Chapter 43: Iron Deficiency and Overload

DEFINITION AND HISTORY

Iron deficiency is the state in which the content of iron in the body is less than normal. Iron depletion is the earliest stage of iron deficiency, in which storage iron is decreased or absent but serum iron concentration, transferrin saturation, and blood hemoglobin levels are normal. Iron deficiency without anemia is a somewhat more advanced stage of iron deficiency, characterized by absent storage iron, usually low serum iron concentration and transferrin saturation, but without frank anemia. Iron-deficiency anemia, the most advanced stage of iron deficiency, is characterized by absent iron stores, low serum iron concentration, low transferrin saturation, and low blood hemoglobin concentration.

Chlorosis, or “green sickness,” was well known to European physicians after the middle of the 16th century. In France, by the middle of the 17th 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 20th 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, but it was not until the classic 1932 studies by Heath, Strauss, and Castle¹ that it was shown that the response of anemia to iron was stoichiometrically related to the amount of iron given and that chlorosis was, indeed, iron deficiency. The history of iron deficiency has been reviewed in greater detail elsewhere.^2,3

EPIDEMIOLOGY

Iron-deficiency anemia is the most common anemia worldwide, and is especially prevalent in women and children in regions where meat intake is low, food is not fortified with iron, and malaria, intestinal infections, and parasitic worms are common.^4,5,6 Women with frequent pregnancies may be particularly susceptible. In the United States, iron deficiency is most common in children 1 to 4 years old and in adolescent, reproductive age, or pregnant women.^7,8,9

ETIOLOGY AND PATHOGENESIS

Etiology

Iron deficiency may occur as a result of chronic blood loss, diversion of iron to fetal and infant erythropoiesis during pregnancy and lactation, inadequate dietary iron intake, malabsorption of iron, intravascular hemolysis with hemoglobinuria, diversion of iron to nonhematopoietic tissues like the lung, genetic factors, or a combination of these factors. Of these, gastrointestinal or menstrual blood loss are the most common. As discussed in Chap. 42, the average adult male has approximately 1000 mg of iron in stores, but on average, women have less than half of this amount. The average daily dietary intake of iron is 10 to 12 mg, but much of this is not absorbed, even when absorption is maximal. Blood loss of each milliliter of packed erythrocytes represents 1 mg of iron. Thus chronic daily blood loss greater than 5 mL of erythrocytes will deplete iron reserves over weeks to months, and even if bleeding stops completely, the repletion of lost iron, including the restoration of iron stores (around 1000 mg in the average adult man), will take many months.

Blood Loss

Gastrointestinal Blood Loss

In men and in postmenopausal women, iron deficiency is most commonly caused by chronic bleeding from the gastrointestinal tract. Table 43–1 lists the causes of such blood loss. After history and physical examination rule out an obvious bleeding source in the genitourinary or respiratory tracts, evaluation of the gastrointestinal tract¹⁰ is necessary because of the potential that the pathologic process causing the blood loss is life-threatening. In the adult, the most common causes are peptic ulcer, erosion in a hiatal hernia, gastritis (including that caused by alcohol or aspirin ingestion), hemorrhoids, vascular anomalies (such as angiodysplasia), and neoplasms.

Gastritis, Varices, Ulcers, and Inflammation

Gastritis as a result of drug ingestion is a common cause of bleeding. Aspirin, indomethacin, ibuprofen, and other nonsteroidal antiinflammatory drugs cause gastritis, but may also cause bleeding by inducing gastric or duodenal ulcers, or lesions in the small intestine¹¹ and even the colon. Gastritis caused by alcohol ingestion¹² can also cause significant blood loss. Chronic blood loss is often the cause of anemia in rheumatoid arthritis (perhaps because of the use of nonsteroidal antiinflammatory medications) and in inflammatory bowel disease.

Chronic blood loss from esophageal or gastric varices can lead to iron-deficiency anemia. Hemorrhoidal bleeding may lead to severe iron-deficiency anemia. Chronic blood loss may result from diffuse gastric mucosal hypertrophy (Ménétrier disease).¹³ Peptic ulcers of the stomach or duodenum are common causes of iron deficiency, and an association between infection with Helicobacter pylori and iron-deficiency anemia has been documented in numerous studies.¹⁴ Some of these iron-deficient patients who are infected with H. pylori do not respond to oral iron alone, but do respond to eradication of H. pylori.¹⁵

Gastric ulceration and bleeding can also occur in disorders of hypergastrinemia, as in Zollinger-Ellison syndrome and pseudo–Zollinger-Ellison syndrome. Although concerns were raised that long-term medical therapy of these disorders with proton pump inhibitors would also cause iron deficiency by raising gastric pH and making iron less soluble, this does not seem to be the case.¹⁶ Anemia that follows subtotal gastrectomy is usually attributed to reduced absorption of dietary iron (see “Malabsorption of Iron” below), but occult intermittent gastrointestinal bleeding from gastrointestinal lesions may also be a contributory factor, and requires endoscopic evaluation.¹⁷

Diaphragmatic Hernia

Diaphragmatic (hiatal) hernia is often associated with gastrointestinal bleeding.^18,19,20 The frequency of anemia ranges from 8 to 38 percent. Bleeding is much more likely to occur in patients with paraesophageal or large hernias than in those with sliding or small hernias. 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.²¹

Intestinal Parasitism

Hookworms are a major cause of gastrointestinal blood loss in many parts of the world.²²

Vascular Anomalies

The lesions of angiodysplasia may occur in any part of the gastrointestinal tract.²³ These tiny vascular anomalies may be the cause of significant blood loss. Endoscopy is usually required for diagnosis, and often needs to be repeated as bleeding can be intermittent. Gastric antral vascular ectasia²⁴ exhibits a characteristic endoscopic appearance (“watermelon stomach”), and is another cause of blood loss. Hemorrhage into the biliary tract is a rare cause of chronic iron-deficiency anemia.²⁵

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 scleroderma²⁶ and in Turner syndrome,²⁷ as a manifestation of bleeding from abnormal blood vessels. Cutaneous hemangiomas (blue rubber bleb nevus) may be associated with hemorrhage from intestinal hemangiomas.²⁸

In hereditary hemorrhagic telangiectasia (Chap. 122), 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.

Meckel Diverticulum

Meckel diverticulum is a very common abnormality representing a vestigial remnant of the omphalomesenteric duct. In children, bleeding from this structure accounts for a small proportion of cases of iron-deficiency anemia.²⁹

Genitourinary Tract

Heavy menstrual bleeding³⁰ is a very common cause of iron deficiency. The amount of blood lost with menstruation³¹ varies markedly from one woman to another and is often difficult to evaluate by questioning the patient. The average menstrual blood loss is approximately 40 mL per cycle. Blood loss exceeds 80 mL (equivalent to approximately 30 mg of iron) per cycle in only 10 percent of women. 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. Oral contraceptives reduce menstrual blood loss, but the use of an intrauterine coil for contraception increases menstrual blood loss, especially during the first year of use. Because the daily dietary intake is usually between 10 and 12 mg of iron and only a few milligrams of this can be absorbed, 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.

In the absence of hematuria, urinary iron losses as high as 1 mg/day have been reported in rare patients with nephrotic syndrome, some of whom had hypoferremia and hypochromic anemia.³² We found only one report of a patient in whom abnormally high urinary iron loss may have caused anemia without proteinuria or hematuria.³³

Bleeding Disorders

Hemostatic defects, particularly those related to abnormal platelet function or number may lead to gastrointestinal bleeding, although unless the thrombocytopenia or platelet dysfunction is severe, gastrointestinal bleeding usually signifies an abnormality in the gastrointestinal tract. Gastrointestinal bleeding is common in von Willebrand disease (Chap. 126), but often because of coexistent peptic ulcer disease. 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 (Chap. 84).

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, but that an anatomic lesion of the gastrointestinal tract may also be present.

Nosocomial (Iatrogenic) Anemia

Iatrogenic anemia is particularly prevalent in intensive care units³⁴ where repetitive blood sampling may result in removal of 40 to 70 mL of blood daily, and this iatrogenic phlebotomy can result in iron-deficiency anemia.

The use of extracorporeal dialysis for treatment of chronic renal disease may cause iron deficiency,^35,36 often superimposed upon the anemia of chronic renal disease (Chap. 37). Patients treated with chronic hemodialysis experience multiple sources of blood loss with the dialysis equipment is a major cause, along with gastrointestinal bleeding, blood sampling and bleeding related to vascular access.

Anemia Incident to Blood Donation

Each whole-blood donation removes approximately 200 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 they are excluded from donation, some blood donors are iron depleted^37,38,39 and may readily develop iron-deficiency anemia with relatively small additional blood loss.

Factitious Anemia

Factitious anemia as a result of 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), or part of Munchausen syndrome (based on the Rudolf Raspe book, The Surprising Adventures of Baron Münchausen).^40,41 Most patients are women, and are often employed in a medical setting. There is often a history of numerous blood transfusions. The anemia is chronic and may be severe. 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. The patients may be depressed and suicidal; some also suffer anorexia nervosa. Psychiatric care is needed, but often is unsuccessful. Rarely, the outcome of self-bleeding may be fatal.⁴²

Cow’s Milk Anemia

Ingestion of whole cow’s milk may induce protein-losing enteropathy and gastrointestinal bleeding in infants,^43,44 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. At least during the first year of life, children should not be given whole bovine milk, either raw or pasteurized. More protracted heating, as in preparation of infant formulas, eliminates this problem. Intrinsic lesions of the gastrointestinal tract, such as those listed above, may cause bleeding in infants, as well as in older children.

Respiratory Tract

Persistent recurrent hemoptysis may lead to iron-deficiency anemia. It may be a result of 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 hemosiderosis⁴⁵ and of Goodpasture syndrome (progressive glomerulonephritis with intrapulmonary hemorrhage). 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. Iron deficiency occurs in a large proportion of patients with cystic fibrosis,^46,47 and occurs even in the absence of hemoptysis, suggesting that inflammatory inhibition of dietary iron absorption and iron loss in purulent sputum could contribute to the deficiency.

