Pediatric Clinics of North America - CIPERJ

ORAL IRON CHELATORS
465
of 50 children who had sickle cell disease and were receiving regular red
cell transfusions for primary stroke prevention in the Stroke Prevention
Trial in Sickle Cell Anemia (STOP), great variability in the rate of rise
of serum ferritin despite similar transfusion regimens was found among
patients [19]. Serum ferritin levels also underestimate liver iron concentration
in patients who have thalassemia-intermedia and nontransfusionassociated
iron overload [20].
Given that the liver is the major target organ for iron accumulation after
multiple transfusions, the liver iron concentration is a good indicator of
total iron burden [21]. Various methods are available to estimate liver
iron concentration, but liver biopsy generally is considered the gold standard
for accurate iron measurement. In addition, this procedure allows direct
assessment of liver inflammation and fibrosis. Liver iron concentration
is a useful predictor of prognosis in patients who have thalassemia: levels in
excess of 15 mg/g dry weight are associated with an increased risk for cardiac
complications and death [22]. Maintenance of the liver iron concentration
between 3 and 7 mg/g dry weight in those receiving chelation therapy is
considered ideal [23]. Several limitations to liver biopsy exist, however.
First, it is an invasive procedure, which restricts the acceptability to patients
and its frequent use to monitor trends over time. In addition, liver fibrosis
and cirrhosis cause an uneven distribution of iron, which may lead to an
underestimation of liver iron in patients who have advanced liver disease
[24]. Finally, although high levels of liver iron predict an increased risk
for cardiac disease, the converse not always is true: low levels do not always
predict a low risk for cardiac disease [25]. This may reflect the different
organ-specific rates of iron accumulation and iron removal in response to
chelation therapy. In patients who have a history of poor chelation and
high iron levels in the past who subsequently use chelation, hepatic iron
may be removed more rapidly then cardiac iron, so liver iron levels can
fall before cardiac iron levels improve [26].
The superconducting quantum interference device (SQUID) technique
uses magnetometers to measure very small magnetic fields and can be
used as a noninvasive technique to measure ferritin and hemosiderin in
the liver [27]. Estimation of liver iron concentration by SQUID correlates
linearly with concentrations measured by liver biopsy [27]. Because this is
a noninvasive technique, repetitive iron concentration measurements by
SQUID have been used to monitor the efficacy of chelation in several studies
[16,28–30]. A major limitation to using SQUID is that it is a highly specialized
and expensive approach. In addition, in recent clinical trials of the oral
chelator, deferasirox, SQUID measurements underestimated liver iron concentrations
obtained by biopsy by approximately 50% [15]. Currently, only
four sites worldwide offer the technology, limiting accessibility to patients.
MRI increasingly is used to monitor iron overload. This technique takes
advantage of local inhomogeneities of the magnetic field caused by iron
deposition in tissues [31]. Magnetic resonance scanners are more widely