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CHAPTER 38 IRON DEFICIENCY

CHAPTER 38 IRON DEFICIENCY
Williams Hematology

CHAPTER 38 IRON DEFICIENCY

VIRGIL F. FAIRBANKS
ERNEST BEUTLER

Definition and History
Etiology and Pathogenesis

Etiology

Pathogenesis

Prevalence
Clinical Features
Laboratory Features

Blood Cells

Marrow

Serum Iron Concentration

Iron-Binding Capacity and Transferrin Saturation

Serum Ferritin

Erythrocyte Ferritin

Erythrocyte Zinc Protoporphyrin

Serum Transferrin Receptor

Reticulocyte Hemoglobin Content

57Co Absorption

Iron Tolerance Tests
Differential Diagnosis

Differentiation from Other Forms of Anemia

Special Studies

Therapeutic Trial
Therapy, Course, and Prognosis

Oral Iron Therapy

Parenteral Iron Therapy

Course

Prognosis
Chapter References

Iron deficiency and iron deficiency anemia are common nutritional and hematologic disorders in North America and worldwide, affecting an estimated 2 billion people. In infants and young children iron deficiency is most commonly due to insufficient dietary iron. In young women it is most often the result of blood loss in menstruation or as a result of pregnancy. In older adults bleeding may be from the gastrointestinal tract, as from hemorrhoids, bleeding peptic ulcer, hiatus hernia, colon cancer, or angiodysplasia. It may result from uterine leiomyomas or carcinoma, or a renal tumor. Pulmonary blood loss is usually evidenced by chronic hemoptysis due to infection, malignancy, or as a result of idiopathic pulmonary hemosiderosis. However, bloody sputum may be swallowed, and pulmonary bleeding may be mistaken for gastrointestinal bleeding. Iron deficiency has adverse effects on activity of numerous enzymes and in infants can result in impairment of growth and intellectual development. The hematologic features of iron deficiency are nonspecific and too often confused with other causes of microcytic anemia such as thalassemias, chronic disease, renal neoplasms, and other disorders. A low serum ferritin concentration is an excellent indicator of iron deficiency. Erythrocyte zinc protoporphyrin assay is a useful screening test but lacks specificity. Other laboratory tests that may prove useful include assays for serum transferrin receptor, erythrocyte ferritin concentration, or serum ferritin iron saturation. Diagnosis of iron deficiency, particularly in an adult, obliges the clinician to determine the site and cause of blood loss and to rectify that if possible. Treatment of iron deficiency with ferrous salts, in doses of 100 to 200 mg of elemental iron daily, is superior to, much safer, and far less costly than parenteral therapy. Enteric-coated and prolonged-release preparations should be avoided. Complete correction of anemia is expected in 8 to 12 weeks, depending on patient’s age. If this response is not achieved, the patient and the diagnosis require reevaluation. Administration of iron should be continued for 8 months after correction of anemia or as long as bleeding continues.

The following abbreviations and acronyms may be found in this chapter: MAO, monoamine oxidase; MCH, mean erythrocyte hemoglobin content; MCV, mean corpuscular volume; RDA, recommended daily allowance; RDW, red cell distribution width; TIBC, total iron-binding capacity; UIBC, unsaturated or latent iron-binding capacity.

DEFINITION AND HISTORY
Iron deficiency is the state in which the content of iron in the body is less than normal. It occurs in varying degrees of severity that merge imperceptibly into one another. Iron depletion is the earliest stage of iron deficiency, in which storage iron is decreased or absent but serum iron concentration and blood hemoglobin levels are normal. Iron deficiency without anemia is a somewhat more advanced stage of iron deficiency, characterized by decreased or absent storage iron, usually low serum iron concentration and transferrin saturation, without frank anemia. Iron deficiency anemia is the most advanced stage of iron deficiency. It is characterized by decreased or absent iron stores, low serum iron concentration, low transferrin saturation, and low hemoglobin concentration or hematocrit value.
In certain rare disorders, such as idiopathic pulmonary hemosiderosis or paroxysmal nocturnal hemoglobinuria (see Chap. 56), iron deficiency anemia may occur without iron depletion as a result of redistribution of body iron.
The clinical manifestations of iron deficiency anemia appear to have been recognized in earliest times. A disease characterized by pallor, dyspnea, and edema was described in about 1500 BC in the Papyrus Ebers, a manual of therapeutics believed to be the oldest complete manuscript extant.1 This ancient disease may have been due to chronic blood loss from hookworm infestation. Chlorosis, or “green sickness,” was well known to European physicians after the middle of the sixteenth century. In France, by the middle of the seventeenth century, iron salts and other remedies (including, oddly enough, phlebotomy) were used in its treatment. Not long thereafter, iron was recommended by Sydenham as a specific remedy for chlorosis. For the 100 years preceding 1930, iron was used in the treatment of chlorosis, often in ineffective doses, although the mechanism of action of iron and the appropriateness of its use were highly controversial.
By the beginning of the twentieth century, it had been established that chlorosis was characterized by a decrease in the iron content of the blood and by the presence of hypochromic erythrocytes. Most of the fundamental work on iron metabolism and iron deficiency has been carried out during this century.2
ETIOLOGY AND PATHOGENESIS
ETIOLOGY
Iron deficiency may occur as a result of chronic blood loss, inadequate dietary iron intake, malabsorption of iron, diversion of iron to fetal and infant erythropoiesis during pregnancy and lactation, intravascular hemolysis with hemoglobinuria, or a combination of these factors.
BLEEDING
Gastrointestinal In men and in postmenopausal women iron deficiency is most commonly caused by chronic bleeding from the gastrointestinal tract. A partial list of causes of such blood loss is presented in Table 38-1. In the adult the commonest causes of gastrointestinal bleeding are peptic ulcer, hiatal hernia, gastritis (including that due to alcohol or aspirin ingestion), hemorrhoids, vascular anomalies (such as angiodysplasia), and neoplasms. Helicobacter pylori infection has been associated with an increased incidence of iron deficiency, even in the absence of frank peptic ulceration.3

TABLE 38-1 SOURCES OF BLOOD LOSS

Diaphragmatic (hiatal) hernia is frequently associated with gastrointestinal bleeding. The frequency of anemia ranges from 8 to 38 percent.4,5,6 and 7 Bleeding is much more likely to occur in patients with paraesophageal or large hernias than in those with sliding hernias or small ones.4,5,8 It is likely that hemorrhage follows mucosal injury at the neck of the sac, where the herniated stomach rides to and fro over the crus of the diaphragm during respiration.4,5,7 Mucosal changes cannot always be demonstrated by esophagoscopy or gastroscopy in patients who have had blood loss from hiatus hernia. However, a linear gastric erosion, also called a Cameron ulcer, commonly occurs on the crests of mucosal folds at the level of the diaphragm and appears to be the site of bleeding. In a series of 109 cases of large diaphragmatic hernias, a third had such linear erosions; most of these patients were anemic.8
Gastritis due to drug ingestion is another common cause of bleeding. Aspirin ingestion is as likely to cause bleeding in patients without preexisting ulcer as in those with peptic ulcer.9 Other medications (such as glucocorticoids, indomethacin, ibuprofen, or other nonsteroidal antinflammatory drugs) may also cause bleeding by inducing gastric or duodenal ulcers or colitis.10 Use of enteric-coated medications containing potassium chloride has led to serious bleeding from enteric ulcerations. Gastritis due to alcohol ingestion may also cause significant blood loss.
In one study of 114 outpatients referred to gastroenterologists for investigation of iron deficiency, 45 had upper gastrointestinal and 18 had colonic sources of bleeding.11 In 100 other patients in whom the site of bleeding could not be established by any means short of laparotomy, a malignancy was found to be the cause in 10 percent.12 Enteritis after therapeutic irradiation of abdominal viscera12 may also be a cause of gastrointestinal bleeding leading to iron deficiency anemia. Colon cancer, colonic diverticula, periampullary tumors, leiomyomas, adenomas, and other malignant or benign neoplasms of the intestine are among the causes of chronic blood loss.13,14,15 and 16
Chronic blood loss from esophageal or gastric varices may lead to iron deficiency anemia. In hereditary hemorrhagic telangiectasia (Chap. 121 and Plate XXV-41, and Plate XXV-42), characteristic lesions commonly occur on fingertips, nasal septum, tongue, lips, margins (helices) of ears, oral and pharyngeal mucosa, palms and soles, and other epithelial and cutaneous surfaces throughout the body. Those lesions that occur in the gastrointestinal tract are particularly likely to bleed and to cause iron deficiency to occur. Tortuous, dilated sublingual venous structures, the cherry hemangiomas commonly seen in the elderly, and the spider telangiectases of chronic liver disease are usually easily distinguished from the lesions of hereditary hemorrhagic telangiectasia. Bleeding from intestinal telangiectases has also been observed in scleroderma17 and in Turner syndrome.18 Cutaneous hemangiomas (blue rubber bleb nevus) may be associated with hemorrhage from intestinal hemangiomas.19,20 and 21 Chronic blood loss is often the cause of anemia in rheumatoid arthritis (perhaps a result of the aspirin or glucocorticoid therapy), ulcerative colitis, and regional enteritis. Hemorrhoidal bleeding may lead to severe iron deficiency anemia. Chronic blood loss may result from diffuse gastric mucosal hypertrophy (Ménétrier disease).22 Gastric ulceration and bleeding may also occur in disorders of hypergastrinemia, as in Zollinger-Ellison syndrome and pseudo-Zollinger-Ellison syndrome.23 Polycythemia vera is typically associated with iron deficiency as a result either of spontaneous gastrointestinal hemorrhage that commonly occurs in this disorder or phlebotomy therapy, or both mechanisms.
Anemia that follows subtotal gastrectomy has usually been attributed to reduced absorption of dietary iron,24,25 but occult intermittent gastrointestinal bleeding may also be a contributory factor. Of 8 patients whose erythrocytes were labeled with Na251CrO4 to permit precise quantitation of daily fecal blood loss,26 7 were shown to lose from 3.2 to 6.5 ml of blood per day. This is a very slight but significant increase in daily fecal blood loss which is normally less than 2 ml per day. Over a span of several years this could well lead to iron deficiency anemia. Chemical tests for fecal blood loss are usually insensitive to a daily loss of less than 5 to 10 ml of blood, although this depends to some extent on the site of bleeding within the gastrointestinal tract.
The lesions of angiodysplasia may occur in any part of the gastrointestinal tract but are most frequent in the cecum or ascending colon.27 These tiny vascular anomalies may be the cause of significant blood loss. Endoscopy is usually required for diagnosis.27,28,29 and 30 Vascular ectasia of the gastric antrum exhibits a characteristic endoscopic appearance (“watermelon stomach”) and is another cause of blood loss.28,31,32 and 33 Hemorrhage into the gallbladder is a rare cause of chronic iron deficiency anemia.34
Intestinal parasitism, particularly by hookworms, is a major cause of gastrointestinal blood loss in many parts of the world. Hemostatic defects, particularly those related to abnormal platelet function or number, may lead to gastrointestinal bleeding. Gastrointestinal bleeding is common in von Willebrand disease (Chap. 135). When a patient with a disorder of hemostasis suffers from gastrointestinal bleeding, one must consider the possibility that the bleeding may not be caused by a hemostatic defect alone and that an anatomic lesion of the gastrointestinal tract may also be present.
Ingestion of whole cow’s milk may induce protein-losing enteropathy and gastrointestinal bleeding in infants,35,36,37,38 and 39 probably on the basis of hypersensitivity or allergy. In four such cases observed endoscopically, erosive gastritis or gastroduodenitis was demonstrated as the probable source of bleeding.37 At least during the first year of life, children should not be given whole bovine milk, either raw or pasteurized.39 More protracted heating, as in preparation of infant formulas, eliminates this problem. Anemia itself may increase the amount of blood lost in the infant’s feces, perhaps because of an adverse effect of iron deficiency on the intestinal mucosa. Intrinsic lesions of the gastrointestinal tract, such as those listed above, may cause bleeding in infants and in older children as well. In infants or small children, peptic ulcer is an uncommon cause of gastrointestinal bleeding. Meckel diverticulum usually causes gross gastrointestinal bleeding, manifested as hematochezia. Since Meckel diverticulum is usually not demonstrated by gastrointestinal x-ray examination, it is easily overlooked as a cause of gastrointestinal hemorrhage.
Respiratory Tract Recurrent hemoptysis may lead to iron deficiency anemia. It may be due to congenital anomalies of the respiratory tract, endobronchial vascular anomalies, chronic infections, neoplasms, or valvular heart disease. Severe iron deficiency anemia is a manifestation of idiopathic pulmonary hemosiderosis and of Goodpasture syndrome (progressive glomerulonephritis with intrapulmonary hemorrhage).40 In some of these disorders, hemoptysis may not be observed, but sufficient amounts of blood-laden sputum may be swallowed to result in positive tests for occult blood in the stools.
Genitourinary Tract Menstrual bleeding is a very common cause of iron deficiency.41 The amount of blood lost with menstruation varies markedly from one woman to another and is often difficult to evaluate by questioning the patient. The average menstrual blood loss is about 40 ml per cycle. Blood loss exceeds 80 ml (equivalent to about 30 mg of iron) per cycle in only 10 percent of women.42 The volume of blood lost in the course of one menstrual cycle may be as high as 495 ml in apparently healthy, nonanemic women who do not regard their menstrual flow to be excessive. The amount of menstrual blood lost does not seem to vary markedly from one cycle to another for any given individual.43 The use of an intrauterine coil for contraception increases menstrual blood loss,44 especially during the first year of use. Since the absorption of 1 mg of iron per day requires a dietary intake of between 10 and 20 mg of iron, it is easy to understand why, with an average dietary iron intake of approximately 10 mg per day, iron balance in many menstruating women is precarious.
Excessive bleeding may be caused by uterine fibroids and malignant neoplasms. Neoplasms, stones, or inflammatory disease of the kidney, ureter, or bladder may cause enough chronic blood loss to produce iron deficiency.
FACTITIOUS ANEMIA
Factitious anemia due to self-inflicted bleeding may present a formidable diagnostic and therapeutic problem. This rare condition has also been called, in literary allusion to a fictitious character, Lasthénie de Ferjol syndrome. (In Barbey d’Aurevilly’s gloomy novel, Une Histoire Sans Nom, Lasthénie de Ferjol was a young woman noted for extreme pallor and languor, who habitually and secretly practiced autodesanguination by thrusting needles into her heart.) Most patients are women. There is often a history of numerous blood transfusions. The anemia is chronic and may be severe, with blood hemoglobin concentration persistently as low as 5 to 6 g/dl. The site of induced blood loss is obscure. Hence, patients are subjected to numerous radiographic and endoscopic examinations, usually to no avail. The patients are usually refractory to medical advice and therapy.45,46,47 and 48 The patients may be depressed and suicidal; some also suffer anorexia nervosa. Psychiatric care is needed but often is unsuccessful.
NOSOCOMIAL ANEMIA
In the course of medical care, repetitive blood sampling may result in removal of a large amount of blood,49 and this iatrogenic phlebotomy can result in iron deficiency anemia.
ANEMIA INCIDENT TO BLOOD DONATION
Each whole blood donation removes about 200 to 250 mg of iron from the body. Lesser amounts of iron are removed in the course of donating platelets or leukocytes. Potential donors are screened in blood banks so that those with frank anemia are not phlebotomized. Yet, by the time that they are excluded from donation, blood donors are iron depleted and may readily develop iron deficiency anemia with relatively small additional blood loss.50
PREGNANCY
In pregnancy, the average iron loss resulting from diversion of iron to the fetus for erythropoiesis, blood loss at delivery (equivalent to an average of 150 to 200 mg of iron), and lactation is altogether about 900 mg; in terms of iron content, this is equivalent to the loss of over 2 liters of blood. Approximately 30 mg of iron may be expended monthly in lactation. Since most women begin pregnancy with low iron reserves, these additional demands frequently result in iron deficiency anemia. Iron depletion has been reported in some 85 to 100 percent of pregnant women. The incidence is lower in women who take oral iron supplementation.51,52 Furthermore, iron-deficient mothers are likely to have babies with low iron reserves.53 The clear implication is that all pregnant women should receive prophylactic oral iron, a practice that is often neglected by obstetricians.54
DIETARY IRON DEFICIENCY
In infants, iron deficiency is most often a result of the use of unsupplemented milk diets, which contain an inadequate amount of iron. During the first year of life, the full-term infant requires approximately 160 mg and the premature infant about 240 mg of iron for erythropoiesis. About 50 mg of this need is met by the destruction of erythrocytes, which occurs physiologically during the first week of life. The rest must come from the diet. Milk products are very poor sources of iron, and prolonged breast- or bottle-feeding of infants frequently leads to iron deficiency anemia unless there is iron supplementation. This is especially true of premature infants. Table 38-2 lists the iron content of several widely used infant foods. In recognition of the high prevalence of iron deficiency, and its adverse effects, when infant formula is not iron-supplemented, the American Academy of Pediatrics55 has urged that all infant formulas be iron-fortified; unfortunately, this practice is not universal in North America.

