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644 Part VI: The Erythrocyte Chapter 43: Iron Deficiency and Overload 645

THERAPY Desferrioxamine is poorly absorbed from the gastrointestinal tract
The treatment of hemochromatosis consists of removing the accumu- and must therefore be given parenterally, either by the subcutaneous
lated iron. In the case of patients who are able to mount an erythropoi- or intravenous route. Rapid intravenous or intramuscular injection
etic response to phlebotomy, removal of blood is generally the treatment results in the relatively little iron mobilization; instead, it is necessary
of choice. When the patient has marked impairment of erythropoiesis, to administer desferrioxamine by slow intravenous or subcutaneous
as in thalassemia and dyserythropoietic anemia, it is necessary to employ infusion over a period of 8 to 10 hours. Increasing doses of desferriox-
chelating agents to remove iron, although occasionally serial phlebot- amine result in increased iron excretion, and the usual recommended
282,283
omy will stimulate sufficient erythropoiesis to make it a viable therapy. dose is 30 to 50 mL/kg. Vitamin C (up to 200 mg daily) may be
given to enhance iron excretion. The amount of iron excreted will vary
Phlebotomy from patient to patient and depends to a large extent on the iron bur-
Each milliliter of packed red cells contains approximately 1 mg of iron. den. Because the treatment is cumbersome and costly, one should be
Thus, the removal of 500 mL of blood with a hematocrit of 40 percent reasonably certain that sufficient good is being accomplished to justify
removes approximately 200 mg of iron. As the red cell mass is restored the effort. This can be achieved by measuring urine output of iron after
to its prephlebotomy size, iron is mobilized from the stores. When the a test desferrioxamine infusion, bearing in mind that urinary excretion
stores have been exhausted the signs of iron deficiency develop, and may account for only one-third of the iron excreted, fecal excretion
this is the end point of the initial part of the phlebotomy program. The accounting for the rest.
patient is then followed and a schedule of maintenance phlebotomies is Desferrioxamine is usually well tolerated. Minor local reactions,
established with the frequency of phlebotomies tailored to maintain the such as local pruritus, induration, or pain at the site of infusion, are not
serum ferritin level, the best indicator of body stores, below 100 ng/mL. uncommon. Large doses are associated with hearing loss, night blind-
The actual volume of blood removed at each phlebotomy depends ness and other visual abnormalities, growth retardation, and skeletal
on the patient’s size. Most average-size patients tolerate removal of changes. At very high doses occasional cases of kidney and lung abnor-
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500 mL, but patients who weigh 50 kg or less are better treated by the malities have been reported. Approximately 20 percent of patients on
removal of correspondingly smaller volumes of blood. Many patients desferrioxamine alone will continue to have cardiac iron overload.
may complain of symptoms following the first few phlebotomies. Better Oral Chelating Agents
compliance is achieved if such symptoms are minimized by performing The inconvenience and high cost of administration with desferrioxam-
phlebotomies only every 14 days initially, increasing the frequency to ine has stimulated an intensive search for safe, orally active chelating
weekly phlebotomies once the patient has become accustomed to the agents. Deferiprone (L-1) is an orally effective bidentate chelating agent;
procedure and the activity of the marrow has been stimulated so as to three molecules of deferiprone bind one iron atom. Its molecular weight
replace the lost erythrocytes rapidly. The hematocrit or hemoglobin and is only 139 daltons and it is excreted almost entirely in the urine. The
the MCV of the red cells should be measured before each phlebotomy usual dose is 75 mg/kg per day divided into three doses. Deferiprone
is undertaken. If there has been a substantial decrease in the hematocrit administration is associated with a number of toxic effects, including
or hemoglobin, the phlebotomy should be deferred. The MCV may rise gastrointestinal disturbances, arthropathy, transient increases in the
early in the treatment program, but as iron deficiency develops it will serum levels of liver enzymes, and zinc deficiency. The main concern
fall, signaling that the end point has been reached or is near. The trans- has centered on the propensity of the drug to produce neutropenia
ferrin saturation and serum ferritin level should be measured every 2 or and agranulocytosis. The latter complication occurs in approximately
3 months. When the transferrin saturation is less than 10 percent and 1 percent of patients. It appears to be idiosyncratic, is more common in
the serum ferritin less than 10 ng/mL, phlebotomy should be discontin- females, and appears to be reversible. Neutropenia with a granulocyte
ued and the patient monitored every 4 to 8 weeks. When the serum fer- level between 0.5 and 1.5 × 10 /L (500 and 1500/μL) occurs in an addi-
9
ritin is in the 50 to 100 ng/mL range, the maintenance phase should be tional 5 percent of patients. Treatment should be stopped at the first sign
initiated. Some patients may require phlebotomies monthly to maintain of a fall in the leukocyte count. It has been suggested that deferiprone
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a normal ferritin value, whereas others may only require two or three may be more effective in removing iron from the heart and desferriox-
phlebotomies per year.
amine more effective with respect to liver iron accumulations. Pre-
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Chelation Therapy liminary investigations suggest that a combination of desferrioxamine
Chelation therapy instituted in a timely manner can decrease the poten- and deferiprone may be more effective than either alone. It has been
tial morbidity caused by iron overload and prolong the life of patients proposed that deferiprone enters cells and removes their iron and then
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with hereditary chronic iron-loading disorders such as β-thalassemia passes the iron to desferrioxamine. The combination may be partic-
major or intermedia. It also has a place in the management of some ularly useful in patients with heart failure from iron overload where it
patients with acquired marrow dysplasias provided that the prognosis may decrease mortality, and in patients with endocrinopathies. 283
of the underlying disorder, and the patient’s psychological state, justifies Deferasirox (ICL670 or Exjade), a tridented triazole component,
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the somewhat cumbersome implementation of parenteral chelation. As is a newer oral iron-chelating agent with a long plasma half-life. At a
oral chelating agents become more readily available, the application of dose of 30 mg/kg per day, it was found as efficient as desferrioxamine
chelation therapy to myelodysplastic states may broaden. and is generally well tolerated. It has been recommended for patients
who are noncompliant with desferrioxamine, and like deferiprone,
Desferrioxamine may be effective at removing cardiac iron. Its main toxicity is renal and
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Desferrioxamine is a naturally occurring iron-chelating compound hepatic, but it may also cause gastrointestinal hemorrhage. Combina-
elaborated by the microorganism Streptomyces pilosus, having evolved tion therapy with the two oral chelators is still experimental.
to enable the microbe to obtain iron from its environment. One mole-
cule of this chelator binds one atom of iron. Its molecular weight is 560 COURSE AND PROGNOSIS
daltons. The iron complex is excreted into the urine and feces. Urine The outlook in this disease has changed to one in which the life span of
iron is derived primarily from red cells broken down by macrophages, patients with hemochromatosis is normal or nearly so. This is largely
whereas fecal iron is believed to be from iron chelated in the liver. 282 a result of the change in the definition of the disorder. In the early

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