Pregnancy and Parturition

Although physiologic decrease in hemoglobin concentration is an expected consequence of hemodilution associated with pregnancy, true iron deficiency frequently results in more severe anemia. In pregnancy, the average iron loss resulting from diversion of iron to the fetus, blood loss at delivery (equivalent to an average of 150 to 200 mg of iron), and lactation is altogether approximately 900 mg; in terms of iron content, this is equivalent to the loss of more than 2 L of blood. Approximately 30 mg of iron may be expended monthly in lactation. Because 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. Iron-deficient mothers are likely to have smaller babies. The incidence of anemia and iron deficiency is lower in women who take oral iron supplementation, daily or intermittently.^48,49,50,51 In regions with endemic malaria, iron supplementation may increase the risk of malaria and some recommend that it be combined with malarial prophylaxis.⁵² Most experts agree that oral iron supplementation during pregnancy is desirable despite side effects. Increasing safety and convenience of parenteral iron therapy may lead to reevaluation of its role in the prevention and treatment of iron-deficiency anemia of pregnancy.⁵³

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 approximately 240 mg of iron to meet the needs of an expanding red cell mass. Approximately 50 mg of this need is fulfilled by the destruction of erythrocytes that occurs physiologically during the first week of life (Chaps. 7 and 33); 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 iron supplementation is implemented. This is especially true of premature infants. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Committee on Nutrition urges that all infant formulas be iron-fortified⁵⁴; in North America, the use of iron-fortified formula is now generally accepted, but there is controversy about the appropriate level of fortification.⁵⁵ In older children, an iron-poor diet may also contribute to the development of iron-deficiency anemia, particularly during rapid growth periods.

Infants and young women are usually in precarious iron balance, their iron intake being less than 80 percent of the recommended daily allowance (RDA).⁵⁶ Fortification of bread and cereals with ferrous sulfate or metallic iron is commonplace. This practice was suspended in Sweden because of concern for the possibility of increasing iron storage in patients with the hemochromatosis genotype, resulting in increased incidence of iron-deficiency anemia.⁵⁷

The scant iron supply of the American diet places young women and children at particular risk of negative iron balance. Because the adult male needs to absorb only approximately 1 mg iron daily from his diet to maintain normal iron balance, iron deficiency in older men is very rarely caused by insufficient dietary intake alone.

Malabsorption of Iron

Gastric secretion of hydrochloric acid is often reduced in iron deficiency.⁵⁸ Histamine-fast achlorhydria has been found in as many as 43 percent of patients with iron deficiency. Gastric function may improve after correction of the iron deficiency, so that iron deficiency may be both a cause and a result of impairment of gastric iron secretion. However, in persons older than the age of 30 years, the achlorhydria is usually irreversible. Furthermore, when atrophic gastritis coexists with iron deficiency, no improvement in gastric secretory function has followed iron therapy. Autoimmune gastritis, which is often associated with H. pylori infection,^14,15 may play an important role in both iron-deficiency anemia and, in later life, in the development of pernicious anemia.

Intestinal malabsorption of iron is quite an uncommon cause of iron deficiency except after gastrointestinal surgery and in malabsorption syndromes. Ten to 34 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 post–partial gastrectomy patients. Moreover, gastrointestinal blood loss may also play an important role in anemia following gastric resection (see “Gastrointestinal Blood Loss” earlier). In malabsorption syndromes, absorption of iron may be so limited that iron-deficiency anemia develops over a period of years. Celiac disease, whether overt or occult, may be associated with iron-deficiency anemia.^14,15,59,60

Intravascular Hemolysis and Hemoglobinuria

Iron-deficiency anemia may occur in paroxysmal nocturnal hemoglobinuria (Chap. 40) and in hemolysis resulting from mechanical erythrocyte trauma from intracardiac myxomas, valvular prostheses (particularly if malfunctioning), or patches (Chaps. 33 and 51). In these disorders, up to 10 mg/day of iron is lost in the urine as hemosiderin and ferritin in desquamated tubular cells and as hemoglobin dimers, an amount sufficient to cause systemic iron deficiency.^61,62

Iron deficiency occurs frequently in athletes engaged in a variety of sports (Chaps. 33 and 51), especially female athletes.⁶³ There may be mild anemia. Increased intravascular hemolysis, presumably with some renal loss of iron, may play a role, but gastrointestinal blood loss has also been demonstrated in persons engaged in strenuous athletic pursuits. Hemoglobinuria and hemosiderinuria are also seen in competitive and recreational runners, that is, march hemoglobinuria (Chaps. 33 and 51). Strenuous exercise also elicits a rise in serum interleukin (IL)-6 and hepcidin, and this could decrease dietary iron absorption.⁶³

Women soldiers undergoing basic training experience iron depletion as determined by serum ferritin measurements, and this can be partially reversed by iron supplementation.⁶⁴ The etiology may be similar to the iron deficiency seen in athletes.

Genetic Factors

Based on twin studies,⁶⁵ genetic factors play a role in iron deficiency. Mutations in multiple genes, including HFE and transferrin, show weak associations with iron stores but only mutations of the membrane serine protease Tmprss6⁶⁶ have been identified in genome-wide association studies as genetic factors that cause or predispose to iron deficiency. The genetic syndrome of iron-refractory iron deficiency anemia is mediated by inappropriately increased hepcidin as a result of homozygous or compound heterozygous mutations in Tmprss6.^67,68,69 Increased hepcidin diminishes iron absorption and causes inappropriate retention of available iron in splenic macrophages and Kupffer cells.

PATHOGENESIS

As iron deficiency develops, different compartments are depleted in iron in an overlapping sequence, as illustrated schematically in Fig. 43–1.

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. Hemoglobin synthesis in the marrow decreases, first as a result of fewer erythroblasts,⁷⁰ but eventually also per erythroblast if iron deficiency becomes more severe, resulting in hemoglobin-deficient erythrocytes. The concentration of many other iron-containing proteins is affected, often in an organ-specific manner.⁷¹ Studies in laboratory animals on defined iron-deficient diets are most informative about this process, because human iron deficiency is often confounded by other forms of malnutrition. In such models of severe (pure) iron deficiency, skeletal muscle myoglobin is mildly depleted but cardiac myoglobin is not. Cytochromes and other mitochondrial ferroproteins are depleted but selectively so. Since these classical studies were performed, it has become apparent that the synthesis of many ferroproteins is regulated in an iron-dependent manner, mainly via the iron-responsive element (IRE)/iron-regulatory protein (IRP) system (Chap. 42). The changes in iron-containing proteins may thus be adaptive,⁷² to allow the survival of the organism until more iron becomes available.

Muscular Function and Exercise Tolerance

Decrements in high-intensity exercise performance can be detected even during nonanemic iron deficiency,⁶³ and worsen with increasing anemia.⁷³ The limitation of high-level exercise by oxygen delivery, and, therefore, hemoglobin content of blood, is well known, and has given rise to surreptitious blood doping and erythropoietin abuse by some athletes. The impairment of performance during nonanemic iron deficiency consists of decreased spontaneous activity (seen in humans and in animal models) and decreased ventilatory threshold, that is, the point at which ventilation starts increasing more rapidly than oxygen consumption.⁷⁴ Other deficits that have been reported include decreased endurance and increased muscle fatigue. The biochemical basis of the deficits associated with nonanemic iron deficiency is not well understood but is attributed to the depletion of iron-containing mitochondrial proteins that are involved in energy metabolism.⁶³ The condition is reversible with iron supplementation.

Neurologic Changes

Iron deficiency is associated with both developmental abnormalities in children and with restless leg syndrome in adults, but in neither case has iron deficiency been established as the primary cause.^75,76 The substantia nigra is a particularly iron-rich region of the brain and contains dopaminergic neurons that are suspected of involvement in restless leg syndrome. In mouse models of iron deficiency, iron depletion of the substantia nigra is highly strain-dependent,⁷⁷ suggesting that iron deficiency and as yet incompletely characterized genetic variations may cooperate in the pathogenesis of restless leg syndrome by allowing the depletion of iron from susceptible brain regions involved in dopaminergic signaling.⁷⁸

Host Defense and Inflammation

In multiple publications, iron deficiency has been reported to impair various immune functions, but the effects appear minor and inconsistent.⁷⁹ Perhaps surprisingly, the evidence for a narrowly protective and proinflammatory effect of iron deficiency appears stronger. Iron deficiency decreases the risk and severity of malaria,^80,81 and iron supplementation may have the opposite effect, especially when not targeted to patients with iron deficiency.^52,82 The mechanism of this effect is of great interest but not yet well understood.⁸³ There are some indications that iron deficiency may have a proinflammatory effect. In a mouse model, iron deficiency potentiated the systemic effect of lipopolysaccharide in a hepcidin-dependent manner,⁸⁴ and in a mouse model of asthma, iron deficiency promoted allergic inflammation.⁸⁵

Growth and Metabolism

Iron-deficient children have been reported to suffer from growth retardation but it is difficult to isolate the effect of iron deficiency from other nutritional and environmental causes of stunting. Two comprehensive analyses of randomized controlled trials did not detect an effect on growth of iron supplementation alone.^86,87 Decreased thermoregulation in response to cold exposure is seen in both humans and laboratory models.⁸⁸ It has been attributed to the conflicting effects on blood flow of decreased oxygen content of blood and need to minimize heat loss, as well as the effect of iron deficiency on thyroid function.

Histologic Findings

Severe 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,⁸⁹ stomach,⁹⁰ and small intestine.⁹¹ 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.⁹² Buccal mucosa has shown thinning and keratinization of epithelium and increased mitotic activity.^93,94 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.⁹⁵ 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.⁴⁵

Widening of diploic spaces of bones, particularly those of the skull and hands,^96,97,98 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 β-thalassemia major there is maxillary hypertrophy, whereas in severe iron-deficiency anemia maxillary growth and pneumatization are normal.

CLINICAL FEATURES

Clinical Manifestations of Anemia

The anemia in iron-deficient patients can be very severe, with blood hemoglobin levels as low as less than 4 g/dL being encountered in some patients. Severe iron-deficiency anemia is associated with all of the various symptoms of anemia, resulting from hypoxia and the body’s response to hypoxia, as described in Chap. 32. Thus, tachycardia with palpitations and pounding in the ears, headache, light-headedness, and even angina pectoris, may all occur in patients who are severely anemic.

Clinical Manifestations That May Be Unrelated to Anemia

The clinical features of iron deficiency encompass nonhematologic effects and symptoms caused by the anemia itself. A number of controlled studies show that various manifestations of iron deficiency can occur in individuals whose hemoglobin is within the accepted normal range.