TABLE 38-2 IRON CONTENT OF INFANT FOODS

In older children, an iron-poor diet may contribute to the development of iron deficiency anemia, but other factors, such as intestinal parasitism or bleeding gastrointestinal lesions, may be present.
Estimates of average daily iron intake for various segments of the U.S. population are shown in Table 38-3. These estimates used surveys that asked participants for 24-h recall of their food intake and then estimated the iron intake from the known content of the foods consumed. Since nearly half of the dietary iron intake of Americans is in the form of iron-fortified cereals,56 the assimilable iron content of the diet may be considered to be approximately half of the figures shown in Table 38-3. For most persons in the United States, iron intake is approximately 5 to 7 mg/1000 cal. Children and young women are usually in precarious iron balance, their iron intake being less than 80 percent of the recommended dietary daily allowance (RDA).57

TABLE 38-3 DAILY DIETARY IRON INTAKE IN THE UNITED STATES, MEAN VALUES FOR SELECTED GROUPS*

The RDAs for iron shown in Table 38-3 differ from those shown in Chap. 24 (Table 25-2) and in previous editions of Hematology. In a study of the 24-h-recall dietary data of the Second National Health and Nutrition Examination Survey (NHANES II), conducted in 1976 to 1980, the estimated mean dietary iron intake of young, nonpregnant, nonlactating women was 10.7 mg (median 9.8 mg), or 56 percent of the then-stated RDA.58 Consequently, in 1989 the Food and Nutrition Board of the National Research Council (USA) reduced the RDA from 18 to 15 mg for young, nonpregnant women, and from 15 to 6 mg for infants.59 In the subsequent NHANES III dietary recall survey (conducted in 1988 to 1991), the estimated mean dietary iron intake of young women was 70 to 80 percent of the 1989 RDA, an apparent improvement in iron nutrition, although the estimates of mean iron intake were nearly identical in the two surveys.57 With the lower 1989 RDA for infants, infant iron nutrition also appeared ample.
Iron is present in varying amounts in most foods. Liver is relatively rich in iron. Beans, peas, red meat, poultry, and fish contain smaller amounts of iron, generally not more than 1 mg of iron per ounce. All vegetables (except legumes and cruciferous vegetables such as broccoli) and nearly all fruits are either poor in iron, or, as in spinach, contain unabsorbable iron chelates. Raisins have an undeserved reputation as an iron source; simply because they are dried, the proportion by weight of all minerals is higher than in grapes. Domestic U.S. wines, beers, and other alcoholic beverages contain little iron.60 Nearly all flour in the United States is “enriched” with 12 mg of finely powdered metallic (“reduced”) iron per pound. This provides about 36 mg of iron per kg of enriched bread, rolls, or buns. Thus, a gram of enriched bread has about the same iron content as a gram of beef. However, millers do not add ionic iron because bread made from flour enriched with ferrous salts quickly develops an unpleasant flavor. The iron added to flour is metallic iron, thus insoluble and poorly absorbed, and because flour contains phytates that chelate ionic iron, rendering it unabsorbable, the iron fortification of flour appears to have little, if any, nutritional value (Table 38-4). Microencapsulated ferrous sulfate may improve the bioavailability of iron that is added to food. Another strategy would be iron fortification of dairy products.61,62

TABLE 38-4 IRON FORTIFICATION OF WHITE FLOUR, WHITE BREAD, ROLLS, AND BUNS IN THE UNITED STATES

The iron content of unmodified milk is no greater than that of municipal drinking water obtained from aquifers (prior to water-softening). All dairy products are similarly iron-poor. During the past 30 years there has been an extraordinary change in dietary patterns of Americans. As shown in Fig. 38-1, there has been a marked decline in consumption of red meat and a marked increase in consumption of iron-poor dairy products and snack foods. For example, in the United States, mozzarella cheese consumption has increased approximately 9 percent per year, with consumption increasing from 220 million pounds to more than 2 billion pounds annually in a 25-year interval. Pizza has become a staple in the diet of many Americans. Many secondary and primary schools have franchised commercial pizza vendors in their cafeterias. Potato chips, french fries, and packaged snack foods also now contribute substantially to the average American diet: all are high in fat and low in iron. This is a diet that is conducive to obesity, atherosclerosis, type II diabetes mellitus, and iron deficiency.

FIGURE 38-1 Changes in patterns of food consumption in the United States from 1980 to 1992, showing a marked decrease in consumption of food that has fair to moderate iron content and a marked increase in consumption of iron-poor food. (Based on data from: Third Report on Nutrition Monitoring in the United States, 1995.)57

The scant iron supply of the American diet places young women and children at particular risk of negative iron balance. Since the adult male needs to absorb only about 1 mg iron daily from his diet in order to maintain normal iron balance, the iron requirements of males are very small. Therefore, iron deficiency in men is only very rarely caused by dietary iron deficiency alone. Exceptions to this rule are known, such as the case of a man who remained on a nearly iron-free diet for 27 years.63
MALABSORPTION OF IRON
Intestinal malabsorption of iron is quite an uncommon cause of iron deficiency except after gastrointestinal surgery and in malabsorption syndromes. As many as 50 percent of patients who have undergone subtotal gastric resection develop iron deficiency anemia years later. Many such patients have impaired absorption of food iron, caused in part by more rapid gastrojejunal transit and in part by partially digested food bypassing some of the duodenum as a result of the location of the anastomosis. Fortunately, medicinal iron is well absorbed in postpartial gastrectomy patients. Moreover, gastrointestinal blood loss may also play an important role in anemia following gastric resection (see section on bleeding, gastrointestinal). In malabsorption syndromes, absorption of iron may be so limited that iron deficiency anemia develops over a period of years.64,65 Celiac disease, whether overt or occult, may be associated with iron deficiency anemia.40
INTRAVASCULAR HEMOLYSIS AND HEMOGLOBINURIA
Iron deficiency anemia may occur in paroxysmal nocturnal hemoglobinuria (Chap. 56) and in hemolysis resulting from mechanical erythrocyte trauma from intracardiac myoxomas,66 valvular prostheses, or patches67,68 and 69 (Chap. 50). In these disorders, iron is lost in the urine as hemosiderin and ferritin in diquamated tubular cells and as hemoglobin.69
Iron deficiency occurs frequently in athletes engaged in a variety of sports (Chap. 52), especially long-distance running but also in swimmers.70,71,72,73,74 and 75 There may be mild anemia. In runners, this appears to be due to gastrointestinal bleeding. In swimmers it has been attributed to hemolysis,73 but the existence of swimmer’s anemia has been disputed.74
DIALYSIS TREATMENT OF CHRONIC RENAL DISEASE
The use of extracorporeal dialysis for treatment of chronic renal disease may cause iron deficiency, often superimposed upon the anemia of chronic renal disease. The retention of blood in the dialyzing equipment is the cause, and this problem usually can be avoided by returning as much blood as possible to the patient after each dialysis.76
CYSTIC FIBROSIS
Iron deficiency occurs in about a third of patients with cystic fibrosis, but is not related to severity of disease and may simply be due to failure to prescribe iron supplements for these children.77
PATHOGENESIS
Figure 38-2 shows the changes that take place in various iron compartments as iron deficiency progresses from a state of mild iron depletion to one of advanced iron deficiency anemia.78

FIGURE 38-2 Stages in the development of iron deficiency. Early iron deficiency (iron depletion) is usually not accompanied by any abnormalities in blood; at this stage, serum iron concentration is occasionally below normal values and storage iron is markedly depleted. As iron deficiency progresses, development of anemia precedes appearance of morphologic changes in blood, although some cells may be smaller and paler than normal; serum iron concentration is usually low at this time, but it may be normal. With advanced iron depletion, classic changes of hypochromic, microcytic, hypoferremic anemia become manifest.

