Chapter 9: Iron-Deficiency Anemia and Iron Overload

• Iron deficiency is one of the most common chronic maladies in humans. One third to one half of healthy females of reproductive age in the United States have absent iron stores, and 10% have iron-deficiency anemia, which is also common in infants and adolescents.

• Iron overload denotes an excess of iron in the body.

• Iron depletion: storage iron decreased or absent

• Iron deficiency: storage iron absent with low serum iron concentration and transferrin saturation

• Iron-deficiency anemia: storage iron absent, low serum iron concentration and transferrin saturation, and low hemoglobin level

• Chronic blood loss

• Diversion of maternal iron to fetus/infant during pregnancy/lactation

• Inadequate dietary intake of iron, primarily in infants and children

• Malabsorption of iron

• Intravascular hemolysis with hemoglobinuria and or hemosiderinuria

• Combinations of the above

Dietary Causes

• Infants most often develop iron deficiency because milk is a poor source of dietary iron and the additional requirements for iron imposed by rapid growth are not satisfied.

• In children, poor dietary intake plus intestinal parasites and/or bleeding gastrointestinal lesions are the usual causes.

• In the United States, average iron intake is 12 to 20 mg/d, varying by age and gender. Children and menstruating women are in precarious iron balance and at risk for iron deficiency.

Malabsorption

• Iron absorption is decreased in the malabsorption syndromes.

• After subtotal gastrectomy, malabsorption of dietary iron occurs in 50% of patients because of rapid gastrointestinal transit and because food bypasses the site of maximal absorption due to location of anastomosis. In contrast, medicinal iron is well absorbed after partial gastrectomy.

• In postgastrectomy anemia, there may be bleeding from anastomotic ulcer(s).

Chronic Blood Loss

• Menorrhagia is the most common cause of iron deficiency in women.

• Chronic blood loss may occur from the respiratory, gastrointestinal, or genitourinary tracts, or from phlebotomy for blood donation or laboratory testing, or may be self-induced.

• The most common cause of iron deficiency in men and postmenopausal women is gastrointestinal bleeding.

Pregnancy and Lactation

• The average iron loss from transfer to the fetus and blood in the placenta is 900 mg. Lactation losses of iron average 30 mg/mo.

• Lack of iron decreases heme synthesis, which leads to reduced hemoglobin synthesis and defective erythropoiesis.

• There is decreased activity of iron-containing enzymes, such as the cytochromes and succinic dehydrogenase.

• Neurologic dysfunction may occur, with impaired intellectual performance, paresthesias, and so on.

• Impaired performance during physical exertion is often present, especially in children and young adults.

• Atrophy of oral and gastrointestinal mucosa may occur, although this is unusual except in severe prolonged deficiency.

• In severe iron deficiency, gastric acid secretion may be reduced, often irreversibly.

• Patients develop the general symptoms of anemia (eg, easy fatigability, dyspnea on exertion, loss of sense of well-being).

• There is poor correlation between hemoglobin levels and severity of symptoms. Some patients with marked iron deficiency may deny the common symptoms of fatigue, weakness, or palpitations, whereas patients with mild iron deficiency may be symptomatic.

• Irritability and headache can occur.

• Children may have poor attention span, poor response to sensory stimuli, retarded developmental and behavioral achievement, and retarded longitudinal growth.

• Paresthesias and burning of the tongue may occur, possibly because of tissue iron deficiency.

• Pica, a craving to eat unusual substances such as clay or ice, is a classic manifestation, now most commonly reported by women of non-European ancestry.

• Often unremarkable, especially when iron deficiency is mild

• Pallor, if anemia moderate or severe, best seen in the conjunctivae

• Smooth red tongue, stomatitis

• Angular cheilitis

• Koilonychia (rare and limited to severe chronic deficiency)

• Retinal hemorrhages/exudates (rare and limited to severe chronic deficiency)

• Splenomegaly (rare and limited to severe chronic deficiency)

Red Blood Cells

• Earliest change is anisocytosis and increased red cell distribution width (Figure 9–1), although at early stages in patients with minimal and even moderate anemia, these abnormalities can be absent.

• Mild ovalocytosis is present, with target cells.

• Progressive hypochromia (low mean cell hemoglobin concentration) and microcytosis (low mean cell volume [MCV]) occur.

