Correspondence
Disorders of Iron Metabolism
N Engl J Med 2000; 342:1293-1294April 27, 2000
- Article
To the Editor:
In her review of iron metabolism (Dec. 23 issue),1 Dr. Andrews omits one of the most common causes of iron deficiency, the functional iron deficiency seen in uremia. This form of iron deficiency is multifactorial and distinct from the anemia of chronic disease, despite sharing some of the same laboratory characteristics.2 One important distinction is that the deficiency seen in uremia often responds to iron supplementation, even when ferritin levels are within the standard normal range, and different targets are therefore sought in this context (typically >100 to 200 μg per liter).3,4 Another clue is the presence of a high percentage of circulating hypochromic red cells, which are a hallmark of the functional iron deficiency thought to be due to reduced movement of iron from the labile iron pool to developing erythroblasts.3,4 The functional iron deficiency of uremia is exacerbated by factors such as aluminum toxicity, hyperparathyroidism, and inadequate dialysis, and if present these factors should be aggressively corrected.3
4 ReferencesPeter A. Andrews, M.D.
South West Thames Renal Unit, Carshalton SM5 1AA, United Kingdom1
Andrews NC . Disorders of iron metabolism. N Engl J Med 1999;341:1986-1995
Full Text | Web of Science | Medline2
Kaltwasser JP. Disturbances of iron metabolism in the anemia of chronic disorders. In: Bauer C, Koch KM, Scigalla P, Wieczorek L, eds. Erythropoietin: molecular physiology and clinical applications. New York: Marcel Dekker, 1994:189-206.
3
Macdougall IC . Poor response to erythropoietin. BMJ 1995;310:1424-1425
CrossRef | Web of Science | Medline4
Horl WH ,Cavill I ,MacDougall IC ,Schaefer RM ,Sunder-Plassman G . How to diagnose and correct iron deficiency during r-huEPO therapy -- a consensus report. Nephrol Dial Transplant 1996;11:246-250
Web of Science | Medline
To the Editor:
In her timely review article on iron metabolism, Dr. Andrews oversimplifies the issue of iron excretion. She states that humans have no physiologic pathway for iron excretion and that iron deficiency results from any condition in which dietary iron intake does not meet the body's demands. There is a basal obligatory loss of iron from the body that results from the physiologic exfoliation of cells from epithelial surfaces, including the skin, genitourinary tract, and gastrointestinal tract. Dr. Andrews refers to the “set-point” mechanism that regulates iron absorption during the development of enterocytes and mentions that ferritin is lost when senescent cells are sloughed. The amount of iron incorporated into the developing crypt cell varies according to the state of iron repletion, and Dr. Andrews mentions that this process represents an important mechanism of iron loss. Surely this should be considered a physiologic pathway for iron excretion. The integument may represent a similar avenue for iron excretion, related to the plasma transferrin saturation,1 which, in turn, is correlated with the state of the body iron stores.2 In our studies on total and compartmental iron losses, we reported that iron status influences the rate of iron loss.1 Patients with iron overload of the African type excreted, on average, over twice as much iron as did those considered to have normal iron stores. Earlier data suggested that iron losses fall to about 0.5 mg daily in patients with iron deficiency.3 From these data, it appears that the variable component of iron excretion might differ by a factor of four between patients with iron deficiency and those with iron overload. The incompletely understood physiologic mechanisms of iron excretion cannot entirely be discounted in equations for body iron balance, in either health or disease.
3 ReferencesRalph Green, M.D.
University of California, Davis, Sacramento, CA 958171
Green R ,Charlton R ,Seftel H , et al. Body iron excretion in man: a collaborative study. Am J Med 1968;45:336-353
CrossRef | Web of Science | Medline2
Bothwell TH, Charlton RW, Cook JD, Finch CA. Iron metabolism in man. Oxford, England: Blackwell Scientific, 1979.
3
Dubach R ,Moore CV ,Callender S . Studies in iron transportation and metabolism. IX. The excretion of iron as measured by the isotope technique. J Lab Clin Med 1955;45:599-615
Medline
To the Editor:
The illustrations in the article by Dr. Andrews are simple and stunning. However, they may be overly simplistic, and the review fails to address certain areas of biologic relevance regarding absorption of iron.