ERYTHROCYTE SURVIVAL AND FERROKINETICS
Slight to moderate shortening of erythrocyte survival is characteristic of iron deficiency anemia, particularly when it is severe.79,80 A study of the movement of iron between various iron compartments (such as plasma pool, labile pool, and hemoglobin compartment) may be performed by intravenous injection of radioactive iron (59Fe) followed by measurement of the rate of clearance of 59Fe from plasma and of its incorporation into the hemoglobin of circulating erythrocytes. The principles underlying such “ferrokinetic” studies are discussed in Chap. 29.
In iron deficiency, plasma iron clearance is rapid and is closely inversely correlated with the serum iron concentration. The plasma iron transport rate may be normal or increased. The percentage of iron utilized in hemoglobin synthesis is normal or increased.80 There is usually little or no evidence of ineffective erythropoiesis.
IRON-CONTAINING PROTEINS
As the body becomes depleted of iron, changes occur in many tissues. Hemosiderin and ferritin virtually disappear from marrow and other storage sites. There is a decreased activity of many other important iron proteins: cytochrome c,81,82,83,84 and 85 cytochrome oxidase,83,84,86,87 and 88 succinic dehydrogenase,83,84 and 85,89 aconitase,90,91 xanthine oxidase,92 and myoglobin.93 Reduced activity has also been reported for some enzymes which do not contain or require iron. Phosphocreatine content is decreased and inorganic phosphorus is increased in skeletal muscle of iron-deficient rats.84 Many of the affected enzymes are in the oxidative glycolysis (Krebs) cycle of mitochondria. On the other hand, the activities of several mitochondrial matrix enzymes are increased in skeletal muscle of iron-deficient animals.83,84
MUSCULAR FUNCTION AND EXERCISE TOLERANCE
Iron-deficient rats have impaired exercise tolerance and are prone to lactic acidosis when exercised. The activity of a-glycerophosphate dehydrogenase was diminished in the skeletal muscle of iron-deficient rats, and this finding might explain the greater proclivity of iron-deficient rats to lactic acidosis94 upon exercise. However, in skeletal muscle of iron-deficient guinea pigs, the activity of this enzyme is normal.95 The brown fat of iron-deficient rats has lower-than-normal activities of NADH and of succinate and a-glycerophosphate oxidases.96
Besides these metabolic aberrations of muscle cells in iron-deficient rodents, ultrastructural studies show swollen mitochondria with distorted cristae.85 Despite these changes, mitochondrial cytochrome c increases adaptively on repetitive electrical stimulus of muscle.85
A study of energy transport pathways of submitochondrial particles of rat liver and skeletal muscle showed the latter to be less sensitive to iron depletion than the former.97 31Phosphorus magnetic resonance spectroscopy studies demonstrated increased breakdown of phosphocreatine in muscles of iron-deficient rats,98 but mitochondrial abnormalities could not be demonstrated in humans.99
NEUROLOGIC CHANGES
That dysfunction of the nervous system may also occur in iron deficiency is suggested by the fact that some iron-deficient patients complain of paresthesias, and approximately 40 instances of papilledema and other neurologic manifestations have been described.3,100 Other neurophysiological aberrations have been ascribed to iron deficiency in adults. These include asymmetries in electroencephalographic recording101 and ST-T segment changes in electrocardiograms obtained during treadmill tests.102 In infants iron deficiency is associated with poor attention span, poor response to sensory stimuli, and retarded behavioral and developmental achievement even in the absence of anemia.103,104,105,106,107,108 and 109 School children with iron deficiency anemia who received iron treatment had better academic achievement than did those not so treated.103,105,110
Monoamine oxidase (MAO) activity was low in the liver and platelets of patients with iron deficiency.111,112,113 and 114 MAO is involved in the synthesis and catabolism of important neurotransmitters such as dopamine, norepinephrine, and serotonin. Furthermore, iron-deficient children and iron-deficient rats excrete substantially more urinary norepinephrine than do iron-replete children or rats, an anomaly that is corrected within a few days of inception of iron therapy.113,114 Reduction of MAO activity might, therefore, contribute to the impairment in neurological and intellectual development of iron-deficient children. The brains of iron-deficient rats exhibit reduction in the number of dopamine D2 receptors that are also important in neurotransmission.115
Weanling rats given iron-deficient diets showed poor feeding efficiency, growth retardation, decrease in concentration, and greater-than-normal rates of turnover of norepinephrine in brown fat and heart, hypertrophy of brown fat and heart, and reduction in plasma thyroxine and triiodothyronine, low hepatic content of carnitine, and impaired ketogenesis.116,117 and 118 Prolonged iron deficiency in rats also caused abnormal formation of teeth119 and cochlea120 and hearing loss.121 However, these effects have not been described in humans.
HOST DEFENSES
Iron deficiency affects immune function and the susceptibility to infection.122,123 and 124 Some studies found that iron depletion prevents growth of microorganisms and therefore protects against infections; others observed that iron deficency impairs host defenses.
GROWTH, METABOLISM, OTHER EFFECTS
Iron deficiency anemia is associated with reduction in children’s height.106,125 Impaired thermoregulation has also been demonstrated.126,127 Iron deficiency has been proposed as a cause of atrophic rhinitis.128,129 The evidence for this is equivocal; perhaps iron deficiency is a contributory factor.
Thus, in iron deficiency, disturbances in cellular metabolism and function occur in many tissues. Gastric secretion of hydrochloric acid is often reduced.130,131,132 and 133 Histamine-fast achlorhydria has been found in as many as 43 percent of patients with iron deficiency.17,133,134 and 135 Gastric function may improve after correction of the iron deficiency, although in persons over the age of 30 the achlorhydria is usually irreversible.132,135,136 and 137 Furthermore, when atrophic gastritis coexists with iron deficiency, no improvement in gastric secretory function has followed iron therapy.137
HISTOLOGIC FINDINGS
Iron deficiency may lead to histologic changes in various organs. The rapidly proliferating cells of the upper part of the alimentary tract seem particularly susceptible to the effect of iron deficiency. There may be atrophy of the mucosa of the tongue and esophagus,138 stomach,139,140 and small intestine.90,141 The epithelium of the lateral margins of the tongue is reduced in thickness despite increase in the progenitor compartment. This thinning presumably reflects accelerated exfoliation of epithelial cells.142 Buccal mucosa has shown thinning and keratinization of epithelium and increased mitotic activity.143,144 However, light microscopic and electron microscopic examination of exfoliated oral mucosal cells showed no aberrations in morphology of nuclei or cytoplasm of the cells of patients with iron deficiency anemia.145 In the laryngopharynx, mucosal atrophy may lead to web formation in the postcricoid region, thereby giving rise to dysphagia (Paterson-Kelly/Plummer-Vinson syndrome).146,147 If these alterations are of long duration, they may lead to pharyngeal carcinoma.148 Although it has been generally thought that these changes are secondary to long-standing iron deficiency, this mechanism is not universally accepted.149
In iron deficiency anemia resulting from idiopathic pulmonary hemosiderosis, characteristic pathologic changes are found in the lungs, including intense deposition of iron in the littoral cells of the alveoli and interstitial fibrosis.40 Widening of diploic spaces of bones, particularly those of the skull and hands,150,151 may be a consequence of chronic iron deficiency beginning in infancy. In the skull, this is of the same character as in thalassemia, except that in b-thalassemia major there is maxillary hypertrophy, whereas in severe iron deficiency anemia maxillary growth and pneumatization are normal. The sella turcica may be abnormally small in iron-deficient children, and it has been suggested that this implies reduction in pituitary hormonal secretion in long-standing iron deficiency anemia.152
PREVALENCE
On a worldwide basis, caloric insufficiency, manifested as hunger, famine, starvation, appears to be the dominant nutritional problem. Iron deficiency affects at least a third of the world’s population, or 2 billion persons, and is, therefore, second only to hunger as a major, worldwide nutritional problem. In tropical areas, where hookworm infestation is common, iron deficiency anemia has particularly high prevalence. In India, where hookworm disease is prevalent and vegetarianism is mandated by religion, iron deficiency is especially common.
In the United States, where the dominant nutritional problem is obesity, iron deficiency is also the second most common nutritional problem. It is widely believed that the prevalence of iron deficiency has declined during the past few decades, but the evidence for this is doubtful.
Progressive declines in mean hemoglobin concentration and mean hematocrit values were documented by the Centers for Disease Control and Prevention since 1959 in successive Health and Nutrition Examination Surveys. These declines were observed in every age, sex, and ethnic group examined, altogether more than 50,000 persons surveyed. They were most marked in women of ages 18 to 44 years and in African Americans of every age group, both males and females. Part of the explanation may be that the earlier surveys were performed using specimens obtained from persons sitting, and the later surveys from persons recumbent. Fluid shifts that occur with recumbency are known to reduce hemoglobin concentration and hematocrit values. Part of the explanation may be change in the anticoagulant used to collect blood specimens, a dry powder having been used in the earlier studies and a liquid anticoagulant in 0.07 ml volume/collection tube in the later studies. This droplet of anticoagulant signficantly reduces results for measurement of Hb concentration, hematocrit, and erythrocyte count, especially when the sample collection tube is not completely filled. However, differences in sampling methods are not likely to account entirely for the threefold difference in rates of decline in hemoglobin concentration and hematocrit for specimens obtained from African-Americans or white females of ages 20 to 44 as compared with those obtained from white males of ages 20 to 44. These changes may also relate to a decline in the quality of iron nutrition in the United States.
In the state of Georgia a survey showed that the prevalence of iron deficiency was 30 percent among African-American children and 33 percent among white children, although only 2 percent of the children were frankly anemic.153 In St. Paul, Minnesota, a prosperous community with high employment, there is a high prevalence of iron deficiency anemia in infants and children of economically disadvantaged status that are eligible for the WIC (Women, Infants and Children) program of nutritional supplementation: The prevalence rates of anemia are 24 percent for white children, 22 percent for African-American children, 24 percent for Asian children (predominantly Hmong), 16 percent for Hispanic, and 7.9 percent for native American children.154
In Sweden, with a well-fed population and lifestyle not unlike that of middle-class white Americans, surveys have shown high prevalence rates for anemia and iron deficiency despite long-standing efforts to improve iron nutrition by addition of iron to wheat flour and bread. Since there appeared to be neither harm nor benefit from this practice, flour and bread are no longer iron-fortified in Sweden.155,156 and 157 Elsewhere in Europe, iron fortification is not practiced.
Anemia is not a sensitive indicator of the prevalence of iron deficiency, nor is anemia due solely to iron deficiency. However, iron deficiency is by far the commonest cause of anemia. In most populations, the prevalence of iron deficiency may be estimated as being 3 or 4 times the prevalence of anemia. It may reasonably be assumed that most of the economically deprived children of St. Paul, Minnesota, are iron-deficient. Erythrocyte zinc protoporphyrin, a relatively sensitive indicator of iron deficiency (or of lead poisoning) was elevated in nearly half the white children, in nearly half the African-American children, and in nearly 80 percent of Asian children who were admitted to the WIC program in St. Paul.
Thus, poverty remains a major determinant of iron malnutrition in the United States. African-American and Hispanic children are much less likely to have sufficiency of iron nutrition. In homes with low incomes, there may be “dysfunctional nutrition,” and hunger is common and iron intake is inadequate.158
The overall prevalence for iron deficiency anemia in the United States in the last few years of the twentieth century cannot be stated with certainty, but conservative estimates for middle class white Americans are approximately 9 percent for children of ages 1 to 2 years, 3.5 percent for children of ages 3 to 14 years, 4 percent for nonpregnant young women during the reproductive years, 30 percent for pregnant or postpartum women, 4 percent for postmenopausal women, 1 percent for males of ages 20 to 44 years, 3 percent for males of ages 45 to 70 years, and 4 percent or more for both males and females oler than 70 years.159 The prevalence rates of iron deficiency (with or without anemia), as estimated from serum ferritin concentration, in these same age and sex groups are, respectively, 9 percent, 5 percent, 13 percent, greater than 30 percent, 2 percent, and 5 percent. African-Americans of both sexes, Mexican-Americans, native Americans, and poor people of any ethnic group have higher prevalence of iron deficiency anemia. A particularly high prevalence of iron deficiency occurs among the Inuit (Eskimo) people of Alaska and Canada.160 From one-third to one-half of apparently healthy women of reproductive age in the United States,161 Sweden,162 and Japan163 have iron depletion as assessed by marrow examination or serum ferritin or both, although 4 to 10 percent of the women are anemic.
Despite the long recognition of iron deficiency as a major nutritional problem in the United States, and limited efforts to ameliorate it, the prevalence of iron deficiency and iron deficiency anemia has remained high.
CLINICAL FEATURES
When anemia develops slowly, as in patients with chronic occult bleeding, homeostatic mechanisms provide remarkable adaptation. Patients with marked iron deficiency anemia may deny any degree of fatigue, weakness, or palpitation. However, they may recognize improved work tolerance after treatment.
There is a poor correlation between severity of symptoms and blood hemoglobin concentration.164 Fatigue, irritability, and headaches are common complaints of patients with iron deficiency. Depletion of storage iron and, to some extent, of tissue iron precedes the appearance of anemia. These observations suggest that some of the symptoms may be caused by impaired function of iron enzymes or iron proteins other than hemoglobin. In a few studies of this problem, patients received either iron therapy or placebos in random double-blind series. In one of these investigations, patients with iron deficiency had greater symptomatic improvement with iron medication than with placebos165; in other studies with a somewhat different experimental design, this was not true.166,167 Objective measurements of work performance studies using O2 consumption as an index of work performance have also given contradictory results.168,169,170,171 and 172 In subjects rendered iron-depleted but not anemic by repeated blood donation, iron-supplemented and untreated groups showed the same O2 consumption during exercise.168 However, iron-deficient, nonanemic rats exhibited diminished exercise tolerance and evidence of irritability.94,173,174 and 175 In most studies, iron-deficient humans have demonstrated diminished maximal exercise tolerance,176,177,178,179,180,181,182 and 183 although this has not been a universal finding.168,169,184,185
Headache, paresthesias, and a burning sensation of the tongue are symptoms of iron deficiency that are not due to anemia but seem likely to be caused by deficiency of iron within tissue cells (Chap. 35). An increase in the volume of menstrual blood loss has been considered to be a result as well as a cause of iron deficiency,186,187 but this observation has been disputed.188 Pica, the craving to eat unusual substances such as dirt, clay, ice, laundry starch, salt, cardboard, or hair, is a classic manifestation of iron deficiency and is usually cured promptly by iron therapy.189,190,191,192 and 193 Restless legs, a common nocturnal problem, especially in the elderly, has been associated with iron deficiency.194,195
The physical findings in iron deficiency anemia include, in approximate order of frequency: pallor, glossitis (smooth, red tongue), stomatitis, and angular cheilitis. Koilonychia, once a common finding, is now encountered rarely (Fig. 38-3). Retinal hemorrhages and exudates may be seen in severely anemic patients (e.g., hemoglobin concentration of 5 g/dl or less). Proliferative retinopathy has shown rapid acceleration in patients with diabetes mellitus who have developed iron deficiency anemia.196 The spleen is palpable in a small proportion of patients with iron deficiency anemia.