Decreased Work Performance

Objective measurements of work performance and studies using O₂ consumption as an index of work performance have given contradictory results, but a comprehensive review led to the conclusion that severe iron-deficiency anemia (hemoglobin <8 g/dL) and mild iron deficiency anemia (hemoglobin between 8 and 12 g/dL) led to decreased work performance, primarily as estimated by peak oxygen consumption (VO₂max) measurements, but the evidence that nonanemic iron deficiency had such an effect was less convincing.⁹⁹ However, in athletes with low ferritin levels but normal hemoglobin levels, iron-supplemented subjects showed an increased VO₂max without a change in their red cell mass, and in other studies nonanemic subjects treated with iron showed improved performance and/or VO₂max.⁶³

Infant and Childhood Development

It has been proposed that iron deficiency in infants and children is associated with poor attention span, poor response to sensory stimuli, and retarded behavioral and developmental achievement even in the absence of anemia. The causality of these associations is confounded by other coexisting nutritional deficits and socioeconomic deprivation, so reversibility by iron supplementation would be important in establishing causality. However, in systematic meta-analyses, iron supplementation had weak or no effects on these deficits.^{86,100,101,102}

Hyperactivity Syndromes

It has been speculated that there is a relationship between restless legs syndrome, Tourette syndrome, and attention deficit hyperactivity disorder and that iron deficiency contributes to their pathophysiology. Restless legs syndrome, a common nocturnal problem, especially in the elderly, is associated with iron deficiency and is reported to improve on iron therapy, but the beneficial effects are inconsistent and not well predicted by blood ferritin or transferrin saturation.^75,103,104 In children there may be a relationship between iron deficiency and attention deficit hyperactivity disorder, but the association is inconsistent.¹⁰⁵

Other Neurologic Symptoms

Breath holding in children, headaches, and paresthesias have been attributed to iron deficiency but there are no controlled studies to support these impressions. Anecdotal reports of intracranial hypertension with papilledema are buttressed by apparent response to iron therapy.^{106,107,108,109} Stroke in children and in adults, possibly triggered by thrombocytosis, is associated with iron-deficiency anemia.^{110,111,112,113,114}

Oral and Nasopharyngeal Symptoms

Burning of the tongue has also been described anecdotally in many accounts of iron deficiency, and although this symptom has been observed to diminish with treatment, no controlled studies have been performed. The tongue symptoms could be a result of concurrent pyridoxine deficiency. Although iron deficiency has been proposed as a cause of atrophic rhinitis, the evidence for this is weak.

Dysphagia

In the laryngopharynx, mucosal atrophy may lead to web formation in the postcricoid region, thereby giving rise to dysphagia (Paterson-Kelly also known as Plummer-Vinson syndrome).¹¹⁵ If these alterations are of long duration, they may lead to pharyngeal carcinoma. Although it has been generally thought that these changes are secondary to longstanding iron deficiency, this mechanism is not universally accepted. The frequency of the condition is considered to have decreased considerably, and it is remarkably rare in many parts of the world where iron deficiency is common.

Pica

The craving to eat unusual substances, for example, dirt, clay, ice, laundry starch, salt, cardboard, and hair, is a well-documented manifestation of iron deficiency and is usually cured promptly by iron therapy.^{116,117,118,119}

Hair Loss

Although the association of hair loss with iron deficiency is controversial,¹²⁰ low ferritin levels were a risk factor for hair loss in a large multivariate analysis.¹²¹ Remarkably, hair loss sparing the face (“mask mouse”) is a sign of iron deficiency in mice.¹²²

Physical Findings

The physical findings in iron-deficiency anemia include pallor, glossitis (smooth, red tongue), stomatitis, and angular cheilitis. Koilonychia (spoon nails), once a common finding, is now encountered rarely. Retinal hemorrhages and exudates may be seen in severely anemic patients (e.g., hemoglobin concentration of <5 g/dL). Splenomegaly has occasionally been attributed to iron-deficiency anemia, but when it occurs, it is probably from other causes.

LABORATORY FEATURES

In severe, uncomplicated iron-deficiency anemia, the erythrocytes are hypochromic and microcytic; the plasma iron concentration is diminished; the iron-binding capacity is increased; the serum ferritin concentration is low; the serum transferrin receptor (TfR) and erythrocyte zinc protoporphyrin concentrations are increased; and the marrow is depleted of stainable iron. However, 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.

Blood Cells

Erythrocytes

Anisocytosis is the earliest recognizable morphologic change of erythrocytes in iron-deficiency anemia (Fig. 43–2).¹²³ The anisocytosis is typically accompanied by mild ovalocytosis. As the iron deficiency worsens, a mild normochromic, normocytic anemia often develops. With further progression, hemoglobin concentration, erythrocyte count, mean corpuscular volume (MCV), and mean erythrocyte hemoglobin content all decline together.^124,125 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. 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 <12 g/dL or in women with hemoglobin concentrations <10 g/dL) (Fig. 43–3). The distribution of erythrocyte volume (e.g., red cell distribution width [RDW]) is usually increased in established iron-deficiency anemia. The RDW is reported often as the coefficient of variation (in percent) of erythrocyte volume (see “Differential Diagnosis” below).

Leukocytes

Leukopenia has been found in some patients with iron-deficiency anemia, but the overall distribution of leukocyte counts in iron-deficient patients seems to be approximately normal.

Platelets

Both thrombocytopenia¹²⁶ and, more commonly, thrombocytosis¹²⁷ have been associated with iron deficiency. Platelet abnormalities correct with iron therapy. Thrombotic complications of iron deficiency have been reported but are very rare.¹²⁸ The etiology of either abnormality is not known. Low-iron-diet-induced iron-deficiency anemia developed in a rat model within 2 weeks, and this was accompanied by sustained 50 percent increase in platelet count with increased platelet size but without significant changes in known megakaryocyte growth factors (thrombopoietin, IL-6 or IL-11). It has been suggested that high erythropoietin levels may stimulate thrombopoietin receptors because the two hematopoietic factors are structurally related, but this does not seem to be the case.¹²⁹

Reticulocytes

Reticulocyte count is often mildly increased,¹³⁰ a finding consistent with the increased erythroid activity of the marrow (see “Marrow” below).

Marrow

Because most of the iron in the body is normally in erythrocytes, and iron is not excreted, decrease in erythrocyte mass generally results in increased storage iron. Iron-deficiency anemia is the exception, as iron stores are depleted before the red cell mass is compromised. Thus, evaluation of iron stores should be a sensitive and usually reliable means for the differentiation between iron-deficiency anemia and all other anemias. Decreased or absent hemosiderin in the marrow is characteristic of iron deficiency, and is readily 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 approximately 30 percent of erythroblasts, become rare but may not be entirely absent.

Evaluation of the amount of iron in marrow macrophages has long been considered the “gold standard” for the diagnosis of iron deficiency. There are, however, technical barriers to the accurate histochemical determination of marrow iron. First, an invasive procedure, marrow aspiration, is required. Second, the differentiation of iron within macrophages from artifacts takes experience and skill. In one study only 74 of 108 cases had been accurately reported.¹³¹ Moreover, misleading results may be obtained in patients who have been transfused or who have been treated with parenteral iron.¹³² 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. As serum markers of iron deficiency became widely available, the reasons for the primacy of marrow iron estimation have been questioned.¹³³

Serum Iron Concentration

The serum iron concentration is usually low in untreated iron-deficiency anemia, but may rarely be normal.^125,134,135 Iron in blood plasma turns over every few hours and constitutes less than 0.1 percent of total body iron in adults, so iron concentrations are readily perturbed by transient changes in iron supply or demand. 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. This effect is rarely of sufficient magnitude to influence diagnosis.¹³⁶ Serum iron levels decrease at about the time of menstrual bleeding^137,138 regardless of whether the bleeding is physiologic or induced by withdrawal of contraceptive hormonal preparations.

Importantly, the serum iron concentration is reduced in the presence of either acute or chronic inflammatory processes¹³⁹ or malignancy¹⁴⁰ and following acute myocardial infarction.^141,142 The serum iron concentration under these circumstances may be decreased sufficiently to suggest iron deficiency. Conversely, during chemotherapy of malignancy, the serum iron concentration may be quite elevated, as cytotoxic effects of the drugs on erythroblasts inhibit erythropoiesis and related iron uptake by erythroblasts. This effect is observed from the third to the seventh day after inception of chemotherapy of a variety of tumors.¹⁴³

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 multivitamin preparations, which commonly contain approximately 18 mg of elemental iron per tablet, can result in this effect. Oral iron medication should be withheld for 24 hours before blood samples are obtained. Parenteral injection of iron dextran may result in a very high serum iron concentration (e.g., 500 to 1000 mcg/dL), at least with some methods,¹⁴⁴ for several weeks. The elevation of serum iron levels after infusion of sodium ferric gluconate or iron sucrose is of much shorter duration.¹⁴⁵

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 mcg) of iron; because the normal serum iron concentration is approximately 1.8 μmol/dL (100 mcg/dL), transferrin may be found to be approximately one-third saturated with iron. 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 can also be measured directly. In iron-deficiency anemia, UIBC and TIBC are often increased and serum iron concentrations are decreased so that transferrin saturation of 15 percent or less is usually found. Because transferrin concentration and TIBC are decreased during inflammation, a normal value for transferrin saturation often accompanies a low serum iron concentration in the anemia of chronic inflammation.

Serum Ferritin

Serum ferritin, secreted mainly by macrophages¹⁴⁶ and hepatocytes, contains relatively little iron, yet serum ferritin concentration empirically correlates with total-body iron stores,¹⁴⁷ for reasons that are still obscure. Serum ferritin concentrations of 10 mcg/L or less are characteristic of iron-deficiency anemia. In iron deficiency without anemia, serum ferritin concentration is typically in the range of 10 to 20 mcg/L. An increase in serum ferritin concentration occurs in inflammatory disorders, such as rheumatoid arthritis, in chronic renal disease, and in malignancies.¹⁴⁸ 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 becomes difficult. In patients with rheumatoid arthritis who are anemic, some suggest that concomitant iron deficiency may be suspected when the serum ferritin concentration is less than 60 mcg/L,¹⁴⁹ but such empiric guidelines are unlikely to apply to the full spectrum of severity of inflammation. Increased serum ferritin concentrations are also characteristic of some malignancies, as well as of acute and chronic liver disease and chronic renal failure.^{150,151,152,153} In Gaucher disease, juvenile rheumatoid arthritis, and various macrophage activation syndromes, and in ferroportin disease characterized by massive iron loading of macrophages, the serum ferritin concentration is commonly in the range of thousands of mcg/L and may mask iron deficiency.^{154,155,156,157,158}

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.^159,160,161 This assay analyzes the fluorescence of erythrocytes and uses small blood samples. It is quite sensitive in the diagnosis of iron deficiency and practical for large-scale screening programs designed to identify children with either iron deficiency or lead poisoning.^58,159 It does not differentiate between iron deficiency and anemia that accompanies inflammatory or malignant processes.¹⁶²

