Iron deficiency
Iron deficiency remains the most prevalent micronutrient deficiency state worldwide (85). It is estimated that two billion individuals are iron deficient; most of them are women or children in developing countries. Diets with an inadequate content of bioavailable iron are the primary cause, but disorders that increase iron loss as a result of pathological bleeding, particularly hookworm, have a very important role.
Malabsorption due to disorders that affect the upper small intestine can also cause iron defi- ciency. The most common appear to be celiac dis- ease (86, 87) and Helicobacter pylori infections (88–91). Celiac disease may be more prevalent in some Mediterranean and south Asian countries than previously realized (92–94). It is also impor- tant to note that inadequate absorption of multiple nutrients associated with histological abnormali- ties of the intestinal mucosa was thought to con- tribute to the high prevalence of iron deficiency in
countries such as India, Pakistan, Bangladesh and Haiti in earlier studies (3). The prevalence of “tropical sprue” appears to be declining and the specificity of this entity, as well as the overlap with tropical enteropathy, has been questioned recently (95). The possible relevance of these entities to nutritional iron deficiency is unclear and further research is needed. Finally, surgical procedures that alter the anatomy of the stomach and duodenum may also decrease iron absorption.
Impaired iron absorption resulting from muta- tions in genes encoding proteins involved in iron transport appears to be rare, although a G R A mutation at cDNA nucleotide 829 (G277S) has been reported to be a risk factor for iron defi- ciency anemia in homozygous women (96).
Iron overload
Iron overload is far less prevalent than iron defi- ciency. It can be considered under three headings, primary systemic iron overload, secondary iron overload, both of which affect several different
Figure 6.4: Effect of iron status on absorption of heme and nonheme iron. Data from Lynch (80) as adap-
ted from Cook (79).
10
30
100
250
Serum ferritin (mg/L)
4
3,5
3
2,5
2
1,5
1
0,5
0
Ir
o
n
ab
so
rb
ed
(m
g
/d
ay
)
Noheme
Heme
Total
organs and are the result of excessive absorption and abnormal release from stores, and organ/ tissue specific iron overload.
The regulation of iron absorption as iron stores increase in human beings with normal mucosal function is remarkable effective. There are only isolated case reports of clinically signifi- cant iron overload resulting from the ingestion of large quantities of supplemental iron over extended periods of time (3). In contrast to iron deficiency, primary systemic iron overload appears virtually always to result from the pheno- typic expression of an inherited abnormality related to the regulation of iron transport. In the past, sub-Saharan iron overload was considered
to be an exception (3). Men who are at greatest risk for the disorder consume large quantities of highly bioavailable iron (97, 98) and there is little doubt that this excessive intake is an important contributory factor (99). However more recent observations have provided strong circumstantial evidence for an underlying genetic mutation (100) suspected of affecting the function of Fpn (101–104).
Dysregulation of hepcidin and abnormal function of its receptor Fpn, resulting in inappro- priate iron release from stores and excessive absorption, are now considered to be the most important etiological factors in patients with primary systemic iron overload (Table 6.2) (22,
69 Iron metabolism
Table 6.2: Primary systemic iron overload disorders. Adapted from Pietrangelo (105).
HFE – related hereditary hemochromatosis (Type 1) Gene and chromosomal location: HFE, 6p21.3 Autosomal recessive
High transferrin saturation
Parenchymal iron accumulation in liver, heart, endocrine organs Low clinical penetrance, variable organ damage
Juvenile hereditary hemochromatosis (Types 2A and 2B) Gene and chromosomal locations: Type 2A: HJV, 1q21 Type 2B: HAMP, 19q13.1
Autosomal recessive High transferrin saturation
Parenchymal iron accumulation in liver, heart, endocrine organs Early onset, severe organ damage
TfR 2 related hereditary hemochromatosis (Type 3) Gene and chromosomal location: TfR 2, 7q22 Autosomal recessive
High transferrin saturation
Parenchymal iron accumulation in liver, heart, endocrine organs Variable organ damage
Ferroportin related iron overload (Type 4)
Gene and chromosomal location: SLC40A1, 2q32 Autosomal dominant
High transferrin saturation only in late disease
Predominant reticuloendothelial iron overload in early stages Organ damage later in the clinical course
105). HFE related hemochromatosis Type 1, an autosomal recessive trait, is by far the most common genetic disorder of iron metabolism in populations originating in Northern Europe, affecting one in 300 individuals (106). Hepcidin levels are inappropriately low, but not as severely decreased as they are in other related disorders (22). Beutler et al. have estimated that only 1% of homozygotes living in the Unites States develop frank clinical manifestations despite their high bioavailability diet (107). However, a report from Australia demonstrates that many more may have laboratory evidence of organ damage (108). If unrecognized, a small minority of individuals, particularly men, will develop signs and symp- toms, usually in middle age when the body iron content has reached 15–40 g. The mechanism of action of the HFE gene is unknown, but it is sus- pected of being a modulator of signaling for the iron sensor for hepcidin (22).
