Low Serum Lipocalin Levels in Patients With Iron Deficiency Anemia Baris Malbora, MD,* Zekai Avci, MD,* Meltem Gu¨lsan, MD,w Betul Orhan, MD,w and Namik Ozbek, MD*w Summary: In the recent literature, there are studies on the rela- tionship between anemia and lipocalin, but there is no study regarding the relationship between lipocalin and iron deficiency anemia (IDA) up to date. In this study, we aimed to observe lip- ocalin levels at admission, and after iron therapy in children with IDA. We also compared our findings to those in healthy children. Sixty-one children admitted in our outpatient clinic were included in the study. Thirty of these children had IDA (study group) and the rest were healthy (control group). Thirty patients, meeting the IDA criteria, received oral ferrous sulfate of 4 mg/kg/d. As soon as the hemoglobin value reached >11 g/dL, half dose of oral ferrous sulfate therapy was continued for another month. Serum lipocalin levels before and after iron therapies were compared. Hematologic parameters and serum lipocalin levels were also compared between the 2 groups. Mean values of serum lipocalin were 31.01 ± 14.46 and 74.77 ng/dL in patients with IDA at admission and at third month of therapy, respectively (P < 0.0001). The same figure was 57.35 ± 39.51 ng/dL in the control group. Before treatment, mean values of lipocalin levels in patients with IDA was significantly lower than the control group (P = 0.001); however, such a difference was not detected after 3 months of therapy (P = 0.102). We suggest that decreased serum lipocalin levels in our patients during iron insuffi- ciency were caused by iron deficiency rather than anemia. Key Words: iron deficiency, anemia, children, lipocalin, diagnosis (J Pediatr Hematol Oncol 2013;35:218–220) R ecently, an iron-delivery pathway was identified, which involves a member of the lipocalin superfamily 1 ; an antimicrobial protein named lipocalin 2. 2 Lipocalin 2 was first identified as a 25-kDa glycoprotein associated with purified human neutrophil gelatinase. 3 The counterpart of lipocalin 2 identified in a mouse is an oncogene protein, 24p3. 4 Although the physiological role of lipocalin 2 remains to be fully elucidated, a few pivotal functions have recently been reported. These functions include inhibition of bacterial growth by sequestration of the iron-laden siderophore (siderocalin), 5 regulation of the apoptosis of hematopoietic cells, 6–8 and the transport of iron. 9 Lipocalin 2 can bind catecholate-type bacterial ferric siderophores (eg, enterobactin), 5 which are low-molecular compounds that bind ferric iron and are able to acquire iron from mammalian iron-binding proteins, including transferrin (Tf) and lactoferrin. 10 As lipocalin 2 binds enterobactin with higher affinity than the Escherichia coli enterobactin transporter, it effectively interferes with bacterial iron uptake and, in fact, acts as a bacteriostatic agent. 5 In addition to its role as a bacteriostatic agent, lipocalin is an iron-trafficking protein, a member of the non–Tf-bound iron pool, and an alternative to the Tf-mediated iron-delivery pathway. 9 Lipocalin 2 has also been shown to mediate a Tf- independent iron uptake pathway activated during kidney development in an in vitro animal study. 9 The iron delivered to cells by lipocalin 2 is capable of regulating iron-dependent genes, such as ferritin and Tf receptor-1 (TfR1), 9,11 that are sensitive to cellular iron status, 12 indicating that cells can utilize the iron provided by lipocalin 2. Lipocalin 2 induces apoptosis of hematopoietic cells 6–8 and inhibits differentiation of erythroid cells, in vitro. 8 Thus, lipocalin 2 is thought to be involved in the regulation of hematopoiesis, in vivo, 6–8 and in the pathogenesis of certain hematopoietic malignancies. 6,7 However, lipocalin 2 has also been reported to promote survival and differ- entiation of various types of cells except erythroid cells. 13–15 In the recent literature, there are studies on the rela- tionship between anemia and lipocalin 2, but there is no study regarding the relationship between lipocalin 2 and iron deficiency anemia (IDA) up to date. In this study, we aimed to observe lipocalin 2 levels at admission and after iron therapy in children with IDA. We also compared our findings to those in healthy children. SUBJECTS AND METHODS Subjects Sixty-one children, aged 6 months to 6 years, admitted to our outpatient clinic during November 2009 to March 2010 were included in the study. Thirty of these children had IDA (study group: 9 females and 21 males), and the rest were healthy (control group: 13 females and 18 males) (Table 1). In the diagnosis of IDA, the following criteria were required: hemoglobin r10 g/dL, increased red cell distribution range, ferritin <10 ng/mL together with nor- mal serum C-reactive protein (CRP) levels, and mean cor- puscular volume being less than the standard values adjusted for age. Children who had supportive findings for malabsorption and bleeding in the digestive system, chronic disease, thalassemia, or any other hemoglobinopathies were excluded. The control group consisted of children with similar age distribution, who were admitted with the sus- picion of anemia but found to be normal after laboratory work up. They had no acute or chronic disease with normal serum CRP levels. The study was approved by the local ethics committee. Written informed consent was obtained from all the parents. Thirty patients, meeting the IDA criteria, received oral ferrous sulfate 4 mg/kg/d. In addition, iron rich diets were Received for publication May 13, 2012; accepted September 20, 2012. From the Departments of *Pediatric Hematology; and wPediatrics, Faculty of Medicine, Baskent University, Ankara, Turkey. N.O. and B.M.: planned and performed experiments, and wrote the manuscript. Z.A., M.G., and B.O.: performed the experiments. The authors declare no conflict of interest. Reprints: Baris Malbora, MD, Department of Paediatrics, Faculty of Medicine, Baskent University, 6. Cadde, No: 72/3, Bahcelievler, 06490 Ankara, Turkey (e-mail: barismalbora@gmail.com). Copyright r 2012 by Lippincott Williams & Wilkins ORIGINAL ARTICLE 218 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 35, Number 3, April 2013