• Reticulocytes are normal or reduced.

• Measurement of the reticulocyte hemoglobin content in a flow cytometer is a sensitive index of early iron deficiency.

• Soluble transferrin receptor is increased.

Leukocytes

• Leukopenia (3–4.4 × 10⁹/L) is found in a small number of patients. Differential white count is normal.

Platelets

• Thrombocytopenia develops in approximately one fourth of iron-deficient children but is very uncommon in adults.

• Thrombocytosis is found in approximately one third of iron-deficient children but is very common among adults and usually secondary to chronic active blood loss.

Marrow

• Marrow cellularity is normal and myeloid-to-erythroid ratio is variable.

• Sideroblasts are absent.

• There is markedly decreased to absent macrophage hemosiderin by Prussian blue staining.

• Erythroblasts may be small, with narrow rim of ragged cytoplasm and poor hemoglobin formation (micronormoblasts with defective hemoglobinization).

Serum Iron Concentration and Total Iron-Binding Capacity (TIBC)

• Serum iron concentration may be in the low-normal range in mild deficiency.

• TIBC is usually increased but may be in the high-normal range in mild deficiency.

• Saturation (iron/TIBC) is often 15% or less, but this is not specific for iron deficiency. It occurs also in chronic inflammation and severe inflammatory states (eg, arthritis, pericarditis, and others).

• Serum transferrin receptor level may be of utility when ferritin levels are borderline low. Its elevation provides further evidence for the diagnosis of an early stage of iron deficiency.

Serum Ferritin

• Levels of less than 10 μg/L are characteristic of iron deficiency.

• Levels of 10 to 20 μg/L are presumptive but not diagnostic.

• Values may be elevated with concomitant inflammatory diseases (eg, rheumatoid arthritis), Gaucher disease, chronic renal disease, malignancy, hepatitis, or iron administration.

• Iron deficiency can be suspected in rheumatoid arthritis or other severe inflammatory states if the ferritin level is less than 60 μg/L.

Reticulocyte Hemoglobin Content

• Reticulocyte hemoglobin content in a flow cytometer is a sensitive index of early iron deficiency. A value of less than 26 pg/cell is generally indicative of iron deficiency.

Soluble Transferrin Receptor

• Concentration is usually increased in iron deficiency.

• Serum transferrin receptor and its ratio to serum ferritin correlates well with depleted iron stores.

Free Erythrocyte Protoporphyrin (FEP)

• Concentration is usually increased in iron deficiency.

• FEP is a sensitive test for diagnosis of iron deficiency and suitable for large-scale screening of children, detecting both iron deficiency and lead poisoning.

• The physician who establishes a diagnosis of iron deficiency should assiduously search for a source of blood loss if unapparent or if another, much less common, reason for the deficiency is not evident. Because the source of bleeding may represent a greater health threat than the iron deficiency itself, determination of the site and cause of the blood loss is essential.

• As in all deficiency states leading to anemia, the diagnostic findings depend on the severity of the deficiency. If early and mild, the expected changes (eg, decreased serum iron and percent saturation of transferrin) may be mild or within the normal range.

Special Studies

• Gastrointestinal loss is the most prevalent site of blood loss in men and uterine menstrual loss in women. Multiple stools should be tested for occult blood in every patient with iron deficiency.

  — Bleeding may be intermittent.

  — Common screening tests are insensitive to less than 5 to 10 mL blood loss per day.

  — Endoscopic and radiographic studies, including capsule endoscopy, may detect the source of gastrointestinal bleeding.

  — Angiography may be helpful if active bleeding is 0.5 mL/min or greater.

  — Pertechnetate uptake studies may detect a Meckel diverticulum.

• Hemosiderin-laden macrophages are in sputum if intrapulmonary bleeding is present.

• Urinary hemosiderin detection (iron-laden urine epithelial cells) is a definitive way of confirming iron deficiency due to intravascular hemolysis. The first morning urine is the most sensitive sample collection time for finding iron in the urine. Urinary iron loss can also be measured quantitatively by atomic absorption spectroscopy.

• Iron deficiency versus thalassemia versus anemia of chronic disease (Table 9–1)

Therapeutic Trial

• This should initially be by oral route, if possible.

