PEDIATRICS Vol. 111 No. 1 January 2003, pp. 91-96
Iron Overload in Children Who Are Treated for Acute Lymphoblastic Leukemia Estimated by Liver Siderosis and Serum Iron Parameters
* Paediatric Research Centre, Medical School, University of Tampere, Tampere, Finland
Departments of Pediatrics
Pathology, Tampere University Hospital, Tampere, Finland
|| Turku University Central Hospital Laboratories Unit, Turku University Central Hospital, Turku, Finland
¶ Finnish Red Cross Blood Transfusion Service, Helsinki, Finland
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ABSTRACT |
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Objective. To evaluate a secondary liver iron overload and its fate in children who are treated conventionally for acute lymphoblastic leukemia and to assess whether serum soluble transferrin receptor (sTfR) is useful in detecting iron load.
Methods. Liver siderosis was estimated histologically from liver biopsy specimens of 30 children (aged 2.6–17.6 years) close to or at the end of therapy using total iron score (TIS). Serum iron parameters and sTfR were measured at the same time and in 22 patients 1 to 3 years after therapy.
Results. In 19 (63%) of 30 patients, liver TIS was >15, indicating at least moderate iron overload. Serum ferritin, iron, and transferrin iron saturation levels were highest and transferrin level lowest in the patients with the highest liver iron content. Serum sTfR levels did not differ significantly between the patients with varying amounts of liver iron. TIS correlated most significantly positively with serum ferritin (rS = 0.899), transferrin iron saturation (rS = 0.764), and the amount of transfused red blood cells (rS = 0.783). Serum iron parameters normalized in most patients during the follow-up. In 3 (14%) of 22 patients, serum ferritin level remained high (>1000 µg/L).
Conclusions. Long-term iron overload is detected in at least 14% of children after therapy for acute lymphoblastic leukemia. Serum sTfR is an inappropriate marker for liver iron overload, whereas ferritin seems to be the most useful serologic marker for it.
Key Words: acute lymphoblastic leukemia • iron overload • liver siderosis
Abbreviations: ALL, acute lymphoblastic leukemia • RBC, red blood cell • sTfR, soluble transferrin receptor • IR, intermediate risk • HR, high risk • TIS, total iron score
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INTRODUCTION |
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Liver disease associated with acute lymphoblastic leukemia (ALL) has been studied intensively in recent decades.1–8 The most important causes of liver dysfunction are hepatotoxic chemotherapeutic agents6–10 and hepatitis viruses.5,11–13 Recently, a secondary iron overload has also been reported to be a contributing factor to liver disease in the treatment of hematologic malignancies and after allogeneic or autologous bone marrow transplantation.14–17 Previously, transfusional hemosiderosis has been recognized to play a significant role in the development of chronic liver disease in thalassemias and sickle cell anemia.18,19
The chemotherapy protocols for childhood ALL have intensified, indicating the need for more frequent red blood cell (RBC) transfusions, which can predispose to iron overload and liver siderosis. Rapid growth during puberty increases iron requirements.20 Therefore, at least part of the stored iron is thought to be consumed during growth, and iron overload may be reversible. However, the frequency and significance of transfusional hemosiderosis as a long-term complication in children who are treated for ALL remains unknown.
The aim of the present study was to evaluate the frequency and extent of iron overload at the end of therapy for childhood ALL and to investigate whether this condition resolves during the subsequent 1 to 3 years. Iron status was assessed by conventional serum iron parameters, namely serum ferritin, iron, transferrin iron saturation, and transferrin, close to or at the end of therapy by determining the amount of iron from a liver biopsy specimen. We also evaluated the clinical usefulness of a new tool for the detection of iron deficiency,21,22 namely the soluble transferrin receptor (sTfR), which also has been reported to signal the presence of iron overload.23
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METHODS |
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Thirty consecutive Finnish children and adolescents (12 boys, 18 girls) who received a diagnosis of ALL between June 1993 and April 1997 and were aged 2.6 to 17.6 years (at the time of the study) were studied in the Department of Pediatrics at Tampere University Hospital from January 1996 to April 2000. Thirteen of the study patients (43%) were treated according to the Nordic protocol for standard risk, 14 (47%) were treated according to the Nordic protocol for intermediate risk (IR) ALL, and 3 (10%) were treated according to a protocol for high risk (HR) ALL without cranial irradiation and with LSA2L2 maintenance therapy.24 The total duration of therapy was 2.5 years in the standard risk group and 2 years in the IR and HR groups. Packed, irradiated, leukocyte-depleted RBCs with hematocrit 0.60 were transfused 10 mL/kg whenever the hemoglobin level was below 100 g/L during induction, consolidation, and delayed intensification phases of therapy (during the first 6–12 months of therapy).
