Pediatric Clinics of North America - CIPERJ

ORAL IRON CHELATORS
463
large iron-salt aggregates. Both are found principally in the liver, reticuloendothelial
cells, and red cell precursors, but ferritin also is found in the blood,
where it can be measured readily. In iron overload states, high levels of iron
exceed the iron-carrying capacity of transferrin within the plasma, leading to
accumulation of nontransferrin-bound iron [6]. The nontransferrin-bound
iron is taken up into cells, including liver, heart, and endocrine cells. Within
the cells, the iron storage proteins become saturated, and instead, iron is
bound only weakly to various low molecular weight proteins, known as labile
iron [7]. Iron that is not tightly bound can participate in the generation
of free radicals that damage the cells leading to organ toxicity.
Most knowledge of the complications of iron overload comes from
patients who have thalassemia who require lifelong red blood cell transfusions.
Whether or not patients who have different diseases requiring
chronic transfusions, in particular sickle cell disease, develop the same
complications remains to be determined [8,9]. Given the lack of substantial
information about disease-specific responses to iron overload, data from
the thalassemia population continue to guide monitoring and treatment
for other transfused patient populations.
Iron overload leads to many clinical complications. Cardiac toxicity,
including congestive heart failure and arrhythmias, is the leading cause of
death related to iron overload in patients who have thalassemia major
[10]. Excess iron deposition in the liver leads to inflammation, fibrosis,
and cirrhosis [11], which may be exacerbated by concomitant transfusionacquired
viral hepatitis. Iron is toxic to the endocrine organs, leading to
growth failure, delayed puberty [12], diabetes mellitus, hypothyroidism,
and hypoparathyroidism [13]. In a report of 342 North American patients
who had thalassemia major, 38% of subjects had at least one endocrinopathy,
most commonly hypogonadism, and 13% had more than one endocrinopathy
[13]. Moreover, in that study, the prevalence of endocrine
abnormalities increased with age, likely reflecting an accumulating iron burden.
The goal of chelation therapy is to maintain the body iron at levels low
enough to prevent the development of these organ toxicities. Once organ
toxicity has developed, chelation therapy can reverse some of the complications,
such as the cardiac complications (discussed later), although the endocrinopathies
usually are not reversible.
Measurement of iron levels
There are several methods of assessing the degree of iron overload and
each method has benefits and limitations (Table 1). Thus, combinations of
measurements, including serial measurements, are used in clinical practice
to determine individual iron burden and response to iron chelation therapy
over time.
The serum ferritin level is the test that is available most widely and easiest
to perform. Because it is a simple blood test, many measurements can be