• Response to expect is:

  — Peak reticulocytosis at approximately 10 days. However, reticulocyte response is a function of severity of anemia and may be modest in mild anemia

  — Significant increase in hemoglobin concentration at 3 to 4 weeks

  — Hemoglobin level normal at 1 to 4 months

• Unless there is continued bleeding, a coexisting inflammatory disease, or evidence for iron malabsorption, absence of a response indicates that iron deficiency is not the cause of anemia. Iron treatment should be stopped and another mechanism of anemia sought. (See also “Failure to Respond to Therapy,” below.)

Oral Iron Therapy

• Dietary sources are insufficient for treatment.

• Safest, least expensive are oral ferrous salts (eg, ferrous sulfate or ferrous gluconate).

• Coated forms should never be used.

• Administration with meals or antacids or with inhibitors of acid production decreases efficacy.

• Daily total of 150 to 200 mg elemental iron in three to four doses, each 1 hour before meals (65 mg of elemental iron is contained in 325 mg of ferrous sulfate USP, or in 200 mg dried ferrous sulfate) is optimal.

• Some patients may complain of gastrointestinal intolerance to pills, pyrosis, constipation, diarrhea, and/or metallic taste and require:

  — Reduction of daily dose and frequency of administration

  — Change of oral iron preparation

Length of Treatment

• In order to replenish iron stores, continue oral therapy for 6 to 12 months after hemoglobin level is normal.

• Therapy may be needed indefinitely if bleeding continues (eg, menstruating women).

Parenteral Iron Therapy

• Routine use is usually not justified, unless used in renal failure patients on dialysis.

• Indications are:

  — Malabsorption

  — Intolerance to oral iron preparations (colitis, enteritis)

  — Need in excess of amount that can be given orally

  — Preoperative autologous blood donation

  — Patient uncooperative or unavailable for follow-up

  — Renal failure patients on dialysis

• High-molecular-weight iron dextran (Dexferrum)

  — This is the first such agent available in the United States.

  — It can be given in higher single administration than other iron preparations.

  — Be aware of the danger of anaphylaxis or other systemic side effects (Food and Drug Administration [FDA] Black Box Warning).

  — Severe reactions are more common than with other parenteral preparations listed below.

  — This preparation contains 50 mg elemental iron per mL, with approximately 70% readily available for hemoglobin synthesis.

  — It may be given intramuscularly or intravenously.

  — See Williams Hematology, 9th ed, Chap. 43 or product information sheet for dosage calculations.

• Low-molecular-weight iron dextran (InFeD, CosmoFer)

  — This has a lower risk of drug reactions but still retains an FDA Black Box Warning.

• Iron sucrose (Venofer)

  — This is a complex of polynuclear iron ferric hydroxide in sucrose.

  — The manufacturer’s recommended dose is 5 mL (100 mg of elemental iron).

  — Adverse events are reported by more than 5% of treated patients, with hypotension the most common.

• Ferric gluconate complex in sucrose (Ferrlecit)

  — This is a macromolecular complex of ferric iron.

  — The manufacturer recommends administration of doses of 125 mg of elemental iron with the preparation diluted in 100 mL of 0.9% sodium chloride and given intravenously over 1 hour.

  — Adverse events are reported by more than 5% of treated patients, with hypotension the most common.

• Ferumoxytol (Feraheme)

  — This intravenous iron preparation is approved for treatment of the anemia of chronic kidney disease.

  — It is a carbohydrate-coated, superparamagnetic iron oxide nanoparticle.

  — Clinical experience is limited. Approved in 2010, it received an FDA-mandated Black Box Warning in 2015 because of reports of serious reactions.

Failure to Respond to Therapy

• Wrong oral preparation (enteric-coated, insoluble iron, too little iron in each dose)

• Bleeding not controlled

• Therapy not long enough to show response

• Patient not taking medication

• Concomitant deficiencies (vitamin B₁₂, folate, thyroid hormone)

• Concomitant illness limiting erythropoietic response:

  — Inflammation, infection, malignancy, hepatic disease, renal disease

• Diagnosis incorrect:

  — Thalassemia, lead poisoning, and so on

Hereditary causes from inborn genetic errors and secondary acquired causes, such as those associated with inefficient erythropoiesis, hemolysis and transfusions are discussed here.

Etiology and Pathogenesis

(see Table 9–2)

Classic Hemochromatosis (HFE hemochromatosis) (type 1)

• This diagnosis is applied to persons who have the hemochromatosis HFE genotype with increased body iron as suggested by increased serum ferritin levels, as well as to those who merely have the genotype, regardless of the level of their iron stores.

• This is an autosomal recessive disorder. Heterozygotes do not develop the disease.

• The major HFE mutation is cDNA nt 845 C → G (C282Y).

• The gene frequency is 0.06 to 0.08 in northern European populations so that about 15% of people are heterozygous and 0.5% are homozygous.

• It is very rare in non-Europeans.

• About one half of homozygotes have increased serum transferrin saturation and/or ferritin levels, but only 15% of homozygotes are clinically affected, and these are mostly males 40 to 60 years of age.

• Clinically significant disease is only seen in patients with serum ferritin higher than 1000. Thus clinical phenotype of hemochromatosis has a low penetrance and majority of homozygotes neither require nor benefit from therapy.

• A common minor mutation of HFE is cDNA nt 187 C → G (H63D).

• This gene’s frequency is about 0.16 in the European population and is panethnic in its worldwide distribution.

• In the homozygous state (H63D/H63D), or in the compound heterozygous state (C282Y/H63D), this mutation may be also (but far less likely) associated with hemochromatosis.

• A number of “private” HFE mutations have been found in individual families.

• In affected individuals, excessive iron absorption through the gastrointestinal mucosa leads to accumulation of ferritin and hemosiderin in most cells in the body, especially in hepatocytes, with relative sparing of splenic macrophages.

Juvenile Hemochromatosis (type 2)

• The penetrance of the rare juvenile form of the disease is high, with onset of clinical disease during late adolescence and cardiomyopathy and endocrine deficiencies as the major clinical features.

• For list of mutations, refer to Table 9–2.

African Iron Overload

• African hemochromatosis is not caused by HFE or other known mutations.

• It is not clear to what extent African iron overload is a symptomatic condition.

• Many complicating factors, including malnutrition and high “home brewed” alcohol intake, are generally present.

Clinical Features

• Hereditary hemochromatosis usually presents in the fifth decade or later. High alcohol consumption increases the risk of serious manifestations. In the adult form, the male-to-female ratio is 5:1, and the disease is uncommon in premenopausal women.

• The juvenile forms of hereditary hemochromatosis presenting in children and young adults are very rare, affect both genders equally, and can present with multiendocrine failure and lethal cardiomyopathy.

• In adults, the most common symptoms are weakness, lethargy, loss of libido, joint symptoms, and weight loss.

• Arthralgia typically involves second and third metacarpophalangeal joints with swelling and tenderness. Hips and knees may also be involved, but because hemochromatosis is a disease of later life, a cause-and-effect relationship between joint symptoms and hemochromatosis is not established.

• Chondrocalcinosis or calcification of periarticular ligaments is a frequent late manifestation. Synovial fluid may contain calcium pyrophosphate and apatite crystals.

• Skin becomes hyperpigmented primarily from deposition of melanin.

• Cardiac effects are common.

  — Arrhythmias

  — Cardiomegaly (may be a result of restrictive or dilated cardiomyopathy)

  — Congestive failure

• Endocrinopathies are common.

  — Pancreas (may show diffuse fibrosis and loss of islets). Diabetes mellitus occurs in some patients

  — Hypothyroidism (10% of male patients)

  — Hypothalamic pituitary insufficiency, usually involving gonadotropins (about half of patients)

  — Testicular atrophy, azoospermia, reduced libido, and impotence

  — Premature menopause

• Hepatomegaly and liver injury are common.

  — Jaundice is uncommon.

  — Liver function tests may be abnormal.

  — Hepatocellular carcinoma occurs in one third of patients who have fully developed disease.

  — Patients who have hemochromatosis and also consume significant quantities of alcohol are more likely to develop hepatic fibrosis than are patients who abstain from alcohol.

  — Cirrhosis found only in patients who have serum ferritin levels of greater than 1000 ng/mL and who have abnormal liver function tests.

• Splenomegaly is frequently present.

Laboratory Features

• The transferrin saturation exceeds 50% in one half of homozygotes for the C282Y mutation. The serum ferritin is greater than 200 ng/mL in one half of homozygous women and greater than 250 ng/mL in one half of homozygous men.