To determine the amount of iron stores, we measured the serum levels of ferritin, iron, transferrin iron saturation, transferrin, and sTfR in 30 study patients who were close to or at the end of therapy and repeated the measurements in 22 patients 1 to 3 years after cessation of therapy. Liver iron stores at the end (in 27 patients) or during the last year of therapy (in 3 patients) were histologically evaluated from liver biopsy specimens.
Measurements of Serum Iron Parameters
Serum ferritin levels (reference ranges: 5–140 µg/L for girls; 20–260 µg/L for boys) were analyzed by an immunochemiluminometric assay (ACS:180 Plus Apparatus; Ciba Corning Diagnostics, Halstead, UK). Serum iron levels (reference ranges: 6–32 µmol/L for girls; 9–35 µmol/L for boys) were measured using a colorimetric assay (Cobas Integra 700, Hoffmann-LaRoche, Basel, Switzerland), and serum transferrin levels (reference range: 1.9–3.5 g/L) were measured with an immunoturbidimetric assay (Cobas Integra 700). Serum transferrin iron saturation (reference range: 15%–50%) was calculated as the molar ratio of analytes multiplied by 100, bearing in mind that 1 transferrin molecule binds 2 ferric ions (saturation % = serum iron mmol/L x 100%: serum transferrin g/L x 24).
Serum sTfR measurements were conducted using the IDeA sTfR IEMA assay (Orion Diagnostica, Turku, Finland; reference ranges: 0.5–4 years, 1.6–4.0 mg/L; 4–10 years, 1.5–3.7 mg/L; 10–16 years, 1.4–3.4 mg/L, calculated from the population described by Suominen et al25).
Serum sTfR assays were performed in the Turku University Central Hospital Laboratories Unit. All other analyses were done in a clinical chemistry laboratory at Tampere University Hospital.
Grading of Liver Iron Content
A percutaneous liver biopsy was obtained from each study patient during general anesthesia with a disposable 1.4-mm-diameter Hepafix biopsy needle a.m. Menghini (Braun, B.Braun Melsungen AG, Melsungen, Germany). Biopsies were fixed in formalin, processed, and embedded in paraffin. Sections (5 µm) were routinely stained with hematoxylin-eosin and with Perls’ prussian blue for iron. Iron deposition was evaluated by 1 of the authors (J.M.) using the scale developed by Deugnier et al.26 This scoring system encompasses a total liver iron score of 60, divided into the 3 compartments: hepatocytic, sinusoidal, and portal iron deposition. The sum of these scores defines the total iron score (TIS; range: 0–60).26 In the present study, we categorized the patients into 3 groups according to their liver TIS; the patients with TIS from 0 to 14 were categorized as group 1 (no or mild iron overload), those with TIS from 15 to 29 as group 2 (moderate iron overload), and those with TIS from 30 to 60 as group 3 (severe iron overload).
Liver Function and Hepatitis Virus Serology
Serum levels of alanine aminotransferase and alkaline phosphatase were measured at the time of liver biopsy in an accredited laboratory using routine methods. Plasma thromboplastin time was assessed by a nephelometric measurement of the clotting time in the presence of tissue thromboplastin with the Stago prothrombincomplex assay (Diagnostica Stago, Asnieres, France). Hepatitis serology (hepatitis B surface antigen, antibodies for hepatitis B core antigen, antibodies for hepatitis C virus) was determined by commercial Cobas Core enzyme immunoassays (Hoffman-LaRoche).
