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A previous paper on this website covered three aspects of iron deficiency (ID): classification, definitions and reference values, and prevention. This second paper on iron deficiency describes the indications for investigation, the choice of investigations, and their differential diagnosis.
Although the aim of this web site is to present useful and interesting information on nutrition, it is important to consider exactly how a deficiency may be diagnosed and to consider its differential diagnosis. Therefore, reference is also made to many non-nutritional conditions.
Indications for investigation
Clinical presentation
Clinical signs are helpful in severe anaemia including pale conjunctivae (sensitivity 74%) and nail beds (specificity 96%). Blue sclerae have been described in severe anaemia but the value of the sign is doubtful. Milder degrees of anaemia (8-10g/dl, for example) are difficult to detect clinically and early determination of haemoglobin concentration is indicated whenever there is a possibility of anemia.
ID may play a role in many presentations including ischaemic stroke, apparent asthma, cyanotic heart disease and gastric trichobezoar. Other deficiencies often coexist with ID, of vitamin A or D, for instance, so the presence of one deficiency should initiate the search for others.
Wherever possible, children sufficiently ill to attend or be admitted to hospital, whatever their provisional diagnosis, should have a haemoglobin level and RBC indices determined as the simplest form of opportunistic screening. When malabsorption is demonstrated or suspected, an oral iron absorption test is sensitive as a screening tool for upper intestinal absorption.
Age of the child
Most ID occurs in toddlers and adolescents because the increase in haemoglobin iron per unit of body weight is greatest at these ages. There is little increase in total body iron in the first four months of life. As the haemoglobin falls from around 18g/dl at birth to 14g/dl during the first two weeks of life, the liberated iron is stored and then gradually reused as the total mass of circulating haemoglobin begins to increase with growth. Between four and twelve months, total body iron increases by about 130mg, and an external source of iron becomes necessary. If this need is not met, ID occurs and anaemia develops usually after the first birthday. Boys need more iron at adolescence because of the increase of muscle and myoglobin. Subsequently, these increased requirements due to changes in body composition subside, but increased requirements continue in girls following menarche.
Preterm babies are born with a lower concentration of haemoglobin, so any physiological haemolysis liberates less iron for stores. Erythropoeitin, if given, increases iron requirements, as does catch-up growth. Light for gestational age babies often have a raised haemoglobin level at birth reflecting intrauterine hypoxia. Initially, their post-haemolysis iron stores are higher but the rapid catch-up growth increases demands. In a normal term baby, the total haemoglobin mass doubles during the first year of life (from 180 mg at birth to 340mg at one year). In a preterm (1kg) baby, the increase is six-fold (50 to 300mg). In a 2 kg baby born at term, the increase is three-fold (110-330mg).
Many adolescent girls try to control their weight and inadvertently limit iron intake. Other adolescents pass through a temporary period of vegetarianism as a result of their concerns with animal welfare. While adequate iron nutrition is achievable on a vegetarian diet, it must provide iron sources (such as pulses) and enhancers of absorption (vitamin C and fish or poultry, if acceptable). Temporary, unskilled vegetarianism may result in insufficient absorbed iron.
Geographical location
IDA is a major public health problem in developing countries. Inadequate intake of iron-containing foods, poor bioavailability of iron from cereal-based diets and chronic infection, including intestinal blood loss from hookworms, are the major causes of anemia. There is variable evidence concerning the effects of severe maternal iron deficiency (such as often occurs in developing countries) on the haemoglobin of their babies. Generally, few studies have found this factor influences haemoglobin in the neonatal period, but as infancy progresses, the prevalence of anemia increases in the infants of these mothers. It is not clear whether this reflects poor iron stores at birth or the same iron deficient intake shared by both the mother and her baby.
Children of immigrants or refugees have more iron deficiency due to socio-economic deprivation (living in inner city areas with overcrowding and limited parental income), language problems and resulting health education difficulties, and unfamiliarity with foods available in the new environment (often fueling a tendency to rely on milk and puddings). They also have problems surrounding food customs that are difficult to follow such as the need for halal meat by Muslims, which may not be readily available. In such families, mothers inexperienced in providing a balanced vegetarian diet may give their children a meat free diet. Reports describe such problems in children from Southeast Asia, Latin America and Eastern Europe living in the USA, UK, Norway and Switzerland.
Dietary history
Infants who continue to receive only breast milk after the first six months of life are at increased risk. Breastfeeding may continue after six months without difficulty, so long as other foods providing available iron are introduced.
Also at risk are infants who are changed from an infant formula to whole cows’ milk before the age of one year due to an inadequate intake of dietary iron or increased intestinal iron loss.
In toddlers in Cleveland, USA, a simple dietary history predicted microcytic anaemia (sensitivity 71percent, specificity 79 percent), but a quarter of the anaemic children were not identified. In Sydney, a low meat intake (haem iron, in other words) and whole cows’ milk given before the first birthday were significant risk factors.
Athletic performance
Endurance sports may lead to blood loss from the gut and urinary tract. Therefore, athletic girls who have passed menarche and are trying to become or stay slim may be at particular risk of iron deficiency.
Which investigations
It would be impractical to initially use the entire battery of investigations for iron deficiency so simpler approaches for first assessments are used.
Haemoglobin concentration alone
Haemoglobin levels in the general population alone can be useful. Haemoglobin levels among children and adults in an area can be determined through screening. If the distribution of levels in both children and women of childbearing age, but not in men, is moved to the left, then dietary deficiency is likely. If the distribution is moved to the left in men as well, then probably other factors are operating, malaria or hookworm, for instance. This approach has been used to diagnose ID in Pakistan, Zanzibar and Alaska, but has been questioned in Thailand.
The Hemocue method, using a portable machine, is often used when access to a haematology laboratory is difficult or too expensive. It is currently used in many developing countries. As with all methods using capillary blood, it is essential to obtain a free flow of blood from the finger or heel in order to achieve a satisfactory sample.
Haemoglobin and RBC indices
Electronic counters based on impedence or light scattering are in common use in developed countries. The likelihood of iron deficiency may be assessed from such specific indices as mean corpuscular volume (MCV) and red cell distribution width (RDW).
Increasing use is also now made of histogram distributions of red blood cell volume rather than the indices alone, which are summaries of the distributions. With some methods, “Red cell cytograms” are available in which red cell volume is plotted against red cell haemoglobin concentration for all red cells counted. Counter errors sometimes occur due to cold agglutinins causing clumping, high white cell counts, and hyperosmolar plasma. A couple of crude checks for internal consistency include verifying that the haemoglobin in g/dl is about three times the RBC and that the calculated and corrected packed cell volume (PCV) is about three times the haemoglobin level.
Typically, in iron deficiency anaemia, the haemoglobin (Hb) and MCV are reduced, RDW is increased (due to microcytosis and anisocytosis), red cell haemoglobin distribution width (HDW) is increased (due to anisochromia), and the ‘shape’ of the cell cytogram scatter is moved down and to the left with a large proportion of cells in the hypochromic microcytic zone. During treatment and the resulting increase in iron, double peaks (due to older ID cells, and younger iron replete cells) are seen in the histograms for red cell volume and red cell haemoglobin, and the cytogram shows more cells in the normocytic normochromic zone. The application of these more sophisticated methods to population screening has not been evaluated. Some have recommended that MCV and RDW be routinely used in well baby clinics.
Other investigations
Erythropoietic protoporphyrin (EPP) alone (or zinc protoporphyrin, ZPP) is used for screening and also as an indicator for a therapeutic trial of iron in some American paediatric practices. In iron deficiency, zinc fills the iron pocket in the protoporphyrin molecule. ZPP determination requires only 20 microlitres of blood and is easily measured in a haematofluorimeter. It also remains abnormal for a week or so, even if iron therapy commenced before the test. However, it is also abnormal in the anaemias of inflammation and in lead poisoning.
Serum ferritin may be determined on small blood samples but careful methodology is necessary. It is elevated during acute infections, chronic diseases and in liver disease irrespective of the iron stores, but iron deficiency is the only cause of a low level.
Using serum transferrin receptor concentration as a test has garnered considerable interest. The concentration reflects the number of transferrin receptors on immature red cells and so usually reflects the rate of bone marrow erythropoeisis. Iron deficiency, however, also results in an “unproportional” increase in level. An increased concentration is an early indicator of functional iron deficiency and sometimes occurs before the plasma ferritin has fallen. A major advantage with this indicator is that it remains normal in many chronic disorders if iron deficiency is not present. It is, however, elevated in the thalassaemias even when there is no iron deficiency. Its use as an index of iron deficiency in infancy and adolescence has been questioned and it would be unwise to use this test alone without other measurements of ID.
Interpretation of investigations
Hereditary causes of microcytosis, inflammation and various chronic diseases, and occasionally lead poisoning, may cause difficulties when interpreting test results.
Microcytosis
Apart from the thalassaemias, hereditary causes of microcytosis are quite rare. Most are associated with iron overload of tissues but a small number of children have been described with ID due to a defect in absorption.
