Skip to main content

Advertisement

SpringerLink
Log in

Major Depression in Children with Transfusion-Dependent Thalassemia Is Strongly Associated with the Combined Effects of Blood Transfusion Rate, Iron Overload, and Increased Pro-inflammatory Cytokines

  • Clinical Research Report
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Beta-thalassemia major patients are treated with repeated blood transfusions, which may cause iron overload, which in turn may induce immune aberrations, and show an increased risk of depression. The aim of the present study is to examine whether repeated blood transfusions, iron overload, and immune-inflammatory responses are associated with depression in children (6–12 years) with transfusion-dependent thalassemia (TDT). The Children’s Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%), and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in TDT with (n = 54) and without (n = 57) a major depression-like episode (MDLE) and in healthy children (n = 55). The results show that MDLE due to TDT is associated with a greater number of blood transfusions and increased iron overload and IL-1β levels. Partial least squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, iron overload, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of iron overload on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by iron overload and the path from iron overload to immune activation. Iron overload is also associated with increased IL-10 and lower CCL11 levels, but these alterations are not significantly associated with depression. In conclusion, blood transfusions may be causally related to MDLE in TDT children and their effects are in part mediated by increased iron overload and the consequent immune-inflammatory response. The results suggest that effects of iron overload and its consequences including inflammation and oxidative stress toxicity may cause MDLE. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate iron overload and immune-inflammatory responses and to prevent MDLE in children with TDT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Abbreviations

ANOV:

Analysis of variance

AVE:

Average variance extracted

CCL11:

Eotaxin

CDI:

Children’s Depression Inventory

CIRS:

Compensatory immune-regulatory system

CRP:

C-reactive protein

CV:

Coefficient of variance

ELFA:

Enzyme-linked fluorescent immunoassay

GLM:

General linear model

HPLC:

High performance liquid chromatography

ICD-10-CM:

International Classification of Diseases, Tenth Revision, Clinical Modification

IL:

Interleukin

LSD:

Least square difference

LV:

Latent vectors

MDD:

Major depressive disorder

MDLE:

Major depressive-like episodes

PLS:

Partial least squares

SE:

Standard error

SRMR:

Standardized root mean squared residual

TDT:

Transfusion-dependent thalassemia

Th:

T helper cells

TIBC:

Total iron-binding capacity

TNF-α:

Tumor-necrosis factor-α

Treg:

T regulatory

TS%:

Transferrin saturation percentage

UIBC:

Unsaturated iron-binding capacity

References

  • Abdulzahra MS, Al-Hakeim HK, Ridha MM (2011) Study of the effect of iron overload on the function of endocrine glands in male thalassemia patients. Asian J Transfus Sci 5:127–131

    CAS  PubMed  PubMed Central  Google Scholar 

  • Agrawal S, Berggren KL, Marks E, Fox JH (2017) Impact of high iron intake on cognition and neurodegeneration in humans and in animal models: A systematic review. Nutrition reviews 75:456–470

    PubMed  PubMed Central  Google Scholar 

  • Al-Hakeim HK, Almulla AF, Maes M (2020) The neuroimmune and neurotoxic fingerprint of major neurocognitive psychosis or deficit schizophrenia: a supervised machine learning study. Neurotox Res. https://doi.org/10.1007/s12640-019-00112-z

    PubMed  Google Scholar 

  • Al-Hakeim HK, Al-Khakani MM, Al-Kindi MA (2015) Correlation of hepcidin level with insulin resistance and endocrine glands function in major thalassemia. Adv Clin Exp Med 24:69–78

    PubMed  Google Scholar 

  • Atasever B, Ertan NZ, Erdem-Kuruca S, Karakas Z (2006) In vitro effects of vitamin C and selenium on NK activity of patients with beta-thalassemia major. Pediatr Hematol Oncol 23:187–197

    CAS  PubMed  Google Scholar 

  • Baghersalimi A, Hemmati KH, Darbandi B, Kamran MZ, Alizadeh AM, Dalili S et al (2018) Assessment of serum folic acid and homocysteine in thalassemia major patients before and after folic acid supplement cessation. J Pediatr Hematol Oncol 40:504–507

    CAS  PubMed  Google Scholar 

  • Balouchi S, Gharagozloo M, Esmaeil N, Mirmoghtadaei M, Moayedi B (2014) Serum levels of TGFβ, IL-10, IL-17, and IL-23 cytokines in β-thalassemia major patients: the impact of silymarin therapy. Immunopharmacol Immunotoxicol 36:271–274

    CAS  PubMed  Google Scholar 

  • Bender LM, Morgan MJ, Thomas LR, Liu ZG, Thorburn A (2005) The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm. Cell Death Differ 12:473–481

    CAS  PubMed  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate - a practical and powerful approach to multiple testing. J Royal Statis Soc B 57:289–300

    Google Scholar 

  • Boyer TD, Habib S (2015) Big spleens and hypersplenism: fix it or forget it? Liver Int 35:1492–1498

    PubMed  Google Scholar 

  • Cao A, Galanello R (2010) Beta-thalassemia. Genet Med 12:61–76

    CAS  PubMed  Google Scholar 

  • Capellini M, Cohen A, Eleftheriou A (2008) Guidelines for the clinical management of thalassemia (2nd revised edition), Nicosia. 2008.

  • Chang JS, Li YL, Lu CH, Owaga E, Chen WY, Chiou HY (2014) Interleukin-10 as a potential regulator of hepcidin homeostasis in overweight and obese children: a cross-sectional study in Taiwan. Nutrition 30:8099–9007

    Google Scholar 

  • Chao CC, Hu S, Ehrlich L, Peterson PK (1995) Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun 9:355–365

    CAS  PubMed  Google Scholar 

  • Chern JP, Su S, Lin KH, Chang SH, Lu MY, Jou ST, Lin DT, Ho WL, Lin KS (2007) Survival, mortality, and complications in patients with beta-thalassemia major in northern Taiwan. Pediatr Blood Cancer 48:550–554

    PubMed  Google Scholar 

  • Cook JD, Lipschitz DA, Miles LEM, Finch CA (1974) Serum ferritin as a measure of iron stores in normal subjects. Am J Clin Nutr 27:681–687

    CAS  PubMed  Google Scholar 

  • Crichton R, Ward R (2013) Metal-based neurodegeneration: From molecular mechanisms to therapeutic strategies, 2nd edn. John Wiley & Sons

  • Cutler P (1994) Iron overload and psychiatric illness. Can J Psychiatr 39:8–11

    CAS  Google Scholar 

  • Daher R, Manceau H, Karim Z (2017) Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease. Presse Med 46:e272–e278

    PubMed  Google Scholar 

  • Ezer U, Gulderen F, Culha VK, Akgül N, Gürbüz O (2002) Immunological status of thalassemia syndrome. Pediatr Hematol Oncol 19:51–58

    PubMed  Google Scholar 

  • Farmakis D, Giakoumis A, Polymeropoulos E, Aessopos A (2003) Pathogenetic aspects of immune deficiency associated with beta-thalassemia. Med Sci Monit 9:RA19–RA22

    PubMed  Google Scholar 

  • Gan GG, Hue YL, Sathar J (2016) QOL of adult patients with Thalassaemi. Ann Acad Med 45:520–523

    Google Scholar 

  • Ghaffari J, Vahidshahi K, Kosaryan M, Soltantooyeh Z, Mohamadi M (2011) Humeral immune system state in β thalassemia major. Med Glas Ljek Komore Zenickodoboj kantona 8:192–196

    Google Scholar 

  • Ghanizadeh A, Khajavian S, Ashkani H (2006) Prevalence of psychiatric disorders, depression, and suicidal behavior in child and adolescent with thalassemia major. J Pediatr Hematol Oncol 28:781–784

    PubMed  Google Scholar 

  • Gharagozloo M, Bagherpour B, Tahanian M, Oreizy F, Amirghofran Z, Sadeghi HM, Hourfar H, Moayedi B (2009a) Premature senescence of T lymphocytes from patients with beta-thalassemia major. Immunol Lett 122:84–88

    CAS  PubMed  Google Scholar 

  • Gharagozloo M, Karimi M, Amirghofran Z (2009b) Double-faced cellmediated immunity in beta-thalassemia major: stimulated phenotype versus suppressed activity. Ann Hematol 88:21–27

    CAS  PubMed  Google Scholar 

  • Grassi-Oliveira R, Brieztke E, Teixeira A, Pezzi JC, Zanini M, Lopes RP, Bauer ME (2012) Peripheral chemokine levels in women with recurrent major depression with suicidal ideation. Braz J Psychiatry 34:71–75

    PubMed  Google Scholar 

  • Guo H, Jin YX, Ishikawa M, Huang YM, van der Meide PH, Link H, Xiao BG (1998) Regulation of beta-chemokine mRNA expression in adult rat astrocytes by lipopolysaccharide, proinflammatory and immunoregulatory cytokines. Scand J Immunol 48:502–508

    CAS  PubMed  Google Scholar 

  • Hagag AA, El-Shanshory MR, AboEl-Enein AM (2015) Parathyroid function in children with beta thalassemia and correlation with iron load. Adv Pediatr Res 2:3

    Google Scholar 

  • Hamed AA, Elguindy W, Elhenawy YI, Ibrahim RH (2016) Early cardiac involvement and risk factors for the development of arrhythmia in patients with β-thalassemia major. J Pediatr Hematol Oncol 38:5–11

    CAS  PubMed  Google Scholar 

  • Hammond J, Thompson AA, Fogel MA, Hammond K, Kokroko J, Kwiatkowski JL (2019) Combination oral chelation in adult patients with transfusion-dependent thalassemia and high Iron burden. J Pediatr Hematol Oncol 41:e47–e50

    PubMed  Google Scholar 

  • Hasiloglu ZI, Asik M, Ure E, Ertem F, Apak H, Albayram S (2017) The utility of susceptibility-weighted imaging to evaluate the extent of iron accumulation in the choroid plexus of patients with β-thalassaemia major. Clin Radiol 72(10):903.e1–903.e7

    CAS  Google Scholar 

  • Javad G, Saeid A, Mohammadmehdi N (2011) Thalassemia and immune system dysfunction-review article. IJCR 3:105–108

    Google Scholar 

  • Jomova K, Valko M (2011) Importance of iron chelation in free radical-induced oxidative stress and human disease. Curr Pharm Des 17:3460–3473

    CAS  PubMed  Google Scholar 

  • Kennedy A, Kohn M, Lammi A, Clarke S (2004) Iron status and haematological changes in adolescent female inpatients with anorexia nervosa. J Paediatr Child Health 40:430–432

    CAS  PubMed  Google Scholar 

  • Keskek SO, Kirim S, Turhan A, Turhan FG (2013) Depression in subjects with beta-thalassemia minor. Ann Hematol 92:1611–1615

    CAS  PubMed  Google Scