Aluminium and Iron in Humans: Bioaccumulation,Pathology,and Removal

Abstract

It is well known that exposure to various elements has a noticeable effect on human health. The effect of an element is determined by several characteristics, including its similarity to elements of biological necessity, metabolism, and degree of interaction with physiological processes. This review investigates the scientific literature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is reviewed because of its prevalence in daily life, observed interference with several biological processes, controversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these metals has long been investigated for a possible relationship with various pathological states, a substantial volume of research is available regarding the effects of iron and aluminium in biological systems. For both aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility of bioaccumulation, and (3) exploring methods of managing their accumulation.

Aluminium

T o determine the potential for aluminium (Al) to accumulate and cause pathology in humans, a search of the relevant scientific literature was performed. Not all articles found in this search are included in this review. Instead, the results of these searches were analyzed for evidence related to the focus of this review.

Evidence of Al toxicity

Alzheimer disease

Al has been investigated as a contributor to the development and progression of Alzheimer disease (AD) for decades,^1

–4 and the possible role of Al in AD continues to be discussed in the literature. For example, one study³ found Al in human pyramidal neurons, which contained Al either in the cell nucleus or cytoplasm, the latter being relatively high in Al and containing neurofibrillary tangles (NFT). Other studies have suggested Al has at least a secondary role in the development of AD.^5

–8 However, evidence for a primary, causative role of Al in AD induction is inconsistent,^9
–11 so further investigation into this question continues.

Oxidative stress

More generally, Al is also considered to be a mediator of oxidative stress,^5,12

–16 and efforts have been made to understand the underlying mechanisms of Al-catalyzed oxidative stress.^15,17 For example, one study¹⁸ found that Al³⁺ ions augment iron-induced lipid peroxidation in rat liver microsomes at pH 7.4. This study also found Al³⁺ that accelerates the peroxidation of erythrocytes by hydrogen peroxide (H₂O₂). Another study found similar results.¹⁹

Interference with iron metabolism

It is also been postulated that oral Al interferes with iron (Fe) absorption, use, or both, and contributes to some cases of anemia.^20
–22 One study²¹ tested the possibility of Fe binding to transferrin being disrupted by Al in Wistar rats by administration of Al via Camellia sinensis (green tea) decoction. It was found that serum Al increased in a tea dose-dependant manner. It was also observed that the Fe content of all organs tested was reduced compared to controls. This suggests that the Al present in green tea may affect Fe metabolism (discussed below). However, it is known that green tea contains both Al and polyphenols. Polyphenols are known to chelate Fe and perhaps contribute to iron-deficiency anemia.^23
–25 It may be the presence of polyphenols, or Al jointly with polyphenols, that affects Fe metabolism, and not Al alone. Furthermore, Flaten²⁶ asserts that Al from heavy drinking of tea infusions can be a greater contributor to serum Al than from all other dietary sources. Other studies have suggested similar hypotheses related to the possibility of green tea being a significant source of Al.^27,28 It is important to consider the possibility that infusions of the plant C. sinensis may contribute to ill health, especially given the increasing interest in green tea consumption due to its possible health benefits.

Osteomalacia

Al has also been implicated in the development of osteomalacia (bone softening),^16,29–30 especially in hemodialysis patients who experience high Al exposure from the Al-contaminated dialysate used in dialysis procedures.^16,31

–34 Bone disease is also observed in patients undergoing long-term administration of total parenteral nutrition (TPN).^35,36 It has been postulated that this increased incidence of bone disease in TPN is related to Al contamination of nutrition solutions.^35,36 However, note that both of these observations occur in the uncommon circumstances of acute (dialysates) or nongastrointestinal (TPN) Al exposure.

Parathyroid hormone

Further considering Al toxicity, Al is known to disrupt parathyroid hormone (PTH) secretion by interfering with calcium metabolism, which in turn disrupts osteoclast activity.³⁷ However, PTH is not considered by Jeffrey et al.³⁷ to be the primary way by which Al disrupts bone metabolism. Instead, these authors suggest that Al disruption of PTH may contribute to the development of bone disease, aggravate an existing disease, or interact with some other condition, thus precipitating disease.

Kidney damage

Related to the observation that most Al is excreted via urine, it is known that kidneys are affected by Al exposure.³⁸ In Al accumulation in the kidney, renal tubular cells are damaged. In rats with normal kidney function, intraperitoneal Al administration was found to cause swelling, hemorrhaging, and fibrosis in the glomeruli, proximal tubuli, and the Bowman capsules.³⁸ It has been hypothesized that this damage is caused by Al-induced increases in reactive oxygen species (ROS).^38,39 Other studies in rats found Al accumulation in the normal kidney, accompanied by kidney damage.^16,40,41

Breast cancer

Finally, a few studies have suggested that Al present in underarm antiperspirants containing Al salts may increase the risk of breast cancer.^42,43 Further confounding this question is the possibility that underarm shaving habits may disrupt the dermal barrier that may otherwise restrict Al absorption. On the other hand, a few studies have asserted that the possibility of an increased risk of breast cancer due to these Al salts is either nonexistent based on available research⁴⁴ or needs further investigation.⁴⁵ The question regarding the role of Al in the development of breast cancer is still being investigated, and it seems premature to draw a conclusion at this time.

Evidence of Al accumulation

There is considerable evidence to support the hypothesis that Al accumulates in humans. It has been observed that tissue Al levels are positively correlated with age in humans.^46
–48 Furthermore, at least one study⁴⁸ has found tissue Al concentration to increase exponentially with age. This suggests two possibilities. First, common daily exposure is higher than the body's removal capacity, resulting in accumulation. Second, the exponential age-related increase in Al burden may be due to general age-related kidney decline,^49
–51 which would result in an ever-decreasing ability to remove Al with age. Thus, it may be increasingly important to manage Al exposure with advancing age or otherwise declining kidney function.

Although a relatively small proportion of Al is deposited in tissues, Al turnover is important to consider. While Al turnover is difficult to quantify, it has been estimated that Al in the human brain has half-life of 7 years.⁴⁹ This slow turnover is, again, suggestive of the accumulation potential of Al.

Oral availability

Oral bioavailability of Al is low to moderate in humans (0.001–24%) depending on dose, and a larger dose may have lower bioavailability.¹⁷ However, this range includes a wide range of observed absorption rates. Rates in the middle of this range are more commonly observed. For example, one study⁴⁸ indicates that 4% of total Al intake will be retained by humans with normal renal function. Furthermore, it may be that there is no dose-dependency for oral Al bioavailability, as has been observed in some animal studies.⁴⁶

Bodily Al distribution

Once uptake occurs, Al distribution is widespread,¹⁷ with Al being present in most tissues with few exceptions, such as the lens of the eye (in fish).⁵¹ In rats given a single intravenous injection of trace amounts of Al-26, the largest proportion of injected Al was found in bone (0.9%) and kidney (0.2%).¹⁶ The lowest proportion was found in brain and muscle (0.02% each). Sahin et al.⁵³ investigated Al deposition in mice administered aluminium hydroxide orally for 105 days. In the treatment group, they observed Al content of liver, kidney, and brain that was 30%, 60%, and 340% higher, respectively, than the control group. In humans, aluminium is estimated to have a distribution of approximately 60, 25, 10, 3, 1, and <1% in skeleton, lung, muscle, liver, brain, and blood, respectively.¹²

Al accumulation in bone

One primary site of Al accumulation is in bone,¹² where it contributes to the development of osteomalacia,⁵⁴ especially in chronic hemodialysis patients. Jeffrey et al.³⁷ postulated that the half-life of Al in bone may depend on which type of bone it is incorporated into (i.e., cortical vs. trabecular). Jeffrey et al. also suggested that a toxicity threshold for Al exposure would be helpful in preventing Al-related bone disorders.

Al from drinking water

Drinking water, a possible source of chronic Al intake leading to accumulation, can contain Al both by natural as well as water treatment processes. Al bioavailability from this source is estimated to be approximately 0.3%.⁴⁹ Several epidemiological studies have found correlations between AD and high Al concentrations in drinking water. One such study warned that limiting residual Al in drinking water deserves “serious attention.”⁵⁵ It should be noted that epidemiological studies have their limitations, including this one, which were discussed by Levallois.⁵⁶

Al restriction and removal

Substantial evidence exists supporting the hypothesis that Al is toxic. Furthermore, the evidence on the half-life of Al in tissues, as well as on Al distribution, indicates that Al accumulates in humans. Thus, a discussion of Al restriction and removal is appropriate.

Al restriction and complexation chemistry

When attempting to understand ways by which to avoid gastrointestinal absorption of Al, it is important to consider the complexation chemistry of Al. Al complexation chemistry has received substantial attention from researchers. Two aspects of Al complexation are important to discuss: Dissolution for absorption and complexation in the physiological environment. Each of these processes may occur quite differently and thus should be considered separately.

In water at neutral pH, Al is poorly soluble. As pH decreases from 7.0 to 5.0, Al forms hydrate complexes in solution. This phenomenon lends support for the common advice against cooking acidic foods in Al cookware, because Al dissolves more easily in acidic environments. As pH is subsequently increased, successive deprotonations result in the formation of a tetrahedral aluminate at pH >6.2, including the physiological pH.³⁷

Modulators of gastrointestinal Al absorption

Because the physiological pH is close to neutral, researchers have investigated which physiological Al complexes may facilitate Al transport in the body. Several researchers^5,57 have suggested that the complex Al–maltolate may be one such candidate. Maltol is present in the diet as a flavor enhancer added to foods. Al–maltolate is stable over the pH range of 3.0–10.0. Partly due to this chemical behavior of the Al–maltolate complex, it has been suggested as a complex to administer in a rabbit model in the study of AD development and pathology.⁵⁸ Other dietary ligands have been suggested as playing a role in enhancing Al absorption and retention, including ascorbate, lactate, succinate, malate, oxalate, gluconate, citrate, fluoride, glutamate, gallate, chlorogenate, caffeate, protochatechuate, tartrate,¹⁷ and possibly polyphenols.²⁶ Phosphorous¹⁶ and silica^16,17,59 appear to reduce absorption.

Dietary intake of Al

Dietary Al intake has been estimated to be 4–9 mg/day.^46,47 Because Al is abundant in the Earth's crust, most food plants are grown in this medium. Food animals are fed plants raised in soil, so it follows that much of the human food chain may be a source of low, chronic Al exposure. Foods known to be high in Al include corn, yellow cheese, salt, herbs, spices, and tea, as well as foods incorporating Al-containing leavening agents such as sodium aluminium phosphate (SALP), often used in baking powders.^16,60 Restriction of these foods may be helpful in reducing chronic Al burden. Al is also used in drinking water purification. Another source of Al exposure includes Al containers and cookware.

Al in tea

Al content of teas varies widely. Street et al.⁶¹ found tea infusions to vary between 0.2 mg L⁻¹ to 9.3 mg L⁻¹ after a 5-min infusion. To put this in perspective, the World Health Organization (WHO) recommends a maximum Al concentration in drinking water (for “aesthetic” considerations, not health) to be 0.2 mg L⁻¹.⁶¹ This makes the Al concentration in many tea infusions investigated⁶¹ up to 46 times greater than the WHO “aesthetic” standard. This evidence, combined with the possibility that Al from green tea is as well absorbed as Al from other dietary sources due to polyphenolic hydroxyl groups that provide multiple complexation sites,^26,61 causes one to consider that green tea may contribute to the accumulation of toxic levels of Al. One researcher²⁶ asserted that heavy green tea drinking may double one's Al intake (further considering that 95% of Al intake is normally from food, and only 1–2% from drinking water).⁶⁰ Green tea has been investigated for its potential therapeutic and preventative applications, so it would be ill-advised to cease green tea consumption altogether. Whether tea contributes substantially to Al-related toxicity requires further investigation.

Furthermore, consuming green tea without acidic components such as lemon juice, which is sometimes practiced, might be reconsidered. Several studies found acidic components, such as citrate present in citrus juices, facilitated greater gastrointestinal absorption of Al.^12,17,16,62 For example, one study⁶³ in rats found that 1 h after oral Al administration, the extent of aluminium accumulation was increased by a factor of 2 to 5 in the presence of citrate, depending on tissue and other factors.

Nongastrointestinal absorption of Al

Gastrointestinal absorption is not the only route of Al uptake. Other intake routes have been investigated including nasal, dermal, and respiratory.¹⁷ A preliminary study⁶⁴ found approximately 4 μg of Al to be absorbed transdermally by a single administration of an Al-containing antiperspirant. Another study found, in a single patient, plasma and urine Al to decrease after discontinuing antiperspirant use.⁶⁵ The question of transdermal Al absorption is a concern and is still being investigated. For most individuals, oral Al intake is a much greater source of Al exposure.