Serum Transferrin Receptor

The role of TfR in transporting transferrin iron into cells is described in Chap. 42 section “Transport of Iron”. The circulating receptor is a truncated form of the cellular receptor, lacking the transmembrane and cytoplasmic domains of the cellular receptor. It circulates bound to transferrin. Sensitive immunologic methods can detect approximately 5 mg/L of receptor in serum. The levels of circulating TfR mirror the amount of cellular receptor, and therefore are proportional to the number of erythroblasts expressing the receptor. Because receptor synthesis is greatly increased when cells lack iron, the amount of the circulating receptor increases in iron deficiency.^163,164 In anemia of inflammation, the synthesis of the TfR is suppressed by cytokines and this negates the opposing stimulatory effect of iron restriction, resulting in a lower serum TfR concentration than in pure iron deficiency.¹⁶⁵ This test for iron deficiency has gradually come into clinical use, but the methodology has not yet been standardized, making laboratory-to-laboratory comparisons difficult. A method for performing reproducible assays for the soluble TfR has been standardized.¹⁶⁶ Like the serum ferritin and serum iron, serum TfR assay results may be confounded by poorly understood variations in patients with malignancies; in patients in whom the serum TfR concentration is reduced; and in patients with asymptomatic malaria or thalassemia trait,^167,168 in whom, in the absence of iron deficiency, it is increased. The ratio of serum TfR to serum ferritin seems to be a useful but not infallible reflection of body iron stores.¹⁶⁹ Moreover, several studies show that the soluble transferrin index calculated as a ratio of the serum TfR/log ferritin (TfR-F Index) may be superior to other means for detection of iron deficiency.^170,171,172

Reticulocyte Hemoglobin Content and Other Novel Erythrocyte Indices

Some automated hematology instruments offer a method for diagnosis of iron deficiency using an assay of hemoglobin content within reticulocytes. This parameter is an indicator of iron restriction of hemoglobin synthesis during 3 to 4 days prior to the test.^173,174 Percent hypochromic erythrocytes offers a longer term assessment of iron restriction during the preceding few months.^173,175

DIFFERENTIAL DIAGNOSIS

Iron-deficiency anemia is characterized by many abnormal laboratory features. Because none of these are unique, a small deviation from normal will detect most cases of iron deficiency (high sensitivity), but also falsely identify non–iron-deficient subjects as being iron deficient (low specificity). On the other hand, a large deviation from normal will exclude most nondeficient patients (high specificity), but miss many iron-deficient subjects (low sensitivity). This tradeoff is shown graphically in so-called receiver operator characteristic curves. These curves are constructed by plotting the sensitivity against the false-positive rate (1 − specificity) at various values of the analyte. Figure 43–4 shows receiver operator characteristic curve for some tests for iron deficiency. The situation is complicated in the case of iron deficiency by the fact that the diagnostic problem faced by the physician is not one of differentiating a patient with iron-deficiency anemia from a normal person, but rather from a patient who has an anemia with a different etiology. It is partly for this reason that a simple algorithm for the diagnosis of iron deficiency does not exist. In a severely anemic patient, microcytosis would have very high specificity and high sensitivity compared to normal, but compared to a patient with thalassemia the specificity would be very low. Similarly, a low serum ferritin level is an excellent test in the general population, but it has relatively little value in patients with chronic renal disease. Another problem that is inherent in evaluating diagnostic tests for iron deficiency is the standard that is applied to decide who is iron deficient and who is not. Marrow iron has served as one “gold standard” but has limitations, as discussed earlier (see “Marrow” earlier). Alternatively, the response to iron therapy serves as a powerful indicator of whose anemia is actually a result of a deficiency of iron. Here, too, there are limitations, in that some iron-deficient patients may fail to respond adequately because of factors such as infection. Lacking an absolute test for iron deficiency, the ability of the physician to use judgment relevant to the particular patient’s circumstances is of paramount importance.

The forms of anemia that must be distinguished from iron-deficiency anemia most frequently include those of thalassemia minor, chronic inflammatory disease, malignancy, chronic liver disease, and chronic renal disease. It is the microcytic anemias that are most likely to be confused with iron deficiency. These include other conditions in which hemoglobin synthesis is impaired,¹⁷⁶ including thalassemias and thalassemia traits, drug- or toxin-induced impairments of heme synthesis, sideroblastic anemias (Chap. 59), and very rare defects in the delivery of iron to erythrocytes or erythrocyte iron uptake and utilization (Table 43–2).

Thalassemia Minor

In many parts of the world, and in many communities of North America, the frequency of β-thalassemia minor is second only to that of iron deficiency as a cause of hypochromic microcytic anemia (Chap. 48). In African Americans, homozygosity for α-thalassemia-2, that is the state in which only single α-globin gene is present on each chromosome, is a common cause of microcytosis. Approximately 3 percent of African Americans are homozygous for α-thalassemia-2. The condition is associated with only a very modest lowering of the blood hemoglobin level.¹⁷⁷ Heterozygotes may also have microcytosis, although usually they are hematologically normal. Among persons of Mediterranean ancestry both α- and β-thalassemia are very prevalent, particularly the latter. Among Asians, particularly in those from Southeast Asia, β-thalassemia minor, α-thalassemia minor, and hemoglobin E trait, 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 α- or β-thalassemia minor, hemoglobin Lepore trait, and hemoglobin E trait, the erythrocyte count is greater than 5 × 10¹²/L (5,000,000/μL), despite low hemoglobin concentration.^178,179 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 (Chap. 49).¹⁷⁸

In contrast to the findings in these hemoglobinopathies, erythrocyte counts of 5 × 10¹²/L (5,000,000/μL) or higher are relatively uncommon among adults with iron-deficiency anemia.¹⁸⁰ 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. Consequently, while the mean MCV is almost always reduced in α- or β-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.^178,179,181 Algorithmic rules based on red cell counts, MCV or RDW are not sufficiently reliable for distinguishing iron deficiency from thalassemia in populations with high prevalence of iron deficiency compared to thalassemias.

Mild reticulocytosis, polychromatophilia, and basophilic stippling are more likely to be encountered in β-thalassemia minor, δβ-thalassemia minor, and hemoglobin Lepore trait than in iron-deficiency anemia, but may be absent in these disorders. 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 β-thalassemia trait is substantiated by the demonstration of increased proportions of hemoglobin A₂ and F, or by the presence on electrophoresis of hemoglobin H or Lepore (Chap. 48). At present, the diagnosis of α-thalassemia minor is usually made on the basis of exclusion of other causes of microcytosis, but it can be confirmed by direct demonstration of mutations in α-globin genes 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 deficiency¹⁸² (Chap. 46); however, usually the hemoglobin A₂ level remains above the normal range.

Anemia of Inflammation (Anemia of Chronic Disease)

The anemia of inflammation (Chap. 37) is usually normochromic and normocytic, but hypochromic microcytic anemia occurs in 20 to 30 percent of patients with chronic infections or malignancies.¹³⁹ 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,¹³⁹ sometimes severely. In uncomplicated iron deficiency, the TIBC is usually increased, whereas in inflammatory and neoplastic diseases it is commonly decreased, but there is considerable overlap among TIBC values of normal subjects, those with iron-deficiency anemia, and those with chronic inflammatory diseases.

Transferrin saturation may be normal in iron-deficiency anemia, and, conversely, low saturation is sometimes observed in chronic inflammation. However, circulating soluble TfRs increase in iron deficiency but not in the anemia of inflammation.¹⁷⁰ The serum ferritin level is usually diminished in iron deficiency, but it is generally increased in chronic inflammatory and neoplastic disorders.¹⁴⁷ Measurement of the ratio of soluble TfR to ferritin has been found to be useful in distinguishing the anemia of chronic inflammation from that of iron deficiency,¹⁷⁰ but meta-analysis of the relevant clinical studies suggested that the ratio may not be better than soluble TfR assay alone at discriminating between iron deficiency anemia and anemia of inflammation.¹⁸³ Examination of the marrow for stainable iron is invasive and requires skilled reading but may be helpful in an occasional patient. Iron staining of marrow macrophages is greatly decreased in amount or absent in iron deficiency anemia and normal or increased in the other disorders. Low serum hepcidin concentrations are characteristic of iron deficiency and high serum hepcidin indicates anemia of inflammation, but this assay is not yet clinically available and its clinical value is unknown. As would be expected from the inhibitory effect of hepcidin on the absorption of iron, high hepcidin levels predict a poor response to oral iron therapy¹⁸⁴ and low incorporation of dietary iron into erythrocytes.¹⁸⁵

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. Because the blood film in iron-deficiency anemia may also display these features, differential diagnosis must be based on other observations. Low serum ferritin levels are useful in detecting iron deficiency in the setting of cirrhosis,¹⁸⁶ but normal or even increased serum ferritin does not exclude iron deficiency, especially in the presence of active liver injury.^186,187

Anemia of Chronic Renal Disease

Iron deficiency is frequent in patients with chronic renal disease (Chap. 37). Iron-deficiency anemia is particularly difficult to diagnose in patients with chronic renal disease (Chap. 37) where iron delivery to the marrow is inadequate because of coexisting inflammation and because of increased demands from pulsatile erythropoiesis as a result of erythropoiesis-stimulating agents. Because the problem is fairly common, and perhaps because of interest in identifying those patients who can benefit from iron therapy and decreasing their use of erythropoiesis-stimulating agents, a large number of studies have been done to determine the best way to diagnose iron deficiency in patients undergoing extracorporeal dialysis. The diagnostic problem is further complicated by the common occurrence of “functional iron deficiency,”¹⁸⁸ that is, a state in which iron stores are adequate but iron delivery to the marrow is insufficient to meet the increased kinetic requirements of erythropoiesis stimulated by intermittent use of erythropoietin and related agents. If response to intravenous iron therapy is used to diagnose iron deficiency, even many patients with abnormally high ferritins will be iron deficient.^150,189 High serum ferritins do not preclude a response to IV iron, not even in patients with chronic kidney disease who are not on hemodialysis.¹⁹⁰ Although measurements of reticulocyte hemoglobin and percent of hypochromic erythrocytes show promise as markers of response to iron therapy, there is insufficient evidence that any individual biomarker or combination of biomarkers can reliably predict the response to iron treatment in chronic kidney disease.¹⁹¹

Anemia of Hemolytic Disease

Hemolytic disease can usually be distinguished from iron-deficiency anemia on the basis of the blood film. The marked polychromatophilia, spherocytosis, schistocytes, Heinz bodies, basophilic stippling, and other morphologic features characteristic of various types 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. Chapter 49 discusses the detection of unstable hemoglobins.

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. Evaluation of iron content in marrow aspirates or measurement of serum iron concentration and TIBC may clarify the diagnosis in this form of anemia.

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. 35). The reticulocyte count is generally less than 0.5 percent in hypoplastic or aplastic 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; and the percentage transferrin saturation is then elevated. Marrow aspiration may produce scant material for cytologic study, and marrow biopsy may be necessary. An iron stain usually reveals increased amounts of hemosiderin in aplastic or hypoplastic anemia. However, if chronic bleeding has occurred, for example, as a consequence of thrombocytopenia, iron stores may be depleted.

Sideroblastic Anemia

In this heterogeneous group of disorders (Chap. 59), the blood findings often simulate those of iron-deficiency anemia. Reticulocytosis is usually absent, and the serum iron concentration and serum ferritin is generally normal or increased. Marrow examination shows characteristic ring sideroblasts and increased amounts of stainable iron.

Congenital Dyserythropoietic Anemia

In the rare congenital dyserythropoietic anemias (Chap. 39), erythrocyte morphologic abnormalities may resemble those of iron deficiency or thalassemia (Chap. 48). 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. 41), 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 patient with pernicious anemia or folic acid deficiency, early after starting treatment, the serum iron concentration decreases markedly as iron is used rapidly for hemoglobin synthesis.¹⁹² 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 as a consequence of 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. The mixture of microcytic-hypochromic and normocytic-normochromic cells has been called dimorphic anemia (see “Coexisting Microcytic Anemia” in Chap. 41).

Anemia of Hypothyroidism

The anemia of severe hypothyroidism (myxedema; Chap. 38) is usually normochromic and normocytic and may be accompanied by mild-to-moderate depression of serum iron concentration. Marrow examination may be required to determine whether iron deficiency is present, especially as iron deficiency often complicates myxedema because of menorrhagia, which is common in this disorder.

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 is usually by the oral route, but intravenous iron can be used if there is evidence or strong suspicion of coexisting inflammation, iron malabsorption, or intolerance of oral iron preparations. 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 response to oral or, when appropriate, parenteral iron must be taken as evidence that iron deficiency is not the cause of anemia. Iron therapy should be discontinued and another cause for the anemia sought.

Special Studies to Delineate the Cause of Iron Deficiency

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 for fecal occult blood is particularly helpful in determining what additional studies should be carried out. Specimens should be examined on at least 3 days, because bleeding may be intermittent. Occasionally, it is helpful to label the patient’s erythrocytes with chromium-51 (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 other imaging studies often include gastroscopy, esophagoscopy, colonoscopy, and capsule endoscopy, and, rarely, angiography or scintigraphic studies. Numerous clinical studies indicate that intensive investigation of patients, particularly men and postmenopausal women, reveals unexpected bleeding lesions, many of which are curable or treatable.^10,193 H. pylori infection should be sought, particularly in patients who are iron deficient but who do not seem to respond to therapy.^14,15 An iron stain of sputum may reveal hemosiderin-laden macrophages when there is intrapulmonary bleeding.

THERAPY

Once it has been established that a patient is deficient in iron, replacement therapy should be instituted. Iron may be administered orally, as simple iron salts; parenterally, as an iron-carbohydrate complex; or, very rarely, as a blood transfusion. In general, the oral route is preferred, but the intravenous route is increasingly used because of the improved safety and convenience of new parenteral iron preparations. In most patients, iron-deficiency anemia is a disorder of long duration and slow progression, and restoration of normal hemoglobin is not urgent unless the patient suffers from acute cardiac problems, in which case blood transfusion is appropriate. 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.

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 and insignificant amounts of iron in other proteins. Although heme iron is better absorbed than inorganic iron, the quantity of heme iron in meat is actually quite small. In fact, an average (3-ounce) serving of steak provides only about 3 mg of iron, that is, the equivalent of only 3 mL of packed erythrocytes. Provision of sufficient dietary iron to permit a maximal rate or recovery from iron-deficiency anemia might require a daily intake of at least 10 pounds 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 inorganic iron preparation for an adult should contain between 30 and 100 mg of elemental iron. Doses of this magnitude cause unpleasant side effects relatively infrequently.¹⁹⁴ 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.

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. Inexpensive iron preparations can be as effective as the more costly ones. The use of preparations containing several therapeutic agents is unnecessary and may increase side effects. 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 enhance iron absorption, the gain is offset to a large extent by the increase in frequency of side effects, 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 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 hour before meals. Infants may be given 6 mg/kg¹⁹⁵ daily in divided doses for therapy, or a daily dose of 12.5 mg daily for prophylaxis of iron deficiency

Side Effects

Mild gastrointestinal side effects occur occasionally in the form of nausea, heartburn, constipation, or changes in the stool consistency. A metallic taste may be experienced. The majority of patients tolerate the usual therapeutic doses of iron without the least side effect. However, there is no doubt that some patients, perhaps 10 to 20 percent, experience symptoms that may be ascribed to the iron preparation and may be dose-dependent. In such cases, reduction of the frequency of administration to 1 tablet a day for a few days may alleviate the symptoms; later, the patient may be able to tolerate treatment in full dosage. It might 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 approximately 70 percent of that of an equivalent amount of ferrous sulfate.¹⁹⁶ Oral doses as high as 600 mg three times daily did not produce toxic effects.¹⁹⁶

Widespread iron supplementation in regions where malaria and gastrointestinal infections are highly endemic is associated with increased malaria transmission and childhood mortality, presumably from increased infections.¹⁹⁷ Although there is not yet a consensus on optimal strategy in such settings, it seems reasonable to target iron supplementation to children who are iron-deficient.

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 remains a problem, despite public awareness campaigns and safer packaging of medications.¹⁹⁸ In the United States, there were nearly 30,000 reported incidents in 2008. The earliest manifestation of iron poisoning is vomiting, usually within 1 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 but fatal outcomes are now extremely rare. Usually, medical aid is sought early and, with proper treatment, most iron-poisoned children 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. If the patient arrives in the emergency room within minutes of ingestion, gastric intubation and lavage should be performed promptly. Whole-bowel irrigation¹⁹⁸ is currently recommended to for all heavy metal intoxications. Supportive measures should be used as needed for shock or for metabolic acidosis should these develop. IV desferrioxamine is the agent of choice for specific therapy of hyperferremia, at a maximum rate of 15 mg/kg per hour for 1 hour, then lowered to 125 mg/hour. Improvement often appears several hours to a few days after onset of iron poisoning. 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.

Parenteral Iron Therapy

Indications

As parenteral iron preparations have become safer and easier to administer, the use of parenteral iron is increasing. Established indications for the use of parenteral rather than oral iron include malabsorption, either because of systemic inflammation or gastrointestinal pathology, intolerance to iron taken orally, iron need in excess of an amount that can be absorbed in the intestine, and noncompliance. Parenteral iron administration has an erythropoietin-sparing effect in anemic patients on long-term hemodialysis for chronic renal disease.^35,199,200 Because of systemic inflammation and possibly other factors, these patients do not appear to respond adequately to oral iron therapy.

Calculating Dosage

The amount of iron that needs to be given is readily estimated by noting that 1 mL of red cells contains approximately 1 mg of iron. However, various formulas have been used for estimating total dose required for treatment. Because 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 is as follows:

Assuming normal mean hemoglobin concentration of 16 g/dL, a male weighing 170 pounds, 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-pound male with a hemoglobin concentration of 7 g/dL should receive 2530 mg iron.

Parenteral Iron Preparations

Because iron salts are highly toxic when given parenterally, all iron preparations consist of colloidal (nanoparticulate) complex of iron with carbohydrates. To make the iron bioavailable for erythropoiesis and other biologic processes, the iron complexes must be ingested by macrophages and digested so that the administered iron can be gradually delivered to plasma transferrin. Currently available preparations include iron sucrose, low-molecular-weight iron dextran, ferric gluconate, ferumoxytol, ferric carboxymaltose, and iron isomaltoside. High-molecular-weight dextran was associated with anaphylactoid adverse events compared to the other preparations and should therefore be avoided.²⁰¹ The remaining preparations are safe and serious adverse events are extremely rare.²⁰² Although the recommended methods of administration, including the use of test dosing, the amount of iron per infusion, and infusion rates differ among the preparations, these are not based on comparative studies. Currently available data indicate that the preparations do not significantly differ in safety or efficacy. Premedication to prevent allergic responses was commonly used with the older preparations but it is neither needed nor known to be effective with the newer formulations, and may introduce side effects of its own.

COURSE AND PROGNOSIS

Course

If therapy is adequate, the correction of iron-deficiency anemia is usually gratifying. Symptoms such as headache, fatigue, pica, paresthesia, 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 approximately 7 to 12 days, and thereafter decreases. When anemia 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.

When iron-deficiency anemia does not resolve with oral iron treatment, 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, prior gastrointestinal surgery, concomitant deficiencies (vitamin B₁₂, folic acid, thyroid)—that might retard response? Prominent among these are H. pylori infection, autoimmune gastritis, and celiac disease.¹⁵ (5) Is the diagnosis of iron deficiency correct?

Intravenous iron should be effective in patients with established iron deficiency who fail to respond to oral iron after several weeks. Continued loss of blood or, rarely, the genetic disorder iron-refractory iron-deficiency anemia,¹⁵ may account for incomplete response to IV iron.

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. If there is a benign cause of recurrent bleeding that is corrected, 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.

DEFINITION AND HISTORY

The terms iron storage disease and hemochromatosis are used to designate an increase of tissue iron resulting in a disease state; hemosiderosis denotes an increase of tissue iron stores with or without tissue damage. Classically hemochromatosis has been characterized by bronzing of the skin, cirrhosis, and diabetes, and was once called bronzed diabetes. Since the 1970s, usage of the term hemochromatosis has expanded well beyond its original meaning. This diagnosis is now commonly applied to persons who have increased body iron as suggested by increased serum ferritin levels, and even to those who merely have the hemochromatosis HFE genotype, regardless of the level of their iron stores.

Hemochromatosis may be divided into genetic forms and acquired forms. The former have sometimes been designated as primary and the latter as secondary forms. The disorder once designated idiopathic hemochromatosis and now as hereditary hemochromatosis usually is applied to the common genetic form of the disorder, found principally in those of northern European ancestry, and as a result of mutations in the HFE gene (type I hemochromatosis). In the United States, this is by far the most common form of the disease. Juvenile hemochromatosis from hemojuvelin and hepcidin mutations (type 2), hemochromatosis as a result of TfR-2 mutations (type 3), hemochromatosis caused by ferroportin mutations (type 4), and African iron overload are much less common. Table 43–3 classifies hereditary hemochromatosis. Secondary hemochromatosis occurs in patients who receive multiple blood transfusions, and in patients with ineffective erythropoiesis, even when they do not receive transfusions.

Systemic iron overload and hepatic iron accumulation similar to hemochromatosis are also characteristic of atransferrinemia^{203,204,205,206} and of human divalent metal transporter (DMT)-1 mutations.^207,208 A fetal and neonatal disorder termed neonatal hemochromatosis is characterized by hepatic and extrahepatic iron deposition and fulminant hepatitis caused by maternal immune response to fetal antigens.²⁰⁹

Iron accumulation in localized sites, particularly the brain, occurs in disorders other than hemochromatosis. Increased quantities of brain iron are characteristic of a ceruloplasminemia, and are found in Alzheimer disease, parkinsonism, Friedreich ataxia, Hallervorden-Spatz syndrome, and multiple system atrophy. Because none of these are primarily hematologic disorders, and because the role of iron deposition in the pathology of the disorders is uncertain, they are not discussed further here.

