occasional episodes of infections in people with hemochromatosis are often unexpected and sometimes even bizarre. One such case was the tragic death of a prominent microbiologist from the plague [156]. Another unusual case was that of an elderly woman with severe hemochromatosis who suffered a life-threatening infection with Listeria monocytogenes after eating cheese [157]. Common ferroportin variants also undermine resistance to tuberculosis [158].

Two copies of the HFE 282Tyr variant, a combination of HFE 282Tyr and 63Asp variants (compound heterozygotes), the aforementioned single copies of ferroportin variants, and a few less common HAMP, HJV, and TFR2 variants lead to the progressive accumulation of iron in the liver and other tissues and a high risk of the eventual development of hemochromatosis. Homozygous carriers of the HFE 282Tyr allele constitute the majority of individuals with hemochromatosis symptoms [159]. Their risk of developing hemochromatosis is more than 4000 times higher than the risk of people with the common HFE sequence. Iron accumulation is usually slowed in women while they lose blood regularly during menstruation. Even among men, fewer than half of all HFE 282Tyr homozygotes will develop clinically relevant disease. This means that the penetrance of the homozygous HFE 282Tyr genotype is less than 50%. Only a small number of them will die from hemochromatosis, but the risk is still significant and explains the need for interventions. Large population studies indicate that hemochromatosis increases risk of premature death by 30–50% and accounts for nearly 1% of mortality for the entire population [160].

Another type of risk is a slowed wound healing and increased surgical complication rate. One large case series found that patients with two or more copies of HFE variants suffered more complications after open or laparoscopic Roux-en-Y gastric bypass surgery and had a greater length of stay in hospital [161].

A single copy of the HFE 282Tyr, 63Asp, or 65Cys alleles (carried by 20–30% of many populations) will increase ferritin concentration slightly in men [162], particularly in conjunction with alcohol abuse [163] or high iron intake.

A few common variants appear to be related to the risk of iron deficiency in normal populations. There is quite clear evidence that rs3811647 is related to differences in transferrin concentration, though without affecting body iron status. More important is the fact that the common hemochromatosis risk allele HFE rs1800562 A (HFE 282Tyr) provides significant protection against iron deficiency at the same level of iron intake [164]. Two exonic variants in TMPRSS6, rs4820268 and rs855791, however, do seem to be important. In one study, they were related to lower hemoglobin concentration and smaller red blood cell volume, indicators of lower iron availability [165].

Hemochromatosis Interventions

The goal is to maintain adequate but not excessive iron stores. Assessment is most practical by monitoring ferritin concentration in blood, with the aim of keeping it in the midrange. Anybody with one of the known variants causing iron retention or excessive ferritin concentration, or with high transferrin saturation should be considered at risk. Typically, 15–30% of the general public is at moderate risk and slightly less than 1% is at high risk.

The most effective course of action for people with existing hemochromatosis or a high risk of developing hemochromatosis is bloodletting with proper medical supervision. This is initially done at frequent (e.g., weekly) intervals and then less often. Donating blood several times a year is helpful for many people, particularly those with one or more of the iron-retaining HFE alleles. Blood from hemochromatosis donors can be used for general purposes but has to be labeled to state that the donor has hemochromatosis (21 CFR 640.3[d]). The Food and Drug Administration can provide blood banks upon application with an exemption from this labeling requirement.

At-risk individuals should never eat raw seafood (clams, fish, or oysters), because they are not infrequently contaminated with Vibrio vulnificus or other Gram-negative bacteria, to which individuals with iron-retaining conditions are exceptionally vulnerable. Handling raw shellfish should also be avoided.

Iron intake must be tailored to individual needs, particularly taking into account the situation of young women with low ferritin concentration. Dietary measures do not replace the need for iron removal by phlebotomy but have a preventive and supportive value.

Consumption of red meat (beef, lamb, pork, or venison) and processed meat should be tightly limited. Of course, iron-fortified cereals or iron-containing dietary supplements are rarely a good idea for men and older women with the genetic variants known to increase iron retention. The use in young women with genetic risk factors is less concerning, if their iron status is very low.