In North America and Europe, heme is the greatest source of body iron. Although one third of dietary iron is heme, two thirds of body iron is derived from dietary heme. Heme enters intestinal cells as a metalloporphyrin and does not compete with nonheme iron for uptake; ultrastructural studies suggest this is an endosomal process. In countries with little meat in the diet, iron deficiency is prevalent despite consumption of a diet containing similar amounts of iron to that found in countries where meat is a prominent feature of the diet.
Ferric iron uses a different pathway than ferrous iron to enter cells.1 This was shown by competitive-inhibition studies, the use of blocking antibodies against divalent metal transporter 1 (DMT1) and β3-integrin, and transfection experiments in which DMT1 DNA was used. It is suggested that ferric iron uses β3-integrin and mobilferrin to enter cells, whereas ferrous iron uses DMT1. It is not known which pathway transports the majority of iron in humans. Most nonheme dietary iron is ferric iron. In mice and rats, iron absorption may involve more ferrous iron than ferric iron, because these animals excrete moderate quantities of ascorbate in bile. In contrast, humans are a scorbutic species and are unable to synthesize this agent to reduce ferric iron levels. This fact may obscure the detection of DMT1 mutations in humans.
1 ReferencesMarcel E. Conrad, M.D.
Jay N. Umbreit, M.D., Ph.D.
University of South Alabama, Mobile, AL 366881
Conrad ME ,Umbreit JN ,Moore EG . Iron absorption and transport. Am J Med Sci 1999;318:213-229
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Andrews replies:
To the Editor: I appreciate the point made by Dr. Andrews regarding the functional iron deficiency seen in uremia. Because of space limitations, I could not cover all disorders involving defects in iron recycling.
I agree with Dr. Green that losses of iron through sloughing of skin and mucosal cells are important when considering overall iron balance. I should qualify the statement I made in my review article and say that the excretion of iron does not appear to be regulated by the liver or kidney.
Drs. Conrad and Umbreit are correct in saying that heme iron is important in Western diets. The absorption of heme iron is not understood at a molecular level at this time and was therefore not included in the model depicting nonheme iron absorption. I disagree, however, that iron deficiency in underdeveloped countries is due to inadequate absorption of nonheme iron. Rather, it most commonly results from chronic intestinal blood loss due to parasitic infections.
I did not discuss the integrin–mobilferrin hypothesis in the review because it is not widely accepted among investigators studying iron. In the 10 years since this hypothesis was first proposed by Drs. Conrad and Umbreit, no other laboratory has published a paper reporting its experimental validation. For this reason, I thought it was inappropriate to mention the hypothesis in a review for a general audience. In contrast, in less than three years since the role of DMT1 was first reported, many investigators have confirmed that it is important for intestinal iron uptake. Although most dietary iron is in the ferric form, there is enzymatic ferric reductase activity in the duodenal brush border1 that is capable of converting ferric iron to the ferrous form that is transported by DMT1. There is no need to invoke a distinct process of ferric iron transport.
1 ReferencesNancy C. Andrews, M.D., Ph.D.
Children's Hospital, Boston, MA 021151
Riedel H-D ,Remus AJ ,Fitscher BA ,Stremmel W . Characterization and partial purification of a ferrireductase from human duodenal microvillus membranes. Biochem J 1995;309:745-748
Web of Science | Medline
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Hoe Suk Kim, YoonSeok Choi, In Chan Song, Woo Kyung Moon. (2009) Magnetic resonance imaging and biological properties of pancreatic islets labeled with iron oxide nanoparticles. NMR in Biomedicine 22:8, 852-856
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Joseph Lemire, Puja Kumar, Ryan Mailloux, Kathyrn Cossar, Vasu D. Appanna. (2008) Metabolic adaptation and oxaloacetate homeostasis in P. fluorescens exposed to aluminum toxicity. Journal of Basic Microbiology 48:4, 252-259
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