Hemochromatosis was first described by Trousseau in 1865. The massive accumulation of iron that occurred in this disease was recognized as its hallmark. The ingenious development of serial phlebotomy as treatment for the disease suggested by Finch in 1949, and implemented on a larger scale in 1952,²¹⁰ made it clear that iron accumulation was the most important pathogenetic factor. Alcohol consumption and other environmental factors were also commonly found in patients with hemochromatosis.²¹¹ The existence of a long-suspected hereditary factor was firmly established when the disease was shown tightly linked to the human leukocyte antigen (HLA locus). Surprisingly, the gene proved to be HFE (initially named HLA-H), one of the many HLA-like genes on chromosome 6.²¹²

The identification of the HFE gene made it possible, for the first time, to assess accurately the gene frequency and penetrance of the HFE mutations. This brought about a fusion of the apparently contrasting views of genetic and environmental causes. The penetrance of the homozygous state is so low that it could be considered an essential risk factor that required other genetic or environmental factors for disease development.²¹³

EPIDEMIOLOGY

The prevalence of mutations of the HFE gene is very high. The most significant of these is the c.845 A→G (C282Y) mutation, and with a gene frequency of approximately 0.07 in the northern European population, approximately 5 in 1000 northern Europeans are homozygous for the mutation. The C282Y and S65C mutations are almost entirely confined to individuals with European ancestry. The H63D mutation is more widespread geographically, but is also most common in Europeans. Within Europe the highest gene frequencies of the C282Y mutation are encountered in the southern British Isles and in northern France but other northern Europeans, including Scandinavians, also have high gene frequencies, consistent with Celtic or possibly Viking origin of the mutation.²¹⁴

Although earlier studies attributed nonspecific symptoms in patients to hemochromatosis, large controlled series have shown that most such symptoms are not present in homozygotes for the C282Y mutation at a higher frequency than in controls,^215,216,217 or a borderline increase, at most, invariably in groups of patients who were aware of their diagnosis when answering questions about symptoms. These findings are consistent with the very low prevalence of hemochromatosis reported in autopsy series and in hospital surveys. The prevalence of symptomatic clinical hemochromatosis in northern European populations is probably only approximately 5 in 100,000 individuals. If patients with abnormal liver function tests and/or fibrosis on liver biopsy are included, the number of affected may be severalfold higher.^{218,219,220,221} The factors that determine whether a patient with the C282Y homozygous genotype develops disease are not well understood. The patient’s sex is clearly a modifying factor, with more severe manifestations observed in males, as pregnancy and menstrual losses tend to ameliorate the disease in women. Other genetic factors that might interact with the C282Y homozygous genotype in producing clinically significant iron storage disease have been sought, but not found, except rare instances in which coinheritance of mutations of the hepcidin gene may be responsible. An increased proportion of severely affected patients have a large alcohol intake.^222,223

The widespread perception that classical hereditary hemochromatosis frequently led to clinical disease resulted in enthusiasm for population-based screening. However, the cost-to-benefit analysis used was based upon the assumptions that life-threatening disease manifestations will occur in 43 percent of males and in 28 percent of females, estimates that were based upon the prevalence of disease in patients, most of whom had been diagnosed clinically with hemochromatosis. With the realization that the clinical penetrance is much lower, interest in screening the general population for hemochromatosis has largely disappeared.

The prevalence of other forms of hemochromatosis, including juvenile hemochromatosis, hemochromatosis as a result of ferroportin deficiency, and atransferrinemia, is much lower than that the prevalence of classical hereditary hemochromatosis. These forms of hemochromatosis are very rare.

ETIOLOGY AND PATHOGENESIS

Toxicity of Iron

In living organisms, iron associates with proteins to function in oxygen storage and transport and in various metabolic reactions as an electron donor or electron acceptor. The capacity to catalyze oxidation-reduction reactions appears to cause iron-mediated cellular and tissue injury. One of the pathways that is considered to be of greatest importance is the Haber-Weiss reaction:

The sum of these two reactions is the Fenton reaction:

The hydroxyl radical (HO·) has been implicated in producing damage to polysaccharides, DNA, and enzymes, and in causing lipid peroxidation.²²⁴ Although there is no direct evidence that hydroxyl radical generation is the main pathway of tissue damage in hemochromatosis, this common conjecture seems reasonable. Demonstrating a damaging effect of iron alone on experimental animals has been difficult. Although in mouse models of genetic, parenteral, or dietary iron overload subtle biochemical defects have been documented, frank cirrhotic changes have not been found. In gerbils, parenteral iron overload causes hepatic necrosis, fibrosis, and nodular regeneration, as well as cardiac damage.²²⁵ In rats, iron alone does not cause fibrosis, and alcohol alone causes only minor liver abnormalities. However, administration of both excess iron and alcohol results in fibrosis.²²⁶ These findings in rats are quite consistent with the strong association that has been demonstrated to exist between alcohol ingestion and cirrhosis in patients with the hemochromatosis genotype. In a number of species, including birds, rhinoceros, tapir, fruit bats, and others, iron overload has been observed in zoos or other restricted settings, particularly after a diet other than the animal’s native diet is fed.

Iron is stored in ferritin in the cytoplasm of all cells. The multiple isoferritins found in human tissues are composed of variable proportions of two subunits: L-ferritin (light) and H-ferritin (heavy).²²⁷ Because free iron is potentially harmful to the cell, it is sequestered and detoxified to the less-soluble ferric form by ferroxidase activity; H-ferritin exerts most of its ferroxidase activity in the cytosol. The mitochondrial ferritin, expressed in the mitochondrial matrix, also has potent ferroxidase activity and is markedly upregulated in sideroblastic anemias.

Causes of Iron Overload

Because body iron content is maintained by regulating absorption, excess body iron can accumulate only when absorption is increased above iron requirements, or when iron is injected into the body, either in the form of medicinal iron or as transfused erythrocytes.

Excessive Iron Absorption

A variety of mutations are known to cause increased iron absorption in experimental animals and in man (see Table 43–3 for a summary). Mutations in the genes encoding HFE, hemojuvelin, TfR-2, ferroportin, and hepcidin are all associated with iron overload. The common pathway that causes hyperabsorption of iron is deficiency of hepcidin which allows excessive activity of the iron exporter ferroportin in the duodenum and in macrophages of the reticuloendothelial system. Normally, hepcidin is upregulated when body iron increases. However, this response is blunted or absent in either Hfe-, TfR-2–, or Hjv-deficient mice,²²⁸ or in the human disease,^229,230,231 all of which exhibit disproportionately low hepcidin levels for the degree of iron overload. Although the biochemistry of their interactions is not known, there is increasing evidence that HFE, TfR-2, and hemojuvelin are part of the signaling pathway that regulates hepcidin expression. In autosomal dominant hereditary hemochromatosis (class 4), ferroportin mutations interfere with binding of hepcidin to ferroportin^232,233 or with the resulting ferroportin endocytosis.

Ineffective Erythropoiesis

Anemias with ineffective erythropoiesis commonly cause systemic iron overload with damage to the liver, heart and the endocrine system. Iron storage disease is particularly common in disorders such as β-thalassemia, hereditary dyserythropoietic anemia, and pyruvate kinase deficiency. The amount of body iron may greatly exceed the quantity that can be accounted for through blood transfusion, and iron overload is common even in patients who are rarely or never transfused.

The iron overload commonly observed in β-thalassemia intermedia and major patients likely results, at least in part, from suppression of the iron-regulatory hormone hepcidin by erythroid factors secreted by massively proliferating erythropoietin-stimulated erythroblasts. Candidate erythroid suppressors of hepcidin include growth differentiation factor 15 (GDF15)²³⁴ and erythroferrone.²³⁵ GDF15 overexpression was also observed in congenital dyserythropoietic anemia.^236,237

Transfusion or Iron Therapy

Iron overload can be iatrogenic in origin. Because erythrocytes contain 1 mg of iron per milliliter, transfusion of 450 mL of whole blood or of 200 mL of red cells adds 200 mg of total iron to the body, iron that will not be excreted. Thus, a patient who receives 2 units of blood monthly for an anemia that is not a result of blood loss will accumulate 4.8 g of iron per year. If the need for transfusion is occasioned by a disorder in which ineffective erythropoiesis plays a prominent role, the accumulation of iron is even greater. Thalassemia is such a circumstance, and iron overload is the most important cause of death in patients with this disorder (Chap. 48).

The homeostatic mechanisms of the body are such that the inappropriate administration of iron by the oral route is very unlikely to produce clinically significant iron overload. Of the few cases that have been described, all but one were documented before the cloning of the HFE gene, raising the possibility that the patients had genetic hemochromatosis that was accelerated by excess iron intake. Documented iron overload after iron injection is even less common and has not been accompanied by demonstrable tissue damage.

Pathology

Affected tissues and organs exhibit a deep brown color. Histologic examination reveals prominent hemosiderin deposition in many tissues and organs.

Liver

The liver is often enlarged. After cirrhosis has developed, the organ becomes granular or coarsely nodular. In the liver of patients with classical hemochromatosis, TfR-2 mutations, and in juvenile hemochromatosis, hemosiderin is found primarily in hepatocytes. Kupffer cells are relatively spared. Prior to the development of cirrhosis, the hemosiderin accumulates primarily in periportal hepatocytes and is less toward the central veins. The iron of cirrhotic livers is mostly in the periphery of regenerative nodules. Fibrosis begins periportally, then fibrous septa traverse the lobules. Usually, the distortion of the architecture is not as severe or as uniform as in alcoholic cirrhosis. The cirrhosis of hemochromatosis usually has a micronodular appearance. Iron in bile duct epithelium has sometimes been considered a specific marker for hemochromatosis, but is not reliable. The amount of iron in the liver is always greatly increased. This is apparent on inspection of sections stained for iron with the Prussian blue reaction, and can be quantitated on liver biopsy specimens. An iron concentration of more than 300 μmol/g dry weight (or about 50 μmol/g wet weight) is considered strong evidence for hemochromatosis when factors such as transfusions are eliminated as the cause.