The red blood cells in IDA and the thalassaemias show similar indices. The degree of anisocytosis and hence the RDW is usually higher in IDA, particularly in relation to the degree of microcytosis. Various mathematical ratios of red cell indices have been suggested to help in differentiating between them. Using cytometry plots, the proportion (%) of hypochromic cells is greater than the proportion of microcytic cells in iron deficiency, whereas the reverse is true in thalassaemia. In thalassaemias, there may be an increase in hypochromic macrocytes, as well. When there is any possibility of thalassaemias, however, it is usually better to proceed directly to haemoglobin electrophoresis and A2 determination; but iron deficiency in association with thalassaemia may temporarily mask the characteristic changes in A2 and HbF. In a United States study, half of people with beta thalassaemia trait had a raised ZPP level and so did a quarter of those with haemoglobin E or alpha thalassaemia trait, suggesting that ZPP may be abnormal in thalassaemia traits. Unfortunately, the exact iron status of the subjects was not defined.
Inflammation
The anaemias of infection and chronic diseases are classically normochromic and normocytic, but hypochromia and microcytosis occur in about a third of infected children. Even after a mild infection, many measurements move in the same direction as occurs in ID, but the ferritin level rises and the serum transferrin receptor level remains normal. On the other hand, tropical infections such as malaria did not interfere with the use of EPP and ferritin in the diagnosis of ID in Zanzibar.
In chronic disease such as rheumatoid arthritis, interpretation is difficult. While measurements suggesting ID may be due to cytokine activity, true ID (demonstrated by bone marrow examination) may also occur.
Lead poisoning
This anaemia is classically normocytic and normochromic but ID is often present as well, which modifies the RBC indices. The ZPP level is raised, not because there is insufficient iron to join with protoporphyrin in forming haem, but because ferrochetalase, which catalyses the reaction, is inhibited by lead.
There is variable evidence linking iron deficiency with an increased risk of lead poisoning. Some years ago, anaemia with pica would prompt investigation for both disorders; but as environmental lead has decreased, the diagnosis is less common. If in doubt, determine the blood lead and watch the response to iron. Lead diuresis and the reduction in blood lead following chelation treatment are less in iron deficient children.
See Also: Iron Deficiency, Part 1 and Iron Deficiency, Part 3
References
An extensive bibliography is given in Wharton BA. Iron deficiency in children: detection and prevention. Br J Haematol. 1999 ;106:270-80.
Some reviews from various countries, published since the first part of iron deficiency appeared on this website in late 2002, are given below. Supplement 1 in the Journal of Nutrition 2003 133 is a convenient collection of papers and so are the series of papers in the October editions of Pediatrics 2003 112 and Am J Clin Nutrit 2003 78. These journals are available on their websites or via Pub Med.
Beard J. Iron deficiency alters brain development and functioning.J Nutr. 2003 May;133(5 Suppl 1):1468S-72S.
Branca F, Rossi L. The role of fermented milk in complementary feeding of young children: lessons from transition countries.Eur J Clin Nutr. 2002 Dec;56 Suppl 4:S16-20.
Davidsson L. Approaches to improve iron bioavailability from complementary foods.J Nutr. 2003 May;133(5 Suppl 1):1560S-2S.
Gera T, Sachdev HP. Effect of iron supplementation on incidence of infectious illness in children: systematic review. BMJ. 2002 Nov 16;325(7373):1142.
Gordon N. Iron deficiency and the intellect.Brain Dev. 2003 Jan;25(1):3-8.
Hurrell R, Bothwell T, Cook JD, Dary O, Davidsson L, Fairweather-Tait S, Hallberg L, Lynch S, Rosado J, Walter T, Whittaker P; SUSTAIN Task Force. The usefulness of elemental iron for cereal flour fortification: a SUSTAIN Task Force report. Sharing United States Technology to Aid in the Improvement of Nutrition. Nutr Rev. 2002 Dec;60(12):391-406.
Jaleel A, Siddiqui IA, Rahman MA. Do we need daily iron supplementation? Comments and controversies. J Pak Med Assoc. 2003 Apr;53(4):162-5.
Narasinga Rao BS. Anaemia and micronutrient deficiency.
Natl Med J India. 2003;16 Suppl 2:46-50
Zlotkin S. Clinical nutrition: 8. The role of nutrition in the prevention of iron deficiency anemia in infants, children and adolescents.CMAJ. 2003 Jan 7;168(1):59-63.
This material has been prepared by members of the IFM's Advisory Committee on Child Health and Nutrition.
January 2004
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