FIGURE 38-3 Koilonychia. Note the ridging, thinning, and splitting, as well as spoonlike concavity of the fingernails.

LABORATORY FEATURES
In severe uncomplicated iron deficiency anemia, the erythrocytes are hypochromic and microcytic, the plasma iron concentration is diminished, the iron-binding capacity increased, the serum ferritin concentration is low, the serum transferrin receptor and erythrocyte zinc protoporphyrin concentrations are increased, and the marrow is depleted of stainable iron. Because physicians may not always be aware of the costs of diagnostic tests, Table 38-5 compares some of the fees that were levied in 1999 for common diagnostic procedures. Unfortunately, the classic combination of laboratory findings occurs consistently only when iron deficiency anemia is far advanced, when there are no complicating factors such as infection or malignant neoplasms, and when there has not been previous therapy with transfusions or parenteral iron.

TABLE 38-5 DIAGNOSIS OF IRON DEFICIENCY, COMPARISON OF FEES OF EXAMINATIONS, $*

BLOOD CELLS
ERYTHROCYTES
Anisocytosis is the earliest recognizable morphologic change of erythrocytes in iron deficiency anemia197 (Fig. 38-4). The anisocytosis is typically accompanied by mild ovalocytosis. As the iron deficiency worsens, there is often mild normochromic, normocytic anemia (blood hemoglobin concentration greater than 11 g/dl, mean corpuscular volume, MCV, less than 80 fl).197,198,199 and 200 With further progression, hemoglobin concentration, erythrocyte count, MCV, and mean erythrocyte hemoglobin content (MCH) all decline together. In infants and children, hypochromia may occur earlier in the course of iron deficiency, and erythrocyte counts in excess of 5.5 × 1012/liter (5,500,000/µl) are sometimes encountered. As the indices change the erythrocytes appear microcytic and hypochromic on stained blood films. Target cells may sometimes be present. Elongated hypochromic elliptocytes may be seen, in which the long sides are nearly parallel. Such cells have been called “pencil cells,” although they more nearly resemble cigars in shape.

FIGURE 38-4 Variability in morphologic diagnosis of iron deficiency anemia from blood film. Interpret and compare them with those of nine experienced hematologists who reviewed the original slides. The slides were part of a coded series that contained blood films from normal subjects and from iron deficiency anemia patients in random order. The fields reproduced here were typical for each slide (X600). (From Fairbanks200; by permission of the J. B. Lippincott Company.) (Upper left) From a young woman with iron deficiency anemia due to excessive menstrual bleeding; hemoglobin 10.1 g/dl; serum iron 36 µg/dl (6.4 µmol/liter). After treatment with ferrous gluconate, hemoglobin concentration increased to 13.1 g/dl. On 13 examinations of this slide by nine hematologists, 11 opinions were that there was no evidence to suggest iron deficiency. (Upper right) From a normal woman. Hemoglobin 14.6 g/dl, MCHC 34%, serum iron 77 µg/dl (13.8 µmol/liter); total iron-binding capacity 300 µg/dl (53.7 µmol/liter). Three of nine hematologists who reviewed this film thought the erythrocytes were morphologically abnormal and consistent with iron deficiency anemia. (Lower left) From a normal young man. Hemoglobin 15.8 g/dl; MCHC 34%, serum iron 141 µg/dl (25.2 µmol/liter); total iron-binding capacity 278 µg/dl (49.8 µmol/liter). Nine hematologists made a total of 13 examinations of this slide; one examiner reported the slide as showing evidence of iron deficiency. (Lower right) From a 56-year-old man with anemia due to bleeding from paraesophageal hiatus hernia. Hemoglobin 4.0 g/dl; erythrocyte count 2.24% 1012/liter; reticulocyte count 2.5%; serum iron 2 µg/dl (0.4 µmol/liter). Hypochromia was marked, and all observers agreed that morphologically the cells suggested iron deficiency anemia.

The red cell indices are consistently abnormal in adults only when iron deficiency anemia is moderate or severe (e.g., in males with hemoglobin concentrations less than 12 g/dl or in women with hemoglobin concentrations less than 10 g/dl) (Fig. 38-5). Measurement of the distribution of erythrocyte volume (e.g., red cell distribution width, or RDW) is made easy by modern cell counters. With some of these instruments the RDW is reported as the coefficient of variation (in percent) of erythrocyte volume. It has been asserted that such measurements permit discrimination between iron deficiency anemia and other microcytic anemias.201,202,203 and 204 However, hemoglobinopathies and thalassemias201,203,205,206 and 207 commonly exhibit increased RDW, as do some anemias that are due to chronic disease.201,208,209 and 210 Highest RDWs are observed in hemolytic disorders, in which the RDW appears to reflect reticulocytosis.206 Thus, the early expectation that RDW would permit diagnosis of iron deficiency anemia has been disappointed.

FIGURE 38-5 Erythrocyte indices in iron deficiency anemia of adults, data obtained with Coulter Counter, Model S. Normal ranges of indices observed in approximately 500 healthy adults348 using the same instrument are indicated by stippling. The dashed line in the upper panel indicates the more widely accepted lower normal limit of MCHC stated in this text. (Upper) Correlation between venous blood hemoglobin concentration and mean corpuscular hemoglobin concentrations (MCHC). More than half of 62 patients with iron deficiency anemia had MCHC values clearly in the normal range. (Lower) Correlation between venous blood hemoglobin concentrations and MCV. Nearly 70 percent of cases exhibited distinct microcytosis. Thus when indices are determined by automated cell-counting methods, the MCV is much more sensitive than is the MCHC in detecting changes of iron deficiency. However, at least 30 percent of cases of iron deficiency anemia will be misdiagnosed if physicians rely on the erythrocyte indices. (From Beutler and Fairbanks,349 by permission of Academic Press.)