In the original description of African iron overload, the liver pathology was deemed to be indistinguishable from that of classical hemochromatosis, but in newer studies²³⁸ it seems that only some of the affected patients manifest iron storage, primarily in the hepatocytes; some have storage primarily in Kupffer cells. In the case of patients with ferroportin mutations that prevent transport of iron, storage of iron takes place mostly in the Kupffer cells, and fibrosis seems to be absent; ferroportin mutations that prevent interaction with hepcidin, on the other hand, are associated with hepatocytes iron overload, as is seen in classical hemochromatosis.^233,239

Heart

Iron accumulates more slowly in the myocardium than in the liver, but the heart is more sensitive to its toxic effects. Myocardial damage is seen when iron loading is rapid, for example, in β-thalassemic patients dying of transfusional iron overload in their 20s and 30s²⁴⁰ prior to effective chelation therapy, and in juvenile hemochromatosis patients who usually present with iron-induced cardiomyopathy and endocrinopathy rather than liver failure.²⁴¹ The myocardium is thickened and the heart is often enlarged; arrhythmias and myocardial failure follows. Accumulation of cardiac iron is the leading cause of death in transfused patients with β-thalassemia major. Patients with transfusion-dependent anemias, such as congenital dyserythropoietic anemia and Diamond-Blackfan syndrome, also develop iron overload-induced cardiomyopathy. In transfused patients with myelodysplastic syndromes, transfusion threshold guidelines of 75 units of blood was suggested as a risk factor of cardiac iron overload but this is not based on firm data. Direct cardiac iron measurement using magnetic resonance imaging predicts cardiac complications and can stratify the risk of subsequent cardiac dysfunction.²⁴² This technique measures the half-life, T2⋆, of cardiac muscle darkening (with respect to echo time) produced by magnetically active stored cardiac iron.

Marrow

The quantity of iron in the marrow of patients with classical hereditary hemochromatosis is only modestly increased, if increased at all. The iron is characteristically distributed into small, equal-size granules, and these are located in endothelial lining cells rather than in macrophages. Indeed, in classical hereditary hemochromatosis, both macrophages²⁴³ and intestinal mucosal cells are iron-poor relative to the overall iron burden.

Genetics

Genetic factors play an important role in the etiology of iron storage disease. This is true not only in the primary forms of the disorder, but also in secondary hemochromatosis, where genetic disorders of erythropoiesis are the most common causes. The genetics of these disorders, including the thalassemias, dyserythropoietic anemias, and red cell enzymopathies, are described in Chaps. 39, 47, and 48. Mutations of several genes that play an important role in iron homeostasis have been found to lead to iron storage disease.²⁴⁴

HFE Mutations

The most common cause of hereditary hemochromatosis is a mutation of the HFE gene. This HLA-like gene resides on chromosome 6. Three polymorphic mutations have been identified. These are located at nucleotides 187,193, and 845 of the cDNA (complementary DNA) and at the protein level encode the H63D, S65C, and C282Y mutations, respectively. The phenotypic severity of these mutations on iron homeostasis is manifested in the following order: C282Y > H63D > S65C. Hereditary hemochromatosis is essentially an autosomal recessive disorder. Approximately two-thirds of homozygotes for the C282Y and a slightly lower percentage of compound heterozygotes for the C282Y and H63D mutations manifest increased serum transferrin saturations and serum ferritin levels. Individuals heterozygous for either the C282Y or the H63D mutation have, on the average, significantly higher transferrin saturations and serum ferritin levels than do wild-type homozygotes. However, the magnitude of this increase is very low.²⁴⁵ For example, the average transferrin saturation of men with the wild-type genotype is 26.69 percent and heterozygotes for the C282Y mutation have a transferrin saturation averaging 30.63 percent. The effect of the H63D mutation is even less, and that of the S65C mutation barely perceptible.

In spite of the minimal effect of the heterozygous state for HFE mutations on iron homeostasis, a number of investigators have proposed that heterozygotes are at increased risk for a variety of disorders. What has not been taken into account in the studies is that the HFE gene is in close proximity to (and therefore likely to be coinherited with) many immune-response genes on chromosome 6; consequently, it is not possible to distinguish the minor effects that HFE mutations may have on iron homeostasis from variation in the immune response.

HAMP (Hepcidin) Mutations

Mutations of hepcidin are rare, and are associated with severe juvenile hemochromatosis.²⁴⁶

SCL40A1 (Ferroportin) Mutations

Mutations of the gene encoding ferroportin cause an autosomal dominant iron storage disease of two types. Gain-of-function mutations, for example the C326S mutation, interfere with hepcidin binding to ferroportin or with the resulting ferroportin endocytosis, so that mutant ferroportin molecules continue exporting iron from enterocytes and macrophages to plasma even in the face of high hepcidin levels²³² that normally cause ferroportin endocytosis and proteolysis. A mouse model of this condition shows that a heterozygous mutation is sufficient to cause severe iron overload but that homozygosity for this mutation is even more severe.²⁴⁷ Loss-of-function mutations are more common and include ferroportin mutations that do not allow ferroportin protein to localize to the cell surface, or prevent transport of iron. Here storage of iron takes place mostly in the Kupffer cells and splenic macrophages, and cirrhosis does not occur. It is not clear why these act in a dominant manner, nor why all of the reported mutations encode amino acid substitutions and none are completely destructive (frameshift or stop codons).^158,248 An attractive explanation is that these mutations act in a dominant-negative manner, but this mechanism has not yet been supported by convincing biochemical data. A common polymorphism c.744G→T (Gln284His) shows an association with African iron overload,^238,249,250 but is clearly not present in all patients who manifest this syndrome.

TfR-2 Mutations

Mutations of TfR-2 cause an autosomal recessive disorder that is indistinguishable clinically from the common HFE-related form of hereditary hemochromatosis.^{230,251,252,253}

Hemojuvelin Mutations

Several different mutations of a gene designated as HFE2 and as HJV cause juvenile hemochromatosis.^{231,254,255,256,257,258} Hemojuvelin belongs to the class of glycosylphosphatidylinositol-anchored repulsive-guidance molecules, and may act as a coreceptor for bone morphogenetic proteins (BMPs). BMP receptor is now known to be a key regulator of hepcidin transcription.²⁵⁹

DMT-1 Human Mutations

DMT-1 human mutations are all associated with hepatic hemosiderosis^207,208,260 and most are associated with abnormal liver function tests in addition to microcytic hypochromic anemia. This is in contrast to mice and rats with DMT-1 mutations, as these DMT-1–deficient rodents are iron deficient. This is likely because humans, unlike rodents, can also absorb heme-containing iron, at least to a small degree in a DMT-1 independent manner while the DMT-1 dependent iron utilization by erythroblasts is severely impaired in both humans and rodents.

Animal Models

Naturally Occurring Models

When kept in zoos or other nonnative habitats, a number of animal species, such as myna birds, the toco toucan, Salers cattle, lemurs, and the browsing rhinoceros, are iron-loaded. Rhinoceroses may represent an interesting paradigm for iron storage in captive species. Although the browsing rhinoceros species are iron loaded, grazing species are not, even when kept under similar conditions. It seems likely that because iron is not readily available in the leaves and twigs eaten by the browsing species, these species have evolved to more efficiently take up iron from their diet—more efficiently than needed when fed a zoo diet. Molecular comparisons of iron-regulatory genes in browser versus grazer rhinoceroses identified some promising candidates, but the ultimate cause of the differences in iron handling has not yet been established.²⁶¹

Models Produced by Iron Loading

Numerous efforts have been made to create models of hemochromatosis by loading laboratory animals with iron, either by the oral or parenteral route. A few of these appear to simulate the human disease in one respect or another. For example, the iron-loaded gerbil^{262,263,264,265} develops heart disease, features of which resemble the human disease. Such models have been used for the study of potential chelating agents.

Targeted Disruption Models

Targeted disruption of most of the genes associated with human iron disorders has been achieved. Included are HFE,²⁶⁶ TfR-2,²⁵² ferroportin,²⁶⁷ hemojuvelin,^255,256 and hepcidin.²⁶⁸ The targeted disruption of several genes, including those encoding BMP-6,^269,270 or the components of the BMP receptor,²⁵⁹ caused iron overload in mice, but the equivalent human diseases have not yet been found.

CLINICAL FEATURES

HFE-Related (Type 1) Hereditary Hemochromatosis

Onset

The clinical features of the most common form of hereditary hemochromatosis are cirrhosis of the liver, darkening of the skin, cardiomyopathies, and diabetes. These features are only seen in the fully penetrant form of the disease and may depend on additional cofactors such as alcohol consumption. In contrast to the juvenile form of the disease, in which onset is usually in the second or third decade of life, classical hereditary hemochromatosis associated with mutations of the HFE gene generally is diagnosed in the fifth or six decade of life.

General Symptomatology

Many symptoms are attributed to hereditary hemochromatosis, including abdominal pain, weakness, lethargy, fatigue, loss of libido, impotence, and arthropathies. However, all of these symptoms are common in an aging population, and epidemiologic studies show that none of them are more common in patients with the HFE hemochromatosis, even those with the biochemical phenotype, than they are in the general population.

Arthropathies

The arthropathy of patients with hemochromatosis has characteristic features.^218,271,272 It is said to tend to begin at the small joints of the hands, especially the second and third metacarpal joints, and that in some cases episodes of acute synovitis may occur, as in calcium pyrophosphate dehydrate deposition arthropathy (pseudogout; chondrocalcinosis). Radiologically, the arthropathy resembles that of osteoarthritis with joint space loss, subchondral cysts, sclerosis, and osteophytosis. The features that have been considered distinctive include the joint distribution, the presence of shape osteophytes emerging from the radial sides of the metacarpal distal epiphysis, and the presence of radiolucent zones in the subchondral area of the femoral head. It is generally recognized that arthritis does not respond to phlebotomy therapy. The possibility that this type of arthritis depends on linkage of HFE to other HLA genes is made less likely by the occurrence of similar arthritis in juvenile hemochromatosis,²⁷³ which is genetically independent of the HLA locus. Hip arthritis at an early age was also noted in a family with hepcidin-resistant ferroportin mutation and iron overload.²³⁹

Liver

Patients with hepatic iron overload are at a greatly increased risk of developing a hepatocellular carcinoma, especially when cirrhosis is present.²⁷⁴ Occasional patients with hereditary hemochromatosis have been reported to develop hepatocellular carcinoma even in the absence of cirrhosis suggesting that iron overload could be directly carcinogenic.

Porphyria Cutanea Tarda

Porphyria cutanea tarda is a disease that is well known to be associated with mild iron overload and that responds to phlebotomy treatment (Chap. 58). Numerous studies document that the prevalence of patients with this disorder who also have mutations of the HFE gene is considerably increased.²⁷⁵

Juvenile Hemochromatosis

The penetrance of the rare juvenile form of the disease seems to be high and cardiomyopathies and endocrine deficiencies are the major clinical features.²⁷⁶ Joint manifestations were found to be relatively common in patients with juvenile hemochromatosis.²⁷³

African Iron Overload

It is not clear to what extent African iron overload is symptomatic. Among the Bantu, where the disorder was originally described, there are many complicating factors, including malnutrition and high alcohol intake. Among African Americans various associated disorders have been noted, but a cause-and-effect relationship is not clear.