Two much rarer types of hemochromatosis have their clinical onset in the second or third decades of life and present a more severe pheno- type (juvenile hereditary hemochromatosis). One, type 2A, is associated with a mutation in the hemojuvelin (HJV) gene. The mechanism of action of HJV is unclear. However, it directly reg- ulates hepcidin expression in vitro (109). Rare cases of juvenile hereditary hemochromatosis (Type 2B) have been linked to mutations in the gene for hepcidin itself, the hepcidin antimicro- bial peptide (HAMP) gene (110, 111).
The phenotype associated with the gene encoding TfR 2 (Type 3) occurs early in life, but is milder than Type 2 juvenile hereditary hemochromatosis (112). The function of TfR2 is unknown, although recent observations indi- cate that it also modulates hepcidin production (113).
Finally, mutations of the hepcidin target, Fpn, may affect its functionality or responsive- ness to hepcidin (114–116). The resulting
phenotype may be similar to Type 1 HFE hemochromatosis or characteristic of ferropor- tin related iron overload (Type 4), with predom- inant reticuloendothelial iron accumulation in the initial stages and an onset in the fourth or fifth decades (105).
Secondary iron overload leads to severe morbidity in patients with thalassemia and sidero- blastic anemia who have accelerated ineffective erythropoiesis (117). They continue to absorb excessive quantities of iron despite increasing iron stores if they are anemic (118). Finch proposed the existence of two regulators of iron absorption, a “stores regulator” and an “erythropoi- etic regulator” (119). The “erythropoietic regulator” was postulated to override the control exerted by the “stores regulator” in these conditions. Recent studies point to a common mediator, hepcidin, for both regulators (22), but also provide support for the apparent dominance of erythropoietic rate in the control of iron absorption. Hepcidin production has been reported to be decreased despite elevated serum ferritin levels (indicative of increased iron stores) in the presence of accelerated erythropoiesis (120, 121), leading to continued iron accumulation. Repeated blood transfusions also contribute signifi- cantly to the iron overload in these patients.
There are several other rarer causes of iron overload. They include atransferrinemia as well as conditions that lead to organ/tissue specific iron overload. They are beyond the scope of this review. Examples include abnormalities of iron trafficking in the mitochondrion (122) and aceru- loplasminemia (123, 124).
Anemia of inflammation (anemia of chronic disease)
The anemia of inflammation is a mild or moderate anemia that is characterized by decreased iron release from macrophage stores, reduced absorp- tion, restriction of the supply available for red cell production and reduced plasma iron and transfer-
rin concentrations (125). Many investigators have postulated that it is a vital host response that evolved to deprive pathogens of iron, and that it is one of the mechanisms that constitute “nutritional immunity” (126, 127).
The accumulating body of experimental evi- dence related to hepcidin indicates that increased hepcidin production, induced by the inflamma- tory cytokine IL6, accounts for almost all of the clinical and laboratory features of the anemia of inflammation (128, 129). The hepcidin response to inflammation appears to be independent of iron status.
Although the former name of the anemia of inflammation, “anemia of chronic disease,” sug- gested slow evolution of the characteristic labora- tory findings, the fall in plasma iron concentration
was well known to occur rapidly after the onset of infection or inflammation. Recent studies demon- strate that synthetic hepcidin administered to mice causes hypoferremia within hours of a sin- gle intraperitoneal injection (130).
C
ONCLUSIONMajor advances have been made in understanding the physiology of human iron metabolism over the past fifty years, although many questions remain to be answered. The scientific knowledge base has provided a sound foundation for approaches to combating nutritional iron deficiency. I have provided only a brief overview of some of the highlights that are relevant to nutrition and nutri- tional anemia.
71 Iron metabolism
R
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