The sensitivity and specificity of erythrocyte indices for iron deficiency may be increased by use of formulae that incorporate MCV, RDW, serum ferritin concentration, and serum transferrin saturation to produce an iron index211 or combinations of other functions.212,213 and 214
LEUKOCYTES
In a review of 100 cases of iron deficiency anemia observed at the Mayo Clinic, 14 percent were found to have leukocyte counts between 3.0 and 4.4 × 109/liter (3000–4400/µl). Leukopenia was unrelated to severity of anemia and could not be ascribed to any other condition. In these cases, differential leukocyte counts were normal.
PLATELETS
Thrombocytopenia and thrombocytosis have both been attributed to iron deficiency. Thrombocytosis has been reported in 50 to 75 percent of adults with classic iron deficiency anemia due to chronic blood loss.215,216 and 217 However, thrombocytosis usually occurs only in those patients who are actively bleeding.218 In infants and children, thrombocytopenia occurs almost as frequently (28 percent) as does thrombocytosis (35 percent); thrombocytopenia is associated with more severe anemia.219 Marked thrombocytopenia may also occur in iron-deficient adults, either as the presenting hematologic problem or early during the response to iron therapy for anemia.210,220,221
The reticulocyte count is usually normal or decreased in iron deficiency.
MARROW
Both the degree of cellularity of the marrow and the relative proportion of erythroid to myeloid cells are variable.222 In severe iron deficiency, erythroblasts of the marrow may be smaller than normal, with narrow, ragged rims of cytoplasm containing little hemoglobin. However, the morphologic changes in the marrow are not sufficiently distinctive to be of diagnostic value.
Decreased or absent hemosiderin in the marrow is characteristic of iron deficiency. Hemosiderin appears in the unstained marrow film as golden refractile granules, but the hemosiderin content of the marrow film is more readily and more reliably evaluated after staining by the simple Prussian blue method. Stored iron in the macrophages of the marrow can be seen in marrow spicules in marrow sections, or in marrow aspirate films. Iron granules, normally found in the cytoplasm of 10 percent or more of erythroblasts, become rare but may not be entirely absent.
The evaluation of marrow iron stores is a sensitive and usually reliable means for the diagnosis of iron deficiency anemia. However, misleading results may be obtained in patients who have been transfused or who have been treated with parenteral iron. The marrow of such patients may contain normal, or even increased, quantities of stainable iron in the face of typical iron-responsive iron deficiency anemia. In such patients, iron that is seen on marrow examination is not readily available for erythropoiesis. Further, the ability of marrow to store iron seems to be impaired in some patients with chronic myelogenous leukemia and possibly in those with myelofibrosis. In such patients, absence of marrow iron is often observed without other evidence of iron deficiency, and such patients do not respond to iron therapy.
SERUM IRON CONCENTRATION
The serum iron concentration is usually low in untreated iron deficiency anemia; however, it may be normal.223,224 The normal range depends to some extent on the assay method used. In most laboratories, the normal range for males is between 13 and 31 µmol/liter (75 and 175 µg/dl); for women it is about 2 µmol/liter (10 µg/dl) lower. The measurement of serum iron concentration is subject to many variables, which may introduce substantial errors into results. Such variables include inadequately processed glassware, contamination of reagents with small amounts of iron, turbidity, and entrapment of iron in plasma proteins during their precipitation. The reagents used in some techniques may not be entirely specific for iron. The presence of free hemoglobin in concentrations too small to be detected visually may give erroneously high results by the atomic absorption method unless a protein-free extract of serum is routinely used.
The serum iron concentration also is influenced by many pathologic and physiologic states. Physiologically, the serum iron concentration has a diurnal rhythm; it decreases in late afternoon and evening, reaching a nadir near 9 PM, and increases to its maximum between 7 and 10 AM.225,226 and 227 Serum iron concentration decreases at about the time of menstrual bleeding either when menses are under normal hormonal control228,229 or when bleeding occurs after withdrawal of oral contraceptive agents.230,231 The serum iron concentration is reduced in the presence of either acute or chronic inflammatory processes232,233 and 234 or malignancy235 and following acute myocardial infarction.236,237 The serum iron concentration under these circumstances may be decreased sufficiently to suggest iron deficiency. On the other hand, during chemotherapy of malignancy, the serum iron concentration may be quite elevated. This effect is observed from the third to the seventh day after inception of chemotherapy of a variety of tumors.238
Normal or high concentrations of serum iron are commonly observed even in patients with iron deficiency anemia if such patients receive iron medication before blood is drawn for these measurements. Even multiple vitamin preparations, which commonly contain about 18 mg of elemental iron per tablet, can result in this effect. Oral iron medication must be withheld for 24 h. Parenteral injection of iron dextran may result in a very high serum iron concentration (e.g., 500 to 1000 µg/dl) for several weeks.
IRON-BINDING CAPACITY AND TRANSFERRIN SATURATION
The iron-binding capacity is a measure of the amount of transferrin in circulating blood. Normally, there is enough transferrin present in 100 ml serum to bind 4.4 to 8.0 µmol (250 to 450 µg) of iron; since the normal serum iron concentration is about 1.8 µmol/dl (100 µg/dl), transferrin may be found to be about one-third saturated with iron; i.e., one-third of the binding sites are occupied. The unsaturated or latent iron-binding capacity (UIBC) is easily measured with radioactive iron or by spectrophotometric techniques. The sum of the UIBC and the plasma iron represents total iron-binding capacity (TIBC). TIBC may also be measured directly. Transferrin is normally 20 to 50 percent saturated with iron. In iron deficiency anemia, UIBC and TIBC are often increased; transferrin saturation of 15 percent or less is often found. A normal value for transferrin saturation often accompanies a low serum iron concentration in the anernia of chronic disease. However, exceptions are so common as to detract considerably from the diagnostic value of measuring transferrin saturation.78
SERUM FERRITIN
Serum ferritin concentration correlates with total-body iron stores, although the correlation is not as strong as has sometimes been suggested.239,240 and 241 Serum ferritin concentrations of 10 µg/l or less are characteristic of iron deficiency anemia. For iron deficiency without anemia, serum ferritin concentration is typically in the range 10 to 20 µg/l. In one series of 73 patients marrow iron was depleted whenever the serum ferritin level was under 70 µg/l.42 In adults older than 50 years, a serum ferritin concentration of less than 50 µg/l may be taken as evidence of iron deficiency. As noted in Chap. 25, serum ferritin predominantly consists of H monomers, which contain less iron than do L monomers; hence, serum ferritin contains relatively little iron. Moderate increase in serum ferritin concentration occurs in inflammatory disorders, such as rheumatoid arthritis, in chronic renal disease, and in malignancies.243,244 In Gaucher disease the serum ferritin concentration is commonly in the range of thousands of µg/l. When one of these conditions coexists with iron deficiency, as they often do, the serum ferritin concentration is commonly in the normal range; interpretation of results of this assay then become difficult. In patients with rheumatoid arthritis who are anemic, concomitant iron deficiency may be suspected when the serum ferritin concentration is less than 60 µg/l.245 Moderate increases in serum ferritin concentrations are also characteristic of some hematologic malignancies and may closely reflect remissions and relapses.246 Marked increases in serum ferritin concentration occur in patients with hepatitis241,247,248 and in patients with end-stage renal disease. Oral or parenteral iron administration also increases serum ferritin concentration.249,250,251,252 and 253 This appears to be particularly a problem in infants given oral iron. In adults with iron deficiency anemia who were given oral iron in a dose of 60 mg of elemental iron thrice daily, the serum ferritin concentration remained below 10 µg/liter for 2 to 3 weeks.250 However, for adults who have taken oral iron medication for more than 3 weeks, the serum ferritin assay would be of no value in confirming a diagnosis of iron deficiency. Parenteral administration of iron dextran results in a rise in serum ferritin concentration to normal or supranormal values within 24 h, and this effect persists for at least a month.250 It has been proposed that measurement of the “percent saturation” of serum ferritin with iron may be a better indicator of iron deficiency or iron overload than the serum ferritin alone.254 As yet, there has been limited experience with this test.
ERYTHROCYTE FERRITIN
Erythrocyte ferritin concentration is increased in thalassemias and sideroblastic anemias and decreased in iron deficiency. These changes appear to parallel those of serum ferritin concentration. Although it has been suggested that basic red cell ferritin was not influenced by inflammation, and could therefore detect iron deficiency when the serum ferritin concentration was normal in the elderly,255 comparative studies show that erythrocyte ferritin and serum ferritin concentration are both elevated in chronic disease. While erythrocyte ferritin determinations appeared to have no more value than those of serum ferritin, the combination of both was more effective in the diagnosis of iron deficiency.256
ERYTHROCYTE ZINC PROTOPORPHYRIN
Erythrocyte protoporphyrin, principally zinc protoporphyrin, is increased in disorders of heme synthesis, including iron deficiency, lead poisoning, and sideroblastic anemias, as well as other conditions. This procedure requires small blood samples. It is quite sensitive in the diagnosis of iron deficiency257 and practical for large-scale screening programs designed to identify children with either iron deficiency or lead poisoning. It does not differentiate among iron deficiency and chronic lead poisoning and the anemia that accompanies inflammatory or malignant processes.
SERUM TRANSFERRIN RECEPTOR
The role of transferrin receptor in transporting transferrin iron into cells is described in Chap. 24. Sensitive immunologic methods can detect about 5 mg/l of receptor in serum. The circulating receptor appears to be a truncated form of the cellular receptor, lacking the transmembrane and cytoplasmic domains of the cellular receptor. It circulates bound to transferrin. The circulating transferrin receptor apparently mirrors the amount of cellular receptor, and, since receptor synthesis is greatly increased when cells lack iron, the amount of the circulating receptor increases in iron deficiency but not in the anemia of chronic disease.258,259 and 260 This test for iron deficiency has gradually come into clinical use but is not yet widely available. Like the serum ferritin and serum iron, serum transferrin receptor assay results may be confounded by poorly understood variations in patients with malignancies, in whom the serum transferrin receptor concentration is reduced, and in patients with rheumatoid arthritis or thalassemia trait, in whom, in the absence of iron deficiency, it is increased. Thus, to be clinically useful, separate reference (“normal”) ranges need to be defined for serum transferrin receptor in these common conditions.261,262,263 and 264
RETICULOCYTE HEMOGLOBIN CONTENT
Automated hematology instruments may offer, as a new method for diagnosis of iron deficiency, an assay of hemoglobin content within reticulocytes.265 However, preliminary data obtained with this method suggest neither a high level of specificity nor a high level of sensitivity.
CO ABSORPTION
The urinary excretion of 57Co, following an oral dose, is greater in iron-deficient subjects than in normal subjects.266,267 This appears to be a sensitive index of increased iron absorption, as occurs in iron deficiency, in iron-loading states (e.g., hemochromatosis), or following recent blood loss. It is not specific for iron deficiency.
IRON TOLERANCE TESTS
In an iron tolerance test,268,269 and 270 the patient receives an oral dose of an inorganic iron compound, and the subsequent change in the serum iron concentration is measured. In iron deficiency, there is an increased rate of absorption of the test dose, and this is often reflected in a more rapid increase and a higher plateau than in normal subjects. However, this test has quite limited practical application.
DIFFERENTIAL DIAGNOSIS
When iron deficiency anemia is severe, it may often be easily recognized. A history of excessive blood loss is sometimes easily obtained. Pallor may be readily apparent. The blood film may display marked hypochromia, poikilocytosis, and microcytosis without polychromatophilia and other signs of erythrocyte regeneration that might suggest a different cause. Under such circumstances, it is reasonable to start iron therapy immediately and to begin a search for the site of blood loss. However, even those morphologic findings considered classic for iron deficiency anemia may occur in other conditions, particularly in chronic disease and in thalassemias: The morphologic diagnosis of iron deficiency must always be regarded as tentative and subject to confirmation by other means, including the response to therapy. The presumptive diagnosis of iron deficiency is often incorrect.271 Early in the course of iron deficiency, changes in the blood may be imperceptible, and the differential diagnosis of anemia may then be more difficult.
DIFFERENTIATION FROM OTHER FORMS OF ANEMIA
The forms of anemia that must be distinguished from iron deficiency anemia include those of thalassemia minor, chronic inflammatory disease, malignancy, chronic liver disease, chronic renal disease, hemolytic anemia, and aplastic anemia. It is the microcytic anemias that are most likely to be confused with iron deficiency. Such anemias are summarized in Table 38-6, and each is discussed elsewhere in this volume. Attention will be directed here primarily to laboratory aids for differentiating iron deficiency anemia from the frequently occurring disorders that may have similar manifestations.