Secondary Hemochromatosis

The clinical findings in patients with hemochromatosis secondary to blood transfusion and/or disorders of erythropoiesis are, in general, indistinguishable from those found in patients with the primary hemochromatosis.²⁷⁷

LABORATORY FEATURES

The main laboratory features of hereditary hemochromatosis are an abnormally high transferrin saturation, and increased serum ferritin level. Five to 10 percent of patients with classical HFE hemochromatosis manifest increased liver enzyme levels in the serum. In secondary hemochromatosis, anemia and other manifestations of the underlying disorder are found. Macrocytosis of the erythrocytes is a common feature; this finding seems unrelated to liver disease and its cause is unknown.

Differential Diagnosis

A large number of methods have been introduced that allow the amount of storage iron to be estimated.²⁷⁸ The suspicion that a patient may have primary hemochromatosis is generally raised by an increased serum transferrin saturation, particularly when it is found together with an elevated serum ferritin level. Increased transferrin saturation commonly occurs in patients with chronic liver disease who have no mutations in the HFE gene.²⁷⁹ Ferritin is an acute phase protein and levels are elevated in a variety of disorders. Particularly high levels are encountered in patients with macrophage activation syndromes, loss-of-function ferroportin mutations, acute hepatitis, Gaucher disease, in some malignancies, and in patients with the hyperferritinemia-cataract syndrome.²⁸⁰ The latter disorder is an uncommon autosomal dominant defect in which a mutation in the 5′ IRE of the ferritin light chain prevents binding of the IRPs, resulting in unrestrained constitutive production of the ferritin chains.

Many clinicians have considered a liver biopsy the “gold standard” for the diagnosis of iron overload. The material obtained at biopsy not only provides the opportunity to assess the histopathology of the liver of the patient, but also to quantitate the amount of nonheme iron in the specimen. Dividing the iron content by the patient’s age provides an iron index; a value greater than 2 implies the presence of hemochromatosis. Although in some situations liver biopsy may provide useful information, it is an invasive procedure that, although low-risk, is no longer required for the diagnosis of hemochromatosis. Enthusiasm for subjecting every patient with potential hemochromatosis to liver biopsy has diminished with the ready availability of genetic analysis. Moreover, a simple way to determine whether a patient is iron overloaded is to institute a program of phlebotomies. This is an essentially harmless way to determine how much storage iron the body contains. Magnetic resonance imaging (MRI) is also capable of detecting and reliably quantifying the amount of iron in the liver.²⁸¹ For detection of cardiac iron overload, T2⋆ MRI²⁴² is a superior diagnostic approach.

THERAPY

The treatment of hemochromatosis consists of removing the accumulated iron. In the case of patients who are able to mount an erythropoietic response to phlebotomy, removal of blood is generally the treatment of choice. When the patient has marked impairment of erythropoiesis, as in thalassemia and dyserythropoietic anemia, it is necessary to employ chelating agents to remove iron, although occasionally serial phlebotomy will stimulate sufficient erythropoiesis to make it a viable therapy.

Phlebotomy

Each milliliter of packed red cells contains approximately 1 mg of iron. Thus, the removal of 500 mL of blood with a hematocrit of 40 percent removes approximately 200 mg of iron. As the red cell mass is restored to its prephlebotomy size, iron is mobilized from the stores. When the stores have been exhausted the signs of iron deficiency develop, and this is the end point of the initial part of the phlebotomy program. The patient is then followed and a schedule of maintenance phlebotomies is established with the frequency of phlebotomies tailored to maintain the serum ferritin level, the best indicator of body stores, below 100 ng/mL.

The actual volume of blood removed at each phlebotomy depends on the patient’s size. Most average-size patients tolerate removal of 500 mL, but patients who weigh 50 kg or less are better treated by the removal of correspondingly smaller volumes of blood. Many patients may complain of symptoms following the first few phlebotomies. Better compliance is achieved if such symptoms are minimized by performing phlebotomies only every 14 days initially, increasing the frequency to weekly phlebotomies once the patient has become accustomed to the procedure and the activity of the marrow has been stimulated so as to replace the lost erythrocytes rapidly. The hematocrit or hemoglobin and the MCV of the red cells should be measured before each phlebotomy is undertaken. If there has been a substantial decrease in the hematocrit or hemoglobin, the phlebotomy should be deferred. The MCV may rise early in the treatment program, but as iron deficiency develops it will fall, signaling that the end point has been reached or is near. The transferrin saturation and serum ferritin level should be measured every 2 or 3 months. When the transferrin saturation is less than 10 percent and the serum ferritin less than 10 ng/mL, phlebotomy should be discontinued and the patient monitored every 4 to 8 weeks. When the serum ferritin is in the 50 to 100 ng/mL range, the maintenance phase should be initiated. Some patients may require phlebotomies monthly to maintain a normal ferritin value, whereas others may only require two or three phlebotomies per year.

Chelation Therapy

Chelation therapy instituted in a timely manner can decrease the potential morbidity caused by iron overload and prolong the life of patients with hereditary chronic iron-loading disorders such as β-thalassemia major or intermedia. It also has a place in the management of some patients with acquired marrow dysplasias provided that the prognosis of the underlying disorder, and the patient’s psychological state, justifies the somewhat cumbersome implementation of parenteral chelation. As oral chelating agents become more readily available, the application of chelation therapy to myelodysplastic states may broaden.

Desferrioxamine

Desferrioxamine is a naturally occurring iron-chelating compound elaborated by the microorganism Streptomyces pilosus, having evolved to enable the microbe to obtain iron from its environment. One molecule of this chelator binds one atom of iron. Its molecular weight is 560 daltons. The iron complex is excreted into the urine and feces. Urine iron is derived primarily from red cells broken down by macrophages, whereas fecal iron is believed to be from iron chelated in the liver.²⁸²

Desferrioxamine is poorly absorbed from the gastrointestinal tract and must therefore be given parenterally, either by the subcutaneous or intravenous route. Rapid intravenous or intramuscular injection results in the relatively little iron mobilization; instead, it is necessary to administer desferrioxamine by slow intravenous or subcutaneous infusion over a period of 8 to 10 hours. Increasing doses of desferrioxamine result in increased iron excretion, and the usual recommended dose is 30 to 50 mL/kg.^282,283 Vitamin C (up to 200 mg daily) may be given to enhance iron excretion. The amount of iron excreted will vary from patient to patient and depends to a large extent on the iron burden. Because the treatment is cumbersome and costly, one should be reasonably certain that sufficient good is being accomplished to justify the effort. This can be achieved by measuring urine output of iron after a test desferrioxamine infusion, bearing in mind that urinary excretion may account for only one-third of the iron excreted, fecal excretion accounting for the rest.

Desferrioxamine is usually well tolerated. Minor local reactions, such as local pruritus, induration, or pain at the site of infusion, are not uncommon. Large doses are associated with hearing loss, night blindness and other visual abnormalities, growth retardation, and skeletal changes. At very high doses occasional cases of kidney and lung abnormalities have been reported.²⁸² Approximately 20 percent of patients on desferrioxamine alone will continue to have cardiac iron overload.

Oral Chelating Agents

The inconvenience and high cost of administration with desferrioxamine has stimulated an intensive search for safe, orally active chelating agents. Deferiprone (L-1) is an orally effective bidentate chelating agent; three molecules of deferiprone bind one iron atom. Its molecular weight is only 139 daltons and it is excreted almost entirely in the urine. The usual dose is 75 mg/kg per day divided into three doses. Deferiprone administration is associated with a number of toxic effects, including gastrointestinal disturbances, arthropathy, transient increases in the serum levels of liver enzymes, and zinc deficiency. The main concern has centered on the propensity of the drug to produce neutropenia and agranulocytosis. The latter complication occurs in approximately 1 percent of patients. It appears to be idiosyncratic, is more common in females, and appears to be reversible. Neutropenia with a granulocyte level between 0.5 and 1.5 × 10⁹/L (500 and 1500/μL) occurs in an additional 5 percent of patients. Treatment should be stopped at the first sign of a fall in the leukocyte count.²⁸² It has been suggested that deferiprone may be more effective in removing iron from the heart and desferrioxamine more effective with respect to liver iron accumulations.²⁸³ Preliminary investigations suggest that a combination of desferrioxamine and deferiprone may be more effective than either alone. It has been proposed that deferiprone enters cells and removes their iron and then passes the iron to desferrioxamine.²⁸³ The combination may be particularly useful in patients with heart failure from iron overload where it may decrease mortality, and in patients with endocrinopathies.²⁸³

Deferasirox (ICL670 or Exjade), a tridented triazole component, is a newer oral iron-chelating agent with a long plasma half-life.²⁸³ At a dose of 30 mg/kg per day, it was found as efficient as desferrioxamine and is generally well tolerated. It has been recommended for patients who are noncompliant with desferrioxamine, and like deferiprone, may be effective at removing cardiac iron. Its main toxicity is renal and hepatic, but it may also cause gastrointestinal hemorrhage.²⁸³ Combination therapy with the two oral chelators is still experimental.

COURSE AND PROGNOSIS

The outlook in this disease has changed to one in which the life span of patients with hemochromatosis is normal or nearly so. This is largely a result of the change in the definition of the disorder. In the early 20th century, the diagnosis was reserved for the rare patient with full-blown bronzed diabetes. Today, the diagnosis is applied to any person found to be homozygous for the C282Y mutation, or, indeed, anyone with an increased transferrin saturation and elevated serum ferritin level. In reality, patients with a diagnosis of hemochromatosis based on genetic and/or biochemical criteria have a normal life span. This is not to suggest that patients do not die of hereditary hemochromatosis; it is simply that the penetrance of the disorder as detected on genetic or biochemical bases is so low that the few deaths that do occur cannot be detected even in very sizable series.

For those patients with classical hereditary hemochromatosis who are clinically affected, it is likely that removal of iron by phlebotomy prevents further complications and prolongs life span. Although controlled studies of the effect of phlebotomy are not ethically feasible, serial observations in patients undergoing phlebotomy suggest that cirrhosis is either stabilized or may, at least in some patients, improve. The course of untreated juvenile hemochromatosis seems much less benign. Cardiac deaths seem to be particularly common,²⁷⁶ and in a few cases cardiac transplantation has been performed successfully, but there are insufficient data concerning this rare disorder to allow one to provide more precise information about the outlook.

Institution of iron chelation has greatly improved outcomes in β-thalassemia major and similar disorders, but the prognosis is grim when iron chelation is not performed (Chap. 48). Death is most frequently a result of cardiac failure but this complication is preventable with modern chelation regimens.