• Patients with fully developed disease may have hyperglycemia and an abnormal glucose tolerance test.

• Serum aminotransferase activities are increased in about 5% to 10% of homozygotes and in all of those with cirrhosis.

• Serum concentrations of pituitary gonadotropins and androgens are often low.

• Serum thyroxine levels may be low and thyroid-stimulating hormone concentrations increased.

Diagnosis

• Early diagnosis of clinically affected patients is imperative because body iron reduction therapy is relatively simple and prevents tissue injury, and complications may be irreversible and lead to death, for example from hepatocellular carcinoma.

• Serum ferritin levels are useful in screening but may be less sensitive than the serum iron level and transferrin saturation for screening but helpful to discriminate affected (ferritin > 1000 ng/mL) from asymptomatic patients.

• Estimates of the amount of marrow iron have little or no diagnostic value.

• Computed tomography scan and magnetic resonance imaging can demonstrate increased iron content of the liver.

• Liver biopsy is occasionally useful but is not required for diagnosis in most cases.

• In normal liver, iron content is less than 2.8 mg/g dry weight (50 μmol/g).

• In alcoholic liver disease, iron content is less than 5.6 mg/g (100 μmol/g).

• In hemochromatosis, iron content exceeds 5.6 mg/g (100 μmol/g), and in hemochromatosis with cirrhosis, iron content is usually greater than 11 mg/g (200 μmol/g).

• Genetic analysis for HFE mutations may be useful in family studies in order to detect other affected individuals.

Treatment

• Phlebotomy

  — Removal of 500 mL blood by venesection every 1 or 2 weeks depletes the body iron burden. Each 500 mL removes about 200 mg of iron.

  — The patient with severe disease usually has accumulated 30 to 40 g of excess iron.

  — Adequacy of treatment may be gauged by progressive fall in hemoglobin level and the MCV, indicating a decrease of body iron below normal.

  — For maintenance, removal of 500 mL blood every few months is usually sufficient. Serial measurements of serum ferritin levels are more useful than estimates of transferrin saturation in monitoring the effects of phlebotomy and should be used to monitor the patient indefinitely, with the goal of maintaining serum ferritin at less than 100 ng/mL.

  — Alcohol and other hepatotoxins should be avoided.

• Oral chelating agents

  — These are more expensive and have more side effects compared to phlebotomies.

  — They may be useful when phlebotomies cannot be used or in acute life-threatening disease when rapid iron depletion is needed.

  — For details, refer to Chap. 43, pp. 627-650, Williams Hematology, 9th ed.

Prognosis

• Life span is normal in patients without cirrhosis.

• Incidence of hepatocellular carcinoma is not diminished by treatment once there is hepatic fibrosis.

• Treatment may improve diabetes, cardiac function, and gonadal insufficiency.

Etiology and Pathogenesis

• Hyperabsorption of iron occurs in many hemolytic anemias, particularly in those accompanied by hyperactive (chronic hemolysis) and ineffective erythropoiesis (thalassemia).

• Blood transfusion adds to the iron burden and accelerates the clinical course.

• The administration of medicinal iron in the mistaken belief that iron will help the anemia is sometimes an aggravating factor.

Clinical Features

• These are the same as in hereditary hemochromatosis but in transfused patients, cardiac manifestations frequently dominate.

Laboratory Features

• Those of the underlying disease

• Elevated serum ferritin and transferrin saturation

Diagnosis

• In transfused patients, the iron burden can be estimated from the number of transfusions received (1 U contains ~200 mg iron), because daily iron loss is very small (~0.5–1.0 mg/dL).

• Elevation of ferritin levels reflects iron burden unless confounded by coexisting inflammation or hepatic injury.

Treatment

• Continuous subcutaneous deferoxamine infusion of 20 to 40 mg/kg/day, using a portable pump, remains the standard of care.

• Two oral iron chelators, deferiprone (25–33 mg/kg three times a day) and deferasirox (10–20 mg/kg once a day), are increasingly used alone or in combination with deferoxamine.

• Combinations of parenteral and oral agents are effective when adjusted for each patient based on iron burden and degree of cardiac involvement, patient compliance and side effects.