Calculation of Transfused RBCs
The cumulative amount of RBCs transfused during therapy was calculated as milliliters per kilogram for each study patient. The volume of 1 unit of RBCs was 280 ± 50 mL.
Ethical Considerations
The study was approved by the Ethics Committee of Tampere University Hospital. Informed consent was obtained from the parents of each study patient before enrollment. The liver biopsies did not involve an extra anesthetic for the children, because they were obtained in the same anesthesia as a routine bone marrow aspiration.
Statistical Analyses
Statistical analyses were performed with SPSS, version 10.1 (SPSS, Inc, Chicago, IL). A nonparametric Kruskal-Wallis 1-way analysis of variance test was used to evaluate differences in laboratory parameters among several study subgroups. A nonparametric Mann-Whitney U test was applied to evaluate differences in laboratory parameters between 2 independent study subgroups. A nonparametric Wilcoxon signed ranks test was used to compare serum iron parameters at the end of therapy and 1 to 3 years after therapy in 22 patients. A 
2 test was used whenever the variables were categorical. A Spearman rank test was applied for correlations. A 2-sided P value below .05 was considered significant.
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RESULTS |
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Serum Laboratory Parameters and Liver Iron Overload at the End of Therapy
At the end of therapy and at the time of liver biopsy, the median serum level of ferritin was 450 µg/L (range: 14–3158 µg/L), of iron was 19.4 µmol/L (range: 6.7–38.4 µmol/L), of transferrin iron saturation was 38% (range: 11–102%), of transferrin was 1.9 g/L (range: 1.1–3.9 g/L), and of sTfR was 2.57 mg/L (range: 1.30–8.73 mg/L) among all study patients. The median liver TIS was 24 (range: 0–37). Eight of 30 patients (27%) had TIS of 0, indicating no iron overload. In 3 of 30 patients (10%), TIS was from 1 to 14; in 12 of 30 patients (40%), TIS was from 15 to 29; and in 7 of 30 patients (23%), TIS was 30 or more. None of the patients had histologic or serologic hepatitis. Only 3 had mild portal and/or periportal fibrosis and their TIS were 16, 29, and 31.
Serum ferritin and transferrin iron saturation showed the strongest positive correlation with TIS (Fig 1). Serum iron level also correlated positively with TIS (rS = 0.642, P < .001). Serum transferrin and sTfR levels were negatively correlated to TIS (rS = -0.800, P < .001; rS = --0.400, P = .035, respectively). In all patients with a TIS of 0, serum ferritin was within the normal range. Two of 3 patients with TIS from 1 to 14 and all patients with TIS >15 had serum ferritin levels above the normal upper limit (Fig 1). Serum transferrin iron saturation level was within the normal range in all patients with TIS <15. The patients with serum transferrin iron saturation levels above normal ranges had TIS of 27 or more (Fig 1).
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Table 1 shows the serum iron and other laboratory parameters in the 3 liver TIS groups. Of the serum iron parameters, significant differences among the 3 groups were detected in ferritin, iron, transferrin iron saturation, and transferrin but not in sTfR levels. Serum ferritin, iron, and transferrin iron saturation levels were highest in group 3. Regarding other laboratory parameters, there were significant differences in serum levels of alkaline phosphatase, which was highest in group 1 and lowest in group 3. There were no significant differences among the 3 groups regarding age, gender, or ALL group (Table 1).
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A significant difference was detected among the 3 TIS groups in the amounts of transfused RBCs. The median amounts of RBCs transfused were on average 0.33 U/kg, 0.5 U/kg, and 0.75 U/kg in groups 1, 2, and 3, respectively (Table 1). There was a significant positive correlation (r = 0.783, P < .001) between the amount of transfused RBCs and TIS.