Al removal

Al restriction is important in preventing and slowing the accumulation of Al. However, some people may currently have a substantial accumulation of Al (i.e., in advanced age^46
–48). Assuming that Al accumulation, left to itself, will eventually result in pathology, it is beneficial to address this accumulation before pathology arises. Of course, this is the case only if methods of Al measurement and removal are not more harmful than the presence of nonpathological Al levels. Moreover, some populations may be subjected to Al exposure due to health conditions requiring treatments that can be contaminated with Al (i.e., hemodialysis patients). Further complicating the issue is the possibility that Al in some tissues may have a fairly long half-life. Thus, dietary Al restriction is helpful, but will not be effective in alleviating Al burden in some circumstances or tissues.

Al, apo-transferrin, and serum albumin

One important characteristic of Al is that it is found bound to apo-transferrin⁶⁶ and serum albumin.^16,67 This characteristic of Al binding to serum is important when considering Al reduction therapies, such as chelation and phlebotomy. One study⁶⁷ investigating competitive binding constants of Al³⁺ and citrate, human serum albumin (HSA), and human serum transferrin (HSTF) concluded that in hemodialysis patients ∼34% of serum Al is bound to HSA, ∼60% is bound to HSTF, and the remainder bound to citrate. This substantial binding to HSA⁶⁷ was in contrast to several other studies (referred to in ref. 66), which estimated a much lower binding to HSA and a much higher binding rate to HSTF.

Al and chelation therapy

Desferroxamine and other chelators used in the treatment of iron (Fe) overload have been frequently discussed in the literature as a chelator of Al.^{12,37,59,68

–71} One study⁷² found desferroxamine therapy to result in a reduction of surface Al on bone from 44% to 13% in hemodialysis patients.

Evaluating the appropriateness of such chelation therapy might be done with the so-called “chelator challenge,”⁷³ whereby a patient is given a single dose of chelator and urinary excretion of the metal (in this case, Al) is compared before and after the treatment. This would assist doctor and patient in evaluating the extent of Al accumulation in the patient.

Side effects of chelators

Desferroxamine and other clinical chelators are known to have serious side effects, such as mucormycosis⁷³ (also referred to as zygomycosis), “ocular and auditory anomalies, sensorimotor neurotoxicity, changes in renal function, and pulmonary toxicity,”⁷⁴ as well as stunted height in developing children.⁷⁴ Thus, alternative methods of Al removal are desired.

Kruck and colleagues⁷¹ investigated the effectiveness of 10 chelators, alone or in combination, in the removal of nuclear-bound Al. They found a combination of ascorbic acid and Feralex-G, a recently described chelator intended for oral use, to be an effective combination. This combination removed between 29% and 35% of nuclear-bound Al(III), dependent on ascorbic acid concentration. The mechanism used to explain the effectiveness of this combination was called “molecular shuttle chelation,” whereby a smaller molecule (ascorbate) penetrates the nucleus, chelates Al, diffuses to regions with the larger chelator (Feralex-G), and relinquishes the Al to that chelator. They further suggest that chelators with cis-hydroxy ketone groups (such as Feralex-G) are particularly useful in chelating nuclear bound Al. Chelators found to be relatively ineffective included fluoride, hydroxyurea, dihydroxyacetone, maltol, citrate, EDTA, and salicylate.

Inositol hexaphosphate (IP6, also known as phytic acid) has been investigated as a chelator for a number of other elements, including Fe (discussed later) and uranium. However, a search of PubMed using phrases that included various terms related to IP6 and chelation returned no results related to Al removal or chelation. IP6 might be investigated as a potential, safe, oral, Al-chelating agent and needs further investigation.

Flora and colleagues⁷⁵ investigated the effectiveness of citric acid (CA) and N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), alone or in combination, on Al burden in blood and brain compartments in Wistar rats. They found that CA and HEDTA reduced blood and Al burden, alone and in combination, but did not have a synergistic effect on these compartments.

The chelator EDTA, used to treat lead poisoning, was not found to cause improvement for AD patients.⁵⁹ However, EDTA was found to prevent Zn(II) and Cu(II) from binding to amyloid-beta (Aβ) sites, so EDTA may still be useful in AD.⁵⁹

Iron

The element iron (Fe) is a critical component of aerobic metabolism of many organisms, including humans. As an oxygen-carrier, Fe²⁺ or Fe³⁺ is bound in the porphyrin heme, four of which are included in the hemoprotein hemoglobin.⁷⁶

It is well known that inadequate Fe can be detrimental and even fatal. However, recent research has illuminated several relationships between “excess” Fe status and pathology. Unfortunately, quantitative values for what constitutes “excess” Fe status have been difficult to determine, partly due to the lack of immediate manifestation of pathology related to excess Fe. These types of pathology that are related to excess Fe take time to manifest, and because of this time lag, it is often difficult to implicate Fe status in these pathologies.

Evidence of Fe toxicity

Fe and AD

Fe (as well as copper and zinc) have been increasingly considered to play a critical role in AD pathology.^77

–80 Mechanisms by which Fe is thought to play a role in AD include Fe-induced oxidative stress⁷⁷ and/or induction of aggregation of hyperphosphorylated tau⁸¹ or Aβ.⁸² Fe has also been found to be elevated in Aβ deposits.^77,83

Fe and cancer incidence, outcome, and survival

The relationship between cancer and Fe stores has been investigated. Observations have been mixed, and relationships between body Fe and cancer seem to exist for some cancer types, whereas no relationship exists for others. One study⁸⁴ found that reduction of Fe by phlebotomy in patients with peripheral arterial disease resulted in a lower incidence of visceral cancer and all-cause mortality. Another study⁸⁵ found no correlation between serum ferritin and stomach or lung cancer incidence. Yet another study⁸⁶ found an increased risk of liver cancer in patients with hereditary hemochromatosis (a disease characterized by Fe accumulation) compared to a control group with non–Fe-related chronic liver disease. Although it seems to have proven difficult to discover the exact mechanisms by which Fe influences cancer risk, outcome, and mortality, the currently available evidence indicates a relationship between Fe and cancer may exist and is yet to be fully understood.

Glucose disposal

Blood sugar control is important for sustaining excellent long-term health, especially for diabetics. Chronic high blood sugar, most commonly presented in diabetics, has been implicated in a number of conditions, including vision loss, nerve damage, and an increase in the risk of heart disease and stroke.⁸⁷ Furthermore, chronic high blood sugar is implicated in the development of type 2 diabetes in those individuals with no previous blood sugar abnormalities. Thus, to prevent possible onset of diabetes, as well as manage complications of the condition, it is important to manage one's blood sugar and insulin sensitivity.

One study⁸⁸ found lacto-ovo vegetarians to be more glucose tolerant than meat eaters. Fe status of the two groups, measured as micrograms of ferritin/L (ng/mL), was found to be 35 and 72, respectively. Insulin sensitivity of the two groups, measured by steady-state plasma glucose (mmol/L), was found to be 4.1 vs. 6.9 in the vegetarian and meat-eater groups, respectively. Moreover, the Fe stores of the meat-eating group were lowered by phlebotomy to levels similar to the vegetarian group. Postphlebotomy tests measured an approximate 40% increase in insulin-mediated glucose disposal in the meat-eating group after phlebotomy. This suggests that Fe status is somehow related to glucose disposal, because it is well known that a meat diet often contains more bioavailable Fe (heme) than does a vegetarian diet. It should be noted that other factors in a high-meat diet, such as fat intake and displacement of fruit and vegetable intake, may account for a small part of the difference in insulin sensitivity between these groups.

A different study⁸⁹ found no difference in insulin sensitivity between groups of high-frequency versus low-frequency blood donators. The average serum ferritin of each group was 23 and 36 ng/mL, respectively. This, combined with the above study, suggests that improvements in insulin sensitivity might be realized by reduction in serum ferritin, but the maximum benefit in insulin sensitivity derived from serum ferritin reduction may be at a serum ferritin level of approximately 35 ng/mL. It has also been suggested that Fe may impede insulin extraction in the liver, impair insulin secretion by the pancreas, and/or interfere with insulin action of, and glucose uptake by, adipocytes.⁷⁸

Fe and lipid peroxidation

Another way in which Fe exerts harmful effects in the body is catalysis of lipid peroxidation,⁹⁰ which can damage cell membranes and other lipids. There are numerous studies that indicate a relationship between body Fe and lipid peroxidation. In one study,⁹¹ it was found that Fe miners, as well as office workers of that mine, had higher serum Fe and markers of lipid peroxidation than controls. A different study⁹² investigated Fe status and markers of lipid peroxidation in a group of young women receiving Fe supplementation for low Fe stores (defined as plasma ferritin of ≤20 ng/mL). Fe supplementation was 98 mg/day of ferrous sulfate. In this low-Fe group (n = 12), it was found that after 6 weeks of supplementation, serum ferritin almost doubled and markers of lipid peroxidation increased by >40%. While it was apparent that the young women in this study could benefit from increased Fe stores, lipid peroxidation had increased considerably. Several ways to reduce this side-effect are theoretically possible, including the use of a different form of Fe, taking a lower dose over a longer period of time, or dividing a dose into several smaller doses to be administered throughout the day. These need further investigation.

Beta-thalassemia major (thalassemia), a disease characterized by the improper formation of blood cells, is often treated by blood transfusions to improve blood cell parameters in these patients. These repeated blood transfusions have the negative side effect of causing Fe accumulation in thalassemia patients. Because of this relationship between thalassemia patients and Fe overload, these patients have been the subject of numerous studies investigating the relationship between Fe and various pathologies.

In one study,⁹³ thalassemia patients were found to have plasma markers of lipid peroxidation more than two-fold higher than controls. In this study, it was also found that serum ferritin was positively correlated with conjugated diene lipid hydroperoxides (CD, a marker of lipid peroxidation). In this study, mean CD was found to be three-fold higher than controls.

Lipid peroxidation,^94,95 and specifically Fe,^96,97 have also been thoroughly investigated as possibly contributing to the development of cardiovascular disease. Research in this area is inconclusive.⁹⁶

Other associations between Fe and disease

A number of other diseases have been associated with excess Fe, including Parkinson disease, Huntington chorea, human immunodeficiency virus (HIV) encephalopathy, basal ganglia disease, pantothenate kinase-associated neurodegeneration (PKAN), and Friedreich ataxia (the latter being associated with mitochondrial Fe accumulation).⁹⁸ These conditions have not all been shown to be caused by excess Fe. Rather, each has been found to have some relationship to elevated Fe levels.

Evidence of Fe accumulation

Human glial cells,⁹⁹ substantia nigra, and globus pallidus have been found to accumulate Fe with age.¹⁰⁰ Fe deposits have also been observed in cerebral cortices, cerebellar nuclei, hippocampus, and subcortical astrocytes.¹⁰¹ After considerable research of the literature, no studies were found that either supported or denied a general, whole-body accumulation of Fe with age in humans. This specific question seems to be a neglected area of research, and it would be helpful to determine whether this occurs. To answer this question, it is important to determine the most reliable means by which to evaluate body Fe stores. Evidence has been accumulated suggesting serum ferritin to be a useful indicator, and this is the indicator often used by medical practitioners. However, other indicators have been discussed, such as serum transferrin, tissue ferritin, free Fe, transferrin saturation (TSat), and hemosiderin (the latter especially in liver). These other Fe compartments may need to be considered during the course of designing a thorough and effective Fe quantification protocol.

A considerable amount of evidence exists showing the accumulation of Fe with age in rodents. Fe has been observed to be positively correlated with age in kidney, brain, liver, muscle,¹⁰² and retinal pigment epithelium ¹⁰³ in rats. One interesting study in rats¹⁰⁴ found Fe to accumulate with age, and this accumulation was markedly attenuated with 40% caloric restriction (CR). Conversely, Borten et al.¹⁰⁵ found 40% CR to not attenuate age-related accumulation of peroxidase-positive astrocyte granules in the dorsal hippocampus of rats. Note that CR did not reduce this Fe accumulation even though these particular rats were not supplemented with Fe to make up for reduced Fe intake associated with CR.

Management of Fe status

Diagnostic measurements of Fe status

Serum ferritin is one of the most common end points used to determine Fe status, partly due to its usefulness in determining Fe deficiency.¹⁰⁶ A commonly cited reference range for serum ferritin is 12–300 ng/mL for males and 12–150 ng/mL for females.¹⁰⁷ Considering this seemingly wide range, one study¹⁰⁸ sought to test the hypothesis of an “optimal” level of serum ferritin, and suggested that it may be approximately 25 ng/mL, a level similar to that found in children and premenopausal women.

One study¹⁰⁸ used phlebotomy as an Fe reduction protocol for patients with peripheral vascular disease. Using serum ferritin as the primary indicator of Fe status, the protocol set a target to lower serum ferritin via phlebotomy to approximately 25 ng/mL. They found that after the 5-year study duration, the treatment group had a 30% reduction of patient mortality versus the control group. When tracking 3.5 years of patient accrual, a 20% reduction was found in the ferritin-reduction group, compared to anticipated values. Thus, if a reduction of Fe bound to serum ferritin was the cause of improved outcomes in the phlebotomy group, serum ferritin may be an appropriate measure for other Fe reduction protocols.

There are several methods other than serum ferritin by which to characterize Fe stores. One study¹⁰⁹ investigated the effectiveness of Fe-dependent bodily regulation of dietary Fe absorption. It is well known that dietary Fe absorption increases during Fe deficiency in healthy humans.¹⁰⁹ This study¹⁰⁹ refers to references of pooled data concluding that only ∼50% of the variation in serum ferritin was related to variations in amounts of stored Fe, indicating that serum ferritin may not be representative of total Fe stores. Hallberg et al.¹⁰⁹ found that there was a strong relationship between Fe absorption and Fe status. Using Fe absorption as the indicator of Fe status (instead of ferritin), they suggested that serum ferritin may not be a good measure of Fe stores in Fe-replete men if their serum ferritin is >70 ng/mL. Furthermore, they suggest that high ferritin may instead represent some other pathological condition affecting ferritin metabolism that is unrelated to Fe stores. This assertion was supported by references to several studies that failed to raise body Fe in Fe-replete, normal subjects using ascorbic acid fortification combined with oral Fe supplements. If this is true, then it may be high ferritin, and not high Fe stores, that must be addressed to reduce the incidence of excess ferritin-related pathology discussed above.

Determination of Fe accumulation in humans seems to be a convoluted problem. For example, a recent review of ferritin¹¹⁰ asserted that ferritin is a useful indicator of Fe overload, at least in pathological conditions related directly to Fe overload or accumulation, such as hemochromatosis and thalassemia. However, this same review noted that organs can accumulate Fe independently of one another, and that the Fe in a single organ is not representative of whole-body Fe. For example, patients can accumulate cardiac Fe while having seemingly normal hepatic Fe, even though the latter (via biopsy) is considered the gold standard for determination of Fe overload.¹¹⁰ Regarding this “compartmentalization” of Fe overload, superconducting quantum interference devices (SQUID) and magnetic resonance imaging (MRI) may be useful diagnostic tools that can help determine Fe in various tissues.

As for Fe accumulation in humans, it may be important first to recognize the compartments that can accumulate Fe (i.e., hemosiderin in liver, heart, pituitary, kidney, and other tissues, and ferritin in blood) and determine the most reliable diagnostic methods of determining such accumulation. Once this is known, these accumulations might be treated as distinct medical issues, rather than classify all of them under the category of “high Fe stores.” Doing the latter may result in Fe reduction strategies that fail to achieve reduction in the specific compartments that have accumulated Fe to a harmful level.

Reducing Fe intake and exposure

Diet

Fe reduction through dietary modification can be effective, but is relatively slow.¹⁰⁸ Fe excretion is limited due to the body's excellent Fe recycling mechanisms^76,108,111 and the lack of a physiological mechanism by which the body may quickly excrete excess Fe.¹⁰⁸ However, daily Fe loss is estimated to be 1–2 mg/day.⁷⁶ Studies in hepatitis C patients¹¹² and mice¹¹³ indicate that limiting dietary Fe intake can reduce markers of Fe storage.

Because heme Fe is absorbed more efficiently than non-heme (inorganic) Fe,¹¹⁴ a distinction must be made between heme and non-heme Fe. Heme Fe is found in meat products, including beef, pork, chicken, and fish.¹¹⁵ Sources high in inorganic Fe (greater than 2.5 mg/serving) include some fortified cereals, soybeans, pumpkin seeds, some beans, blackstrap molasses, and lentils.¹¹⁵ If meat-intake is reduced, the comprehensive dietary effects of such an adjustment should be addressed, such as ensuring adequate protein and vitamin intake from other sources to offset those displaced by this dietary modification.