Consumption of black tea with foods can help to limit the absorption of unwanted non-heme iron but not of heme iron (in fish, meats, and poultry).

Alcohol intake should be kept to a minimum. Individuals with no signs of liver damage may consume up to one serving a day on infrequent occasions.

Dietary supplements with high doses of vitamin C or vitamin A should be avoided. These nutrients should come mainly from vegetables.

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Personalized sports nutrition: Role of nutrients in athletic performance

Vincenzo Sorrenti, ... Alessandro Buriani, in Sports, Exercise, and Nutritional Genomics, 2019

18.2.3.3 Minerals

Dietary trace element supplementation can result in an improvement in athletic performance. Athletes have a higher than normal requirement for minerals and an inadequate diet directly affects athletic performance.

Both iron deficiency and magnesium deficiency can result in a significant reduction in exercise performance. There is evidence that dietary magnesium intake may be suboptimal in some individuals, thus dietary supplementation of this element may be useful in some population groups. At the same time, iron supplements can improve athletic performance in individuals severely deficient in this element. If iron supplements are used, it is important that the level of supplementation is not excessive, as excess iron in the diet can result in an induced zinc deficiency (McDonald and Keen, 1988).

Interindividual variation in iron uptake and metabolism could be explained by polymorphisms in genes governing iron homeostasis. Several studies have examined the hemochromatosis (HFE), transferrin receptor-1 (TFR1), and TMPRSS6 genes in relation to iron storage and absorption. SNPs in these genes were strongly associated with lower serum iron concentration and other hematological variables (Wallace, 2016).

In marked contrast to iron and magnesium, there is little evidence for the idea that zinc deficiency influences exercise performance in humans. Despite this fact, zinc supplements have been widely advocated for the athlete, on the basis that intense exercise can result in changes in zinc metabolism. If zinc supplements are used, it is important that they are not excessive, as excess zinc in the diet can result in a secondary copper deficiency (McDonald and Keen, 1988).

Zinc, copper, and manganese are essential cofactors for the enzyme superoxide dismutase (SOD). SOD is a major antioxidant enzyme, which plays a vital role in the clearance of ROS. Among the isoforms of SOD, copper-zinc superoxide dismutase (SOD1, CuZn-SOD) with copper (Cu) and zinc (Zn) in its catalytic center is localized in the intracellular cytoplasmic compartments, and manganese superoxide dismutase (SOD2, Mn-SOD) plays an important role as a primary mitochondrial antioxidant enzyme. Numerous SOD polymorphisms have been detected, but only a few SNPs have been shown to have an impact in clinical practice. SOD1 + 35A/C (rs2234694) which is located adjacent to the splice site (exon3/intron3 boundary), SOD2 Ala16Val (rs4880) which has been suggested to alter protein structure and function (C/T substitution in exon 2, codon position 2, amino acid position 16) and catalase − 21A/T (rs7943316) which is located inside the promotor region just proximal to the start site, are the main SNPs. During physical activity ROS production increases and at the same time, antioxidant enzymes activity increases. Athletes carrying SNPs in the SOD enzymes might not be able to down-modulate excessive oxidative stress, which can lead to muscle damage in the long term. Another aspect is prolonged hyperglycemia due to genetic background or high caloric diet, which increases reactive oxygen species and modifies structure and function of lipids, proteins, and other molecules taking part in chronic vascular changes. Low activity of scavenger enzymes such as in people with SOD polymorphisms can accelerate this pathological condition leading to chronic diseases such as diabetes. In these athletes, supplementation with zinc, copper, and manganese might be interesting to normalize SOD activity and prevent excessive oxidative stress and related-chronic conditions (Beckett et al., 2014; Flekac et al., 2008).

Nutrigenetics and nutrigenomics are comparatively new tools with which to study micronutrients. A critical evaluation of available data, incorporating omics technologies, strongly suggests that the intake or dietary supplementation with micronutrients should be optimized at an individual level.