Serum Iron Parameters 1 to 3 Years After Cessation of Therapy
The median levels of serum iron parameters in 22 study patients at the end of therapy and 1 to 3 years after cessation of therapy are presented in Table 2. Results of serum sTfR measurements were available for only 14 patients. Three of 22 patients (14%) had serum ferritin levels of >1000 µg/L after therapy (Fig 2). Their serum transferrin iron saturation levels were 20%, 38%, and 64%. All 3 were boys and had been treated according to the IR ALL protocol. At the time of cessation of therapy, the 3 patients were older than the others (median: 17.3; range: 13.7–17.6 years vs median: 5.8; range: 2.6–15.8 years; P = .003), and their TIS were also higher (median: 35; range: 34–37 vs median: 20; range: 0–34; P = .001).
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Serum ferritin, iron, transferrin iron saturation, and sTfR levels were significantly lower and transferrin level significantly higher 1 to 3 years after therapy than at the end of therapy among all restudied patients (Table 2). There were significant differences between the first and the control measurements in serum ferritin in all 3 TIS groups and in serum transferrin iron saturation in groups 2 and 3 (Fig 2).
Of the serum iron parameters measured 1 to 3 years after cessation of therapy, ferritin was positively (rS = 0.908; P < .001) and transferrin was negatively (rS = -0.656; P = .001) correlated with TIS taken at the end of therapy. Serum iron (rS = 0.122; P = .578), transferrin iron saturation (rS = 0.388; P = .067), or sTfR levels (rS = -0.413; P = .100) were not significantly correlated with TIS.
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DISCUSSION |
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The recognition of iron overload is important in long-term survivors of childhood ALL because it is potentially associated with endocrinological and cardiac complications and with hepatic abnormalities, even fibrosis and cirrhosis.27–29 Biochemical determination of hepatic iron concentration has been considered to be the most reliable method to disclose iron overload.29,30 However, it is not always available, and alternative procedures for assessing iron load have been sought. Deugnier et al26 presented a histologic liver iron grading system and used it in evaluating patients with genetic hemochromatosis. In the present study, we applied the aforementioned grading system, because the liver needle biopsy specimens were insufficient for the biochemical estimation of hepatic siderosis.
In the present study, 63% (19 of 30) of the patients had liver TIS >15, indicating at least moderate liver iron overload. There was a definite positive correlation between the amount of RBCs transfused and TIS. Serum ferritin, transferrin iron saturation, and iron levels correlated significantly positively, whereas serum transferrin and sTfR correlated significantly negatively to TIS at the end of therapy (Fig 1). The correlations were strongest for ferritin and transferrin iron saturation. The most extreme pathologic values of all markers were observed in the patients in group 3. The difference in iron status between the patients with no or mild liver iron overload (group 1) and those with moderate or severe liver iron overload (groups 2 and 3) could be significantly demonstrated by all serum markers except serum sTfR.
Despite the substantially elevated TIS and serum markers at the end of therapy, the serum iron parameters normalized during follow-up in most patients with the most marked changes occurring in group 3 (Table 2, Fig 2). This indicates that the transfusion-induced iron overload decreases in the course of time and during growth and is therefore largely reversible in children who are treated conventionally for ALL.
The correlation of ferritin to TIS remained significant during the follow-up of 1 to 3 years. This indicates that ferritin may be the most useful parameter for long-term monitoring of the resolution of an extensive iron load. Serum ferritin values in excess of 1000 µg/L prevailed in 3 (14%) of 22 of the young study patients 1 to 2 years after cessation of therapy, pointing to iron overload. This is consistent with the recent data from adult survivors, which suggest that 15% to 20% of adults with acute leukemia in long-term remission after routine chemotherapy develop iron overload, often with hepatic abnormalities.15,16,31 The 3 patients with sustained iron overload were older than other study patients, indicating that the remaining growth potential at the time of cessation of therapy may be directly related to the reversibility of iron overload. Physical growth is known for its ability to consume iron stores. In this context, we emphasize that only 3 patients in the present study were treated according to an HR protocol, and each of them was younger than 5 years. If there had been more older patients with HR ALL receiving more intensive chemotherapy also with more RBC transfusions, then long-term iron overload probably would have been detected more often.
Transferrin iron saturation has been used to detect early phases and development of both hereditary and acquired hemochromatotic conditions, whereas ferritin has been used to measure transfusional iron overload in renal diseases, thalassemias, and malignancies. Some previous studies, however, have failed to demonstrate a linear relationship between serum ferritin and hepatic iron concentration in diseases with transfusion-related iron overload, namely in thalassemias and sickle cell anemias.32–34 It should be considered that secondary factors such as infection, inflammation, and malignancy increase serum ferritin concentrations,35,36 whereas the final stages of hepatic fibrosis and cirrhosis may be associated with decreased concentrations.29,33 The value of serum ferritin as an indicator of iron overload in the present study may have been enhanced by the patients’ not having viral hepatitis, marked fibrosis, or cirrhosis.
It is interesting that during the follow-up of 1 to 3 years, serum sTfR concentrations were observed to decrease consistently with no differences between the separate liver TIS groups. For this phenomenon, there are several feasible explanations. First, elevated serum sTfR has been shown to signal functional iron deficiency, ie, iron-deficient erythropoiesis in the presence of adequate or increased iron stores.37 This condition is usually induced by a sustained acute-phase reaction and a deranged cytokine balance, situations that often accompany several phases of ALL. Second, at the end of the cytotoxic therapy, some patients may have presented with compensatorily accelerated erythropoiesis, a condition that is reflected by elevated serum sTfR concentrations. Third, serum sTfR concentrations have been shown to decrease with age until 16 years,25 which may have contributed to the observed decrease in serum sTfR during follow-up. There was a considerable overlap in serum sTfR concentrations among the 3 groups, the values usually being in the range of normal to low-normal (Table 1). These observations are consistent with previous reports that serum sTfR accurately portrays subclinical,38 manifest,37,39 and complicated37,39 iron-deficient conditions but is inappropriate for the detection of clinically significant iron overload.
The patients in the present study had no family history of hereditary hemochromatosis, and they were not screened for gene mutations of hereditary hemochromatosis. In current Finnish series, 6.7% to 10.2% of the population are shown to be carriers of Tyr 282 allele.40,41 Thus, the mean frequencies of gene alleles responsible for hereditary hemochromatosis in Finland are similar to those in other Western and European countries.42 However, the recent Finnish study indicated that mutations of the gene of hereditary hemochromatosis do not account for transfusional iron overload in adult patients with acute myeloid leukemia.41
None of our patients had signs of endocrine, cardiac, or other clinical complications associated with iron overload. Liver fibrosis was not detected in liver biopsies taken at the end of therapy in the 3 patients with long-term iron overload.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Liver iron overload was found to be common in children and adolescents after conventional therapy for ALL. In most children, the iron overload seems to be reversible but may not resolve as readily in patients who have already achieved their adult stature by the end of therapy. Unfortunately, we were not able to perform control liver biopsies but instead evaluated the resolution of iron overload by monitoring the values of serum iron parameters, especially ferritin. We suggest that the amount of transfused RBCs should be calculated in every child who is treated for ALL to estimate the body iron load. The evaluation of iron status by serum parameters such as ferritin and transferrin iron saturation in all surviving patients at the end of therapy is also necessary. Furthermore, serum ferritin and transferrin iron saturation values should be monitored at least once a year until they have normalized. A liver biopsy is recommended when massive iron-loading from large amounts of transfused RBCs is expected or when a high liver iron content is suggested by elevated serum ferritin and transferrin iron saturation values.
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ACKNOWLEDGMENTS |
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The study was supported by the Medical Research Fund of Tampere University Hospital and the Nona and Kullervo Väre Foundation.
We thank Raili Salmelin, PhD, for assistance in preparing the figures.
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FOOTNOTES |
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Received for publication Feb 7, 2002; Accepted Jun 4, 2002.
Reprint requests to (P.H.) Paediatric Research Centre, Medical School, University of Tampere, Finn-Medi 3 (3–144B), 33014 University of Tampere, Finland. E-mail: paivi.halonen{at}kotiposti.net
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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