Other dietary factors to take into consideration are inhibitors and enhancers of Fe absorption.²⁴ Inhibitors of Fe absorption might be increased in an Fe-depletion diet. Inhibitors include polyphenols,²³ phytates (discussed later), and calcium. Consuming Fe absorption enhancers with meals high in Fe may also be avoided. Fe absorption is enhanced by vitamin C,¹¹⁵ so its consumption should be avoided at meals that include high Fe components if one wishes to lower Fe stores.

IP6, also known as phytate, is known to inhibit Fe absorption in the gastrointestinal tract (GI) tract.^116,117 IP6 is found in the bran and seeds of plants¹¹⁸ and is also available as a low-cost dietary supplement; it may be an effective adjuvant to other dietary interventions directed to reduce Fe stores (and perhaps other metals). Other dietary compounds useful in reducing Fe absorption in the GI tract may include hemicellulose and lignin.¹¹⁹

Most Fe is obtained via oral consumption, but other routes of exposure exist. Environmental exposure, such as in a workplace, can increase levels of body Fe.⁹¹ Other sources of Fe intake must be considered, including cookware and food utensils. One study¹²⁰ reviewed the use of Fe cooking pots and their effect on reducing the incidence of Fe deficiency in the populations of developing countries. The study concluded that the use of Fe cooking pots may be an innovative method of reducing Fe deficiency in Fe-deficient populations, thus supporting cookware as a substantial source of dietary Fe.

Reducing Fe stores

Chelation therapy

Chelation treatment is used for Fe accumulation caused by repeated blood transfusions required to treat thalassemia, a blood disease characterized by the faulty synthesis of hemoglobin.⁷⁴ Three compounds commonly used in Fe chelation therapy include deferoxamine, deferiprone, and deferasirox. A good discussion of these three compounds and their comparative attributes can be found in a study published in the journal Blood.¹²¹ While useful, a number of Fe chelation compounds have harmful or otherwise unpleasant side effects (noted earlier), which must be weighed against the seriousness of Fe accumulation presented by each patient.

Phlebotomy/blood donation

Phlebotomy or blood donation has been found to be an effective method of reducing body Fe stores as measured by serum ferritin concentrations.^88,89,108 Phlebotomy is used in the treatment of Fe overload in hemochromatosis¹²² and thalassemia. Theoretically, phlebotomy might be considered an extreme measure of Fe removal, because all components of blood are lost during whole-blood phlebotomy/donation, including those components that are critical to optimal health (immune cells, vitamins, minerals, etc.). Whereas phlebotomy has been shown to be effective in reducing serum ferritin, the comprehensive health effects of such an intervention should be evaluated before it is recommended as a routine method of reducing moderate Fe stores.

Conclusions

Al and Fe are both apparently related to a number of disease states, particularly those relating to oxidative stress, a phenomenon that results in a type of damage that can accumulate with age. Both metals also appear to accumulate with age, although the sites of accumulation in humans and the resulting implications are not perfectly clear. Development of reliable and accurate measurement techniques for whole-body Fe and Al burden would be useful.

Al and Fe seem to have substantially different accumulation sites, and it would be beneficial if these were further elucidated. Al seems to be cleared via the renal system and accumulates primarily (as measured by Al mass) on bone. Alternatively, a considerable amount of Fe accumulates in liver and in serum ferritin. While it seems that substantial removal of accumulated Al occurs via the renal system in healthy people, the body appears to lack a high Fe regulatory mechanism, besides the well-known decrease in GI absorption. Chelation therapy may help remove both metals, and phlebotomy has been shown to reduce serum ferritin. However, chelation therapies are not without their negative side effects, many of which may outweigh the benefit of reducing body metal burden in nonpathological states. Chelation therapy also has the risk of removing other metals, some of which are biologically necessary, and it may be that prolonged chelation therapy would contribute to mineral deficiencies. Phlebotomy is effective in reducing serum ferritin, but caution must be used before recommending this treatment because many required blood components are lost in the procedure. Further development of measurement methods and treatments to optimize body Al burden and Fe stores may contribute positively to health span by minimizing negative and accumulating biological effects to which high levels of these metals seem to contribute.

Footnotes

Acknowledgments

Several, constructive, scientific comments were given to this author by John Schloendorn and Mark Hamalainen and implemented into this manuscript. Furthermore, contributions to the formatting of references were made by Alicia L. Mann.

Author Disclosure Statement

No conflicts of interest are considered by this author to exist.

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