TABLE 38-6 MICROCYTIC DISORDERS THAT MAY BE CONFUSED WITH IRON DEFICIENCY

THALASSEMIA MINOR
In many parts of the world, and in many communities of North America, the frequency of b-thalassemia-minor is second only to that of iron deficiency as a cause of hypochromic microcytic anemia (Chap. 46). In African-Americans, homozygosity for a-thalassemia-2 (who have a pair of chromosomes each of which contain only a single a globin gene) is a common cause of microcytosis. Approximately 1 to 3 percent of African-Americans are homozygous for a-thalassemia-2.272,273 and 274 The condition is usually not associated with anemia.272 Heterozygotes may also have microcytosis, although usually they are hematologically normal. Among persons of Italian ancestry who appear to have thalassemia minor on the basis of erythrocyte morphology, approximately 1 of every 40 have hemoglobin Lepore trait275,276; probably 10,000 to 20,000 North Americans have hemoglobin Lepore trait as a cause of mild microcytosis unassociated with anemia. Among more than a million Southeast Asians resettled in the United States during the 1970s and 1980s, a-thalassemia-minor, b-thalassemia-minor, hemoglobin E trait, and iron deficiency all occur frequently. All are characterized by microcytosis, and none can be distinguished reliably from the others on the basis of erythrocyte morphology or erythrocyte indices alone. In each of these conditions there may be only mild to moderate microcytosis without any other distinctive changes. However, in the majority of patients with a- or b-thalassemia-minor, hemoglobin Lepore trait, hemoglobin E trait, the erythrocyte count is greater than 5 × 1012 per liter (5,000,000/µl), despite low hemoglobin concentration.276,277 Homozygous hemoglobin E is also characterized by marked hypochromia, microcytosis, abundant target cells, and elevated erythrocyte count but usually not by more than minimal anemia.278 (See Chap. 46.)
In contrast to the findings in these hemoglobinopathies, only about 3 percent of adults with iron deficiency anemia have erythrocyte counts of 5 × 1012 per liter (5,000,000/µl) or higher.175 However, erythrocytosis may be seen in children with iron deficiency anemia or in polycythemia vera patients who have become iron deficient following hemorrhage or therapeutic phlebotomy.
The MCV is almost always reduced in a- or b-thalassemia-minor and in homozygous hemoglobin E, with values of 60 to 70 fl being the rule. Values this low are seen only in severe iron deficiency anemia. In hemoglobin Lepore trait and hemoglobin E trait, only minimal microcytosis is observed.276,277 and 278 The widespread adoption of the routine measurement of MCV has led to proposals that criteria for differentiation of iron deficiency from thalassemia minor might be based, in part, on the values of the erythrocyte count and the MCV.279 Some proposed rules280 could separate iron deficiency from thalassemia minor with 90 percent reliability when groups of iron deficiency and thalassemic patients were of nearly equal numbers. However, in a population in which iron deficiency is more prevalent than thalassemia minor, use of these criteria would result in an excessive number of diagnostic errors. None of these and other proposed rules204,214,281 seems completely reliable for distinguishing iron deficiency from thalassemia.
Because anisocytosis is an early morphologic feature of iron deficiency, measurements of variation in erythrocyte size, such as RDW, have been proposed as a means of diagnosis (see “Blood Cells,” above). However, the RDW is often increased in thalassemia minor, particularly in those cases with reticulocytosis.206 Hence, these conditions cannot be differentiated reliably by such measurements.
Mild reticulocytosis, polychromatophilia, and basophilic stippling are more likely to be encountered in b-thalassemia-minor, db-thalassemia-minor, and hemoglobin Lepore trait than in iron deficiency anemia but may be absent in these disorders. In contrast, the serum iron concentration is usually normal or increased in thalassemic syndromes and is usually low in iron deficiency anemia. Similarly, examination of marrow iron stores helps to differentiate these disorders. The presence of thalassemia is substantiated by the demonstration of increased proportions of hemoglobin A2 or F, or by the presence on electrophoresis of hemoglobin H or Lepore (see Chap. 46). At present the diagnosis of a-thalassemia-minor is usually made on the basis of exclusion of other causes of microcytosis, but it can be confirmed by measuring globin chain synthetic rates or by direct demonstration of mutations by DNA-based techniques.
Iron deficiency may mask concurrent thalassemia. The amounts of both hemoglobin A2 and hemoglobin H are diminished disproportionately to the reduction in hemoglobin A in the presence of iron deficiency282 (Chap. 46). Thus when a patient with proved iron deficiency and normal hemoglobin studies continues to exhibit microcytosis and hypochromia after adequate therapy, the concentration of hemoglobin A2 should be measured again and electrophoresis performed to determine whether hemoglobin H is present.
ANEMIA OF CHRONIC INFLAMMATORY DISEASE AND MALIGNANCY
The anemia of chronic disease (Chap. 41) is usually normochromic and normocytic, but hypochromic microcytic anemia occurs in 20 to 30 percent of patients with chronic infections or malignancies.233,234 Thus these disorders cannot be distinguished from iron deficiency anemia by examination of the blood film. Furthermore, the serum iron concentration is usually decreased in these disorders,29,233,234 sometimes severely. While in iron deficiency the TIBC is usually increased, it is commonly decreased in inflammatory and neoplastic diseases. However, there is considerable overlap among TIBC values of normal subjects, those with iron deficiency anemia, and those with chronic inflammatory diseases. Among the neoplasms that may lead to erroneous diagnosis of iron deficiency, particularly to be noted are hypernephromas, atrial myxomas, and angiofollicular lymphoid hyperplasia.
In iron deficiency anemia, the transferrin saturation is usually less than 16 percent, whereas in chronic diseases it is usually greater than 16 percent. However, this widely used criterion is actually quite unreliable. Transferrin saturation may be normal in iron deficiency anemia, and conversely, low saturation is sometimes observed in chronic disease.234 However, circulating transferrin receptors increase in iron deficiency but not in the anemia of chronic disease.244,258,259 and 260 The serum ferritin level is usually diminished in iron deficiency, but it is generally increased in chronic inflammatory and neoplastic disorders.242,243 Examination of the marrow for stainable iron is particularly helpful. The latter is greatly decreased in amount or absent in iron deficiency anemia and normal or increased in the other disorders.
ANEMIA OF CHRONIC LIVER DISEASE
The erythrocytes in the blood film from patients with chronic liver disease may be normochromic and normocytic, macrocytic, or hypochromic. Target cells are frequently present in large numbers. Since the blood film in iron deficiency anemia may also display these features, differential diagnosis must be based on other observations. Determination of the serum iron concentration is helpful. In acute chemically induced liver injury, and in hepatitis, the serum iron concentration is usually modestly increased,248,283 possibly owing to release of ferritin into the plasma.247,248 In cirrhosis, the serum iron concentration is likely to be increased unless there has been blood loss.283 The TIBC may be normal or decreased. Thus the percentage transferrin saturation is likely to be increased. The quantity of hemosiderin is normal or increased in marrow aspirates.
ANEMIA OF CHRONIC RENAL DISEASE
Changes in small renal blood vessels may cause marked distortions in erythrocyte structure, producing schizocytes and burr cells. However, these morphologic changes, when present, are nonspecific. Unless there is distinct microcytosis and hypochromia, iron deficiency anemia cannot be differentiated from anemia resulting from chronic renal disease (Chap. 33) on the basis of the blood film. The serum iron concentration may be normal or decreased, depending on the cause of the renal disease. Measurement of the TIBC may be of no help in this circumstance. Serum ferritin concentration may be greater than 100 µg/liter, and may indeed be quite elevated despite iron deficiency. Iron deficiency may complicate the anemia of chronic renal disease in patients who are subjected to repeated extracorporeal hemodialysis, possibly as a result of loss of blood into the dialyzing apparatus.188 When the mechanism of anemia is uncertain or appears to be complex, examination of marrow aspirates for iron content may clarify the pathogenesis.
ANEMIA OF HEMOLYTIC DISEASE
Hemolytic disease can usually be distinguished from iron deficiency anemia on the basis of the blood film. The marked poikilocytosis, polychromatophilia, and other morphologic features characteristic of hemolysis usually are not seen in iron deficiency anemia. Furthermore, reticulocytosis is usually marked in hemolytic disorders but minimal or absent in iron deficiency anemia. However, there are some outstanding exceptions to these generally valid principles.
In unstable hemoglobin disorders, such as hemoglobin H disease or hemoglobin Köln disease, erythrocytic hypochromia may be pronounced. In these disorders, there is moderate reticulocytosis, which helps to differentiate them from iron deficiency anemia. The serum iron concentration is normal or increased. Unstable hemoglobins are easily precipitated by heating or by mixing hemolysates with a buffered dilute solution of isopropanol. These measures of molecular instability are the basis of simple diagnostic tests (Chap. 48).
When there is chronic intravascular hemolysis, erythrocytes in the blood film may display marked morphologic abnormalities, such as burr cells and schizocytes. Yet, because of loss of iron in the urine, iron deficiency may be the dominant cause of the resulting anemia. Measurement of serum iron concentration or TIBC or, better, evaluation of iron content marrow aspirates may clarify the mechanism of this form of anemia. An increase in serum lactic dehydrogenase activity that is secondary to intravascular hemolysis often occurs in iron deficiency anemia. Studies of erythrocyte survival or of iron kinetics may sometimes help in investigation of the mechanism of anemia in these cases. However, these are time-consuming, expensive procedures that do not, in general, add any diagnostically useful information beyond that which can be obtained by the simpler techniques already indicated. Furthermore, iron deficiency anemia alone may result in shortened erythrocyte survival and in some degree of ineffective erythropoiesis. If bleeding occurs during studies of erythrocyte survival, the results are indistinguishable from those that are considered to be characteristic of hemolysis. Because circulating transferrin receptors reflect the erythroid mass they are increased in hemolytic anemia258 and would not aid in distinguishing hemolysis from iron deficiency.
HYPOPLASTIC AND APLASTIC ANEMIA
In their early phases, these disorders cannot reliably be differentiated from mild iron deficiency anemia on the basis of erythrocyte morphology alone (Chap. 22). The reticulocyte count is generally less than 0.5 percent in hypoplastic: or asplastic anemia. The presence of neutropenia and thrombocytopenia suggests a diagnosis of aplastic anemia, but mild neutropenia may also occur in iron deficiency anemia. The serum iron concentration is usually increased in aplastic anemia; the percentage transferrin saturation may be high. Marrow aspiration may produce scant material for cytologic study, and marrow biopsy may be necessary: Iron stain usually reveals increased amounts of hemosiderin in aplastic or hypoplastic anemia. However, if chronic bleeding has occurred, for example, due to thrombocytopenia, iron stores may be depleted.
MYELOPROLIFERATIVE DISEASES
In polycythemia vera, erythrocytes may be small and hypochromic (Chap. 61). Even in the absence of distinctive morphologic changes in erythrocytes, the serum iron concentration is usually decreased, the TIBC is normal or increased, and marrow aspirates show little or no hemosiderin. Ferrokinetic studies show accelerated plasma iron incorporated into the hemoglobin of circulating erythrocytes.284 These findings simply reflect iron deficiency, which is almost always present in this disease, as a result of marked expansion in total hemoglobin mass, increased gastrointestinal blood loss, or therapeutic phlebotomy. The marrow hemosiderin content is often decreased in other myeloproliferative disorders,285 possibly due to a defect in macrophage storage of iron.
SIDEROBLASTIC ANEMIA
In this heterogeneous group of disorders (Chap. 63), the blood findings often simulate those of iron deficiency anemia. Reticulocytosis is usually absent, and the serum iron concentration is generally normal or increased. Diagnosis requires examination of films of marrow aspirates stained for iron; increased amounts of both storage and ringed sideroblasts are present.
CONGENITAL DYSERYTHROPOIETIC ANEMIA
In the rare congenital dyserythropoietic anemias, erythrocyte morphologic abnormalities may resemble those of iron deficiency or thalassemia (Chap. 35). In general, in congenital dyserythropoietic anemias, poikilocytosis is very striking and occurs with less reduction in MCV than in iron deficiency or thalassemias. Often, however, such cases are believed to be thalassemic until the marrow is examined.
MEGALOBLASTIC ANEMIA
In pernicious anemia and other types of megaloblastic anemia (Chap. 37), the blood film usually shows changes sufficiently distinctive that there is little difficulty in differential diagnosis. One potential source of error is the change in serum iron concentration that occurs after therapy. In the untreated patient with pernicious anemia or folic acid deficiency, the serum iron concentration decreases markedly as iron is utilized rapidly for hemoglobin synthesis.286 Thus the finding of a low serum iron concentration in such circumstances should not be taken as evidence of iron deficiency. Iron deficiency anemia and anemia due to folic acid or vitamin B12 deficiency may coexist. During the course of treatment, with the rapid increase in the number of red cells, the typical manifestations of severe iron deficiency may develop.
ANEMIA OF MYXEDEMA
The anemia of myxedema (Chap. 34) is usually normochromic and normocytic and may be accompanied by mild-to-moderate depression of serum iron concentration. Ferrokinetic studies may show a decreased rate of plasma iron transport but normal iron utilization. Marrow examination may be required to determine whether iron deficiency is present, especially since iron deficiency often complicates myxedema because of menorrhagia, that is common in this disorder.
SPECIAL STUDIES
The physician who establishes a diagnosis of iron deficiency resulting from blood loss has the obligation to determine the site and cause of hemorrhage. Examination of the stools for the presence of blood is particularly helpful in determining what additional studies should be carried out. Specimens should be examined on several days, because bleeding may be intermittent. Occasionally, it is helpful to label the patient’s erythrocytes with 51Cr sodium chromate and to determine quantitatively the amount of blood lost daily. When there is reason to believe that bleeding is from the gastrointestinal tract, roentgenographic and other imaging studies and endoscopic investigation are indicated. The latter often include gastroscopy, esophagoscopy, and colonoscopy.
Percutaneous retrograde angiography of celiac or mesenteric arteries has proved valuable in localizing sites of active gastrointestinal bleeding, when rate of blood flow into the intestinal lumen is 0.5 ml/min or greater.13,287,288 This procedure should be considered for any patient actively bleeding from the gastrointestinal tract, in whom the site of blood loss has not been established by other methods, including endoscopy, and for whom surgery is contemplated. Angiography should be carried out prior to barium contrast studies. The rate of bleeding may be increased following angiography.288
Meckel diverticulum is one of the most common causes of obscure gastrointestinal bleeding in children. The diverticulum often contains ectopic gastric muscosa that will concentrate pertechnetate following intravenous injection for scintigraphic study; such scintigrams have been useful in identifying Meckel diverticulum as the cause of gastrointestinal blood loss.289,290 and 291
In rare cases, small-bowel endoscopy by laparoscopy may detect bleeding lesions when less invasive methods have failed.292 Rarely, exploratory laparotomy may be warranted, because some adults with unexplained occult bleeding have gastrointestinal malignancies. There may be an even stronger indication for laparotomy in children and infants with unexplained gastrointestinal bleeding, since Meckel diverticulum may not be detected otherwise.293,294 An iron stain of sputum may reveal hemosiderin-laden macrophages when there is intrapulmonary bleeding.
THERAPEUTIC TRIAL
In the final analysis, the response to iron therapy is the proof of correctness of diagnosis of iron deficiency anemia. Furthermore, some physicians or patients may not have access to all the techniques described for diagnosis of iron deficiency anemia. In this event, the patient’s response to therapy may become a primary diagnostic measure. Iron administration in such a therapeutic trial should usually be by the oral route only. A therapeutic trial under any circumstances should be followed carefully. If the cause of anemia is iron deficiency, adequate iron therapy should result in reticulocytosis with a peak occurring after 1 to 2 weeks of therapy, although if anemia is mild, the reticulocyte response may be minimal. A significant increase in the hemoglobin concentration of the blood should be evident 3 to 4 weeks later, and the hemoglobin concentration should attain a normal value within 2 to 4 months. Unless there is evidence of continued, substantial blood loss, the absence of these changes must be taken as evidence that iron deficiency is not the cause of anemia. Iron therapy should be discontinued and another mechanism sought.
THERAPY, COURSE, AND PROGNOSIS
Once it has been established that a patient is deficient in iron, replacement therapy should be instituted without further delay.
Iron may be administered in one of several forms—orally, as simple iron salts, or parenterally, as an iron-carbohydrate complex or as a blood transfusion. In general, the oral route is preferred. Iron can be administered most economically, in the highest dosage, and in the most readily assimilated form as simple iron compounds. Table 38-7 compares the cost to the patient of each grain of iron administered in each of several forms, as well as the comparative rates of response and possible toxic effects. Clearly, treatment by the oral route is safer and far less expensive than parenteral therapy. In most patients, iron deficiency anemia is a disorder of long duration and slow progression. Precipitous measures to restore a normal hemoglobin concentration overnight by transfusing the patient are never warranted and are, indeed, hazardous. There is usually time to wait for normal mechanisms of erythropoiesis to respond to the body’s needs and for gradual adjustment of the cardiovascular system to reexpansion of the total circulating erythrocyte volume.

TABLE 38-7 COMPARISON OF DIFFERENT METHODS OF IRON THERAPY

ORAL IRON THERAPY
DIETARY THERAPY
The patient should be encouraged to eat a diversified diet supplying all nutritional requirements. Nonetheless, it must be emphasized that neither meat nor any other dietary article contains enough iron to be useful therapeutically. Meat contains small amounts of myoglobin and hemoglobin (blood trapped in capillaries) and insignificant amounts of iron in other proteins. Although heme iron is better absorbed than inorganic iron, the quanitity of heme iron in meat is actually quite small. In fact, an average (3-oz) serving of steak provides only about 3 mg iron. Provision of sufficient dietary iron to permit a maximal rate of recovery from iron deficiency anemia might require a daily intake of at least 10 lb (4540 g) of steak. For these and other reasons, medicinal iron is much superior to dietary iron in the therapy of iron deficiency.
IRON PREPARATIONS
The pharmaceutical market is glutted with iron preparations in nearly every conceivable form, each promoted to appeal to physician or patient for one reason or another. The following simple principles may help the physician to find a way through this chaos.

1.
Each dose of an iron preparation for an adult should contain between 30 and 100 mg elemental iron. Doses of this magnitude cause unpleasant side effects relatively infrequently.295,296 Smaller doses have been popular in the past, but these may result in a slower recovery of the patient or no recovery at all.

2.
The iron should be readily released in acidic or neutral gastric juice or duodenal juice (usually pH 5 to 6), because maximal absorption occurs when iron is presented to the duodenal mucosa. Enteric-coated and prolonged-release preparations dissolve slowly in any of these fluids. Thus with such preparations the iron that eventually is released may be presented to a portion of the intestinal mucosa in which absorption is least efficient. Some patients who have been treated unsuccessfully with enteric-coated or prolonged-release iron preparations respond promptly to the administration of non–enteric-coated ferrous salts (Fig. 38-6).

FIGURE 38-6 Rate of response of patient with iron deficiency anemia to 43 days of treatment with prolonged-release Feosol Spansules (containing 225 mg ferrous sulfate), one capsule daily, the dosage recommended by the manufacturer, followed by 43 days of treatment with nonenteric ferrous sulfate (0.3 g three times daily). Clearly, 225 mg of ferrous sulfate daily in prolonged-release form failed to elicit any significant hemopoietic response in this case. The rapid response subsequently elicited with conventional ferrous sulfate may be taken as a typical response to effect therapy in adequate dosage, whether by oral or parenteral route. (From Beutler and Meerkreebs296; by permission of the Massachusetts Medical Society.)

3.
The iron, once released, should be readily absorbed. Iron is absorbed in the ferrous form; consequently, only ferrous salts should be used.

4.
Side effects should be infrequent. This seems not to be a particular problem for any of the common commercially available iron compounds. Despite the claims of pharmaceutical companies, there is no convincing evidence that any one effective preparation is superior in this respect to any other.

5.
The cost to the patient should be small.

6.
The use of preparations containing several therapeutic agents is to be condemned.
Table 38-8 compares a few of the commonly used iron preparations.

TABLE 38-8 COMPARISON OF COSTS FOR SOME IRON MEDICATIONS*

Physicians should be aware that if ferrous sulfate is prescribed generically, the choice of preparation is left to the pharmacist, who may dispense enteric-coated tablets. It is advisable to specify “nonenteric” or to prescribe by brand name a product that is not enteric-coated.
Although substances such as ascorbic acid, succinate, and fructose have been shown to enhance iron absorption, the gain is offset to a large extent by the increase in frequency of side effects or cost of therapy, or both. There is no convincing evidence to support the use of chelated forms of iron or of iron in combination with wetting agents.
Dosage For the therapy of iron deficiency in adults, the dosage should be sufficient to provide between 150 and 200 mg elemental iron daily. The iron may be taken orally in three or four doses 1 h before meals. Infants may be given 50 to 100 mg daily in divided doses for therapy or 10 to 20 mg daily for prophylaxis of iron deficiency (Table 38-9).

TABLE 38-9 IRON PREPARATIONS FOR PEDIATRIC USE*

Side Effects Mild gastrointestinal side effects occur occasionally in the form of pyrosis, constipation, or loose stools. A metallic taste may be experienced. In some patients these side effects may be psychologic in origin. One should avoid suggesting to patients that adverse effects are to be expected. In truth, they are not: The majority of patients tolerate this dose of iron without the least side effect, and many tolerate much larger doses well. However, there is no doubt that some patients, perhaps 1 or 2 out of 10, experience symptoms that may be ascribed to the iron preparation and may be related in part to the size of the dose.295,297 In such cases, reduction of the frequency of administration to one tablet a day for a few days may alleviate the symptoms; later, the patient may be able to tolerate treatment in full dosage. It may also be useful to change to another iron preparation, especially one with a different external appearance.
Carbonyl iron has been proposed as an alternative to iron salts, on the assertion that it can be given in large doses with minimal side effects. This substance is actually metallic iron powder, with a particle size less than 5 µm. Because it is insoluble, it is not absorbed until converted to the ionic form. The bioavailability of carbonyl iron has been estimated to be about 70 percent of that of an equivalent amount of ferrous sulfate,298 but oral doses of 1 to 3 g/d may be required for optimal therapy. Oral doses as high as 600 mg three times daily did not produce toxic effects. This potentially safer form of iron is not commercially available for treatment of iron deficiency in the United States.*
During the decade of the 1990s there has been much speculation in the medical literature as to a potentially harmful effect of iron in enhancing the risk of acute myocardial infarction. However, this is not a reason for reducing the dosage of iron given to iron-deficient patients. (See also discussion in Chap. 42.)
Acute Iron Poisoning Acute iron poisoning is usually a consequence of the accidental ingestion by infants or small children of iron-containing medications intended for use by adults. Any potent oral preparation may cause acute iron poisoning, and this serious disorder is not at all rare. For example, in the Los Angeles area alone there were 5 deaths from iron poisoning among children 11 to 18 months of age in the 7-month period following June 1992.
The earliest manifestation of iron poisoning is vomiting, usually within an hour of the ingestion. There may be hematemesis or melena. Restlessness, hypotension, tachypnea, and cyanosis may develop soon thereafter and may be followed within a few hours by coma and death. So inexorable a course is not the rule, however, and only about 1 percent of such poisonings have a fatal outcome.299 Usually, medical aid is sought early, and, with proper treatment, most iron-poisoned children should survive. The initial treatment is prompt evacuation of the stomach. In the home this may be induced by digital stimulation of the pharyngeal gag reflex. Oral administration of a tepid solution of baking soda serves two useful purposes: it may provoke emesis, and the bicarbonate ion complexes with the iron and retards absorption. If a child has ingested more than 60 mg of iron per kg body weight, hospital treatment is indicated.300 In the emergency room, gastric intubation and lavage should be performed promptly, preferably with a solution containing 4 g sodium bicarbonate (or 3.6 g disodium phosphate and 0.8 g monosodium phosphate) per deciliter. Before the tube is withdrawn, a solution containing 5 to 10 g desferrioxamine, or approximately 60 ml of the bicarbonate or phosphate solution, should be introduced into the stomach. Supportive measures should be used as needed for shock or for metabolic acidosis should these develop. Desferrioxamine is the agent of choice for specific therapy of hyperferremia. It usually should be administered intramuscularly in an initial dose of 1 g, followed by 0.5 g intramuscularly 4 and 8 h later, and thereafter at 12-h intervals as the clinical status warrants. If the child is hypotensive, the dose may be administered intravenously at a rate not exceeding 15 mg/kg per hour for a total initial dose of 1 g, with repetition of this dosage started every 4 to 12 h as the clinical status of the patient seems to warrant.301 Improvement often appears several hours to a few days after onset of iron poisoning. This improvement may be permanent, but it may also be misleading, because pneumonitis or severe hepatic or neurologic decompensation may soon supervene. There may be seizures, coma, hyperreflexia, jaundice, and bilirubinemia. Children who survive for 3 or 4 days usually recover without sequelae. However, gastric strictures and fibrosis or intestinal stenosis may occur as late complications. These have been reported as early as 6 weeks after acute iron poisoning.300,302,303 and 304
PARENTERAL IRON THERAPY
INDICATIONS
Occasionally it becomes necessary to administer iron by the parenteral route. The indications are malabsorption, intolerance to iron taken orally, iron need in excess of an amount that can be taken orally, and uncooperativeness of the patient. Parenteral iron administration, together with erythropoietin, appears to alleviate the anemia that otherwise may complicate long-term dialysis treatment of patients with chronic renal disease. In rare instances, inability of the patient to follow instructions or to return for follow-up may justify use of parenteral iron. However, in view of the significantly greater hazards of parenteral therapy, the indications must be carefully considered.
PREPARATIONS: IRON DEXTRAN
Iron dextran and ferric saccharate are the only compounds commercially available in the United States for parenteral iron therapy. Because of as-yet-limited experience with the latter, the following discussion pertains to iron dextran.
Chemistry Iron dextran is a colloidal suspension in which the iron-dextran complex exists as microspherules of approximately 5 nm in diameter and an average mass equivalent to 73,000 daltons. Each particle has an electron-dense ferric oxyhydroxide (FeOOH) core surrounded by a shell believed to consist of chains of dextran extending radially from the core.305 The commercial preparation is marketed as a stable, dark brown, slightly acidic (pH 6) solution containing 50 mg elemental iron per ml.
Metabolism After intramuscular injection iron dextran is slowly absorbed, approximately 72 h being required for 50 percent of a dose to move out of the injection site.306,307 It is slowly cleared from plasma. Peak plasma concentrations of thousands of micrograms of iron per deciliter are found even 10 days after intramuscular injection; the plasma iron concentration decreases slowly, reaching normal values after 3 to 4 weeks.306,308 Iron dextran is cleared from plasma by the macrophages, and ultimately the iron is used in hemoglobin synthesis. Mobilization of iron dextran from an intramuscular site is relatively slow and incomplete; 20 to 35 percent of the dose may remain at the injection site 1 month later.309,310 Furthermore, the rate of incorporation of iron dextran into hemoglobin is somewhat slower than that for simpler ferric hydroxide colloids.310,311 It appears that the iron dextran complex is only slowly dissociated in macrophages. At most, approximately 70 percent of the iron is readily utilized in hemoglobin synthesis, the remainder being very slowly liberated from macrophages despite persistent iron deficiency anemia.
Dosage and Route of Administration Iron dextran is often administered in doses of 2.0 ml (100 mg) intramuscularly or intravenously. Total dose infusion has also been employed308,312,313,314,315,316,317 and 318 and is very convenient, but this mode of administration is not included in the approved labeling of the drug in the United States. The rate of intravenous injection of undiluted iron dextran should not exceed 1 ml/min. If any adverse effect is noted, injection must be terminated at once and appropriate countermeasures taken. A syringe containing a solution of epinephrine should be immediately accessible for treatment of anaphylaxis should this occur. The manufacturer recommends intravenous test doses of 0.5 ml before therapy is started.
It is easy to estimate the amount of iron that need be given by merely remembering that 1 ml of red cells contain about 1 mg of iron. However, various formulas have been used for estimating total dose required for treatment. Since total blood volume is approximately 65 ml/kg and the iron content of hemoglobin is 0.34 percent by weight, the simplest formula for estimating the total dose required for correction of anemia only may be derived as follows:
DFe(g) = (Dh/100) × Wkg × 65 × 0.0034
DFe(mg) = Dh × Wkg × 2.2
DFe(mg) = Dh × Wlb
where DFe = total hemoglobin iron deficit
Dh = whole blood hemoglobin deficit, g/dl
Wkg = body weight, kilograms
Wlb = body weight, pounds
Assuming normal mean hemoglobin concentration of 16 g/dl, a male weighing 170 lb, whose hemoglobin concentration is 7 g/dl, would require 170% (16 – 7) = 1530 mg iron to correct this anemia. To this should be added a sufficient quantity of iron to replete iron stores, approximately 1000 mg for men and approximately 600 mg for women. Thus a 170-lb male with a hemoglobin concentration of 7 g/dl should receive 2530 mg iron, equivalent to 50 ml of iron dextran.
Side Effects Intramuscular administration of iron dextran causes a moderate degree of pain at the injection site and a dark stain in the skin that may remain for as long as 1 to 2 years. “Z-track” and other techniques of injection recommended by the manufacturer reduce, but do not eliminate, the discoloration of the skin.
Intravenous administration also may cause local side effects, in the form of thrombophlebitis. This occurs most commonly when iron dextran is diluted with 5 percent glucose solution, less frequently when diluted with isotonic saline solution, and infrequently when iron dextran is injected undiluted. Thrombophlebitis at the injection site appears to be unusual with the technique of total-dose infusion, and other adverse effects appear to be no more frequent than with the intramuscular route.
The frequency of systemic reactions of iron dextran therapy has been markedly variable in different series, ranging from near 0308,314,319 to nearly 50 percent of patients given iron dextran.316,317,320 Dextran is a biologic product the exact structure of which is apparently difficult to control, and the frequency of adverse effects varies, probably due to variations in manufacturing techniques. Arthralgias and fever may be experienced by as many as one-third of patients. Other systemic reactions are infrequent and include hypotension, bradycardia, myalgia, headache, abdominal pain, nausea and vomiting, dizziness, lymphadenopathy, pleural effusion, and urticaria. Generalized gray discoloration of the skin has been reported following total-dose injection.321 The discoloration persisted for 3 months. Regional lymph nodes may become enlarged and tender for a few weeks after injection. Generalized lymphadenopathy322,323 and allergic purpura324 have been noted. In one case,325 fever—temperature up to 41°C (105.8°F)—persisted for 10 days and was accompanied by tachycardia, inguinal lymphadenopathy, increased erythrocyte sedimentation rate, and leukocytosis 15% 109/liter (15,000/µl) with neutrophilia. Several cases have been observed in which iron dextran infusion was followed by an acute febrile illness accompanied by tender lymphadenopathy and splenomegaly lasting 10 to 14 days.326 Pleocytosis of the cerebrospinal fluid has been observed327 during a febrile reaction to iron dextran; in this case there was also a blood leukocyte count of 88 × 109/liter (88,000/µl). In another patient meningismus without increased leukocytes in the spinal fluid but a high spinal fluid iron concentration was documented.319 Pancytopenia may follow iron dextran therapy.328 Acute, severe exacerbation of arthritis has been observed following iron dextran therapy in patients with rheumatoid arthritis329,330 and 331 or ankylosing spondylitis.332
Intramuscular deposition of iron dextran has led to malignancy in some experimental animals.333,334 Fibrosarcoma and undifferentiated pleomorphic sarcoma have developed at the site of injection in several human subjects following repeated or protracted iron dextran therapy.335,336 and 337 This appears to be an extremely rare phenomenon and may in some cases have been coincidental rather than causally related.
The most dangerous complication of iron dextran therapy is anaphylactic reaction. This occurs in fewer than 1 percent of patients treated by either the intramuscular or intravenous route. It is not dose-dependent and may follow the infusion of only a few drops of diluted iron dextran solution or a fraction of a milliliter of intramuscularly injected iron dextran. This calls into question the usefulness of giving a test dose, and it is doubtful whether such a test dose serves any useful purpose. Characteristically, during the first few minutes of infusion, the patient complains of difficulty breathing, or a choking or smothering sensation, becomes sweaty and anxious, may complain of nausea, and may vomit. Respiratory stridor may be observed, followed by apnea. The blood pressure may drop abruptly; stupor and coma may quickly supervene. At the first evidence of this reaction, the infusion must be terminated, and epinephrine should immediately be injected subcutaneously (0.5 ml of 1:1000 aqueous epinephrine). Other measures to combat shock and anaphylaxis are appropriate. Most patients survive. However, at least six deaths are ascribed to iron dextran–induced anaphylactic shock,338,339,340,341 and 342 in some cases despite appropriate treatment. Stroke or myocardial infarction may follow anaphylactic shock induced by iron dextran.343
Freshly opened vials of iron dextran may contain as much as 100 mg divalent iron per deciliter. Iron dextran causes hypotension when administered intravenously to cats, and the hypotensive effect correlates to some extent with the amount of divalent iron in the solution.344 Successful administration of iron dextran after pretreatment with methylprednisolone, diphenhydramine, ephedrine, and Promit (very low molecular weight dextran) has been reported in a patient with a previous anaphylactic response,345 and the use of glucocorticoids to prevent delayed reactions317 had been advocated, but circumstances would need to be very unusual to justify readministration of iron dextran to a patient who had experienced a severe reaction.
Administration of iron dextran does not interfere with blood cross-matching or cause abnormalities of coagulation.326
COURSE
If therapy is adequate, the correction of iron deficiency anemia is usually gratifying. Symptoms such as headache, fatigue, pica, paresthesias, and burning sensation of the oropharyngeal mucosa may abate within a few days. In the blood, the reticulocyte count begins to increase after a few days, usually reaches a maximum at about 7 to 12 days, and thereafter decreases. When aneinia is mild, little or no reticulocytosis may be observed. Little change in hemoglobin concentration or hematocrit value is to be expected for the first 2 weeks, but then the anemia is corrected rapidly. The hemoglobin concentration in the blood may be halfway back to normal after 4 to 5 weeks of therapy. By the end of 2 months of therapy, and often much sooner, the hemoglobin concentration should have reached a normal level. There is little difference in the rate of response whether iron is administered by the oral or the parenteral route, except in patients with intestinal malabsorption.346
PROGNOSIS
When the cause of the iron deficiency is a benign disorder, the prognosis is excellent, provided bleeding is controlled or can be compensated for by continual iron therapy. Too often, therapy is interrupted as soon as anemia has been corrected, and iron stores are not replenished. Such inadequately treated patients are likely to have recurrent anemia.347 For this reason, and because iron therapy brings about replenishment of iron stores very slowly, oral therapy should be continued for at least 12 months after anemia has been corrected. If there is a benign cause of recurrent bleeding that is not an indication for surgical correction, such as hiatal hernia, menorrhagia, or hereditary hemorrhagic telangiectasia, oral iron therapy may be continued indefinitely; if the bleeding is especially brisk, supplementation with parenterally administered iron or, rarely, with transfusion may be needed. Continuous iron administration may also be required in patients with iron deficiency secondary to intravascular hemolysis with hemoglobinuria.
If the diagnosis of iron deficiency anemia is correct, anemia and other manifestations of iron deficiency will respond to adequate therapy. However, the physician is occasionally disappointed in the results of treatment of patients who seem to have iron deficiency anemia. In some cases this apparent failure of therapy is a result of treatment of patients with iron preparations that are virtually insoluble, enteric-coated, or contain iron in only minute amounts. Careful inquiry into the nature, duration, and regularity of iron therapy may reveal a reason for the failure of therapy and permit a gratifying response to be elicited with adequate therapy. Other questions that should be asked in evaluation of such a case are these: (1) Has bleeding been controlled? (2) Has the patient been on iron therapy long enough to show a response? (3) Has the dose of iron been adequate? (4) Are there other factors—inflammatory disease, neoplastic disease, hepatic or renal disease, concomitant deficiencies (vitamin B12, folic acid, thyroid)—that might retard response? (5) Is the diagnosis correct?
*Carbonyl iron is used in the United States in the semisolid infant foods shown in Table 38-2, although the bioavailability of iron in this form is poor.
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Books@Ovid
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

7 comments on “CHAPTER 38 IRON DEFICIENCY

  1. As the name implies, iron deficiency anemia is due to insufficient iron. Without enough iron, your body can’t produce enough hemoglobin, a substance in red blood cells that enables them to carry oxygen. As a result, iron deficiency anemia may leave you tired and short of breath.

  2. Usually, people can eliminate iron deficiency anemia by taking iron as pills or shots and adding iron in their diet. If your anemia is not corrected with these treatments, your doctor will do more testing to look for other causes of your anemia, such as new bleeding or difficulty absorbing iron from pills. These tests may be the same as those initially used to diagnose your anemia.

  3. If you have a mild case of iron deficiency anemia, you may not experience any symptoms. However, many common symptoms are associated with moderate to severe iron deficiency anemia and can vary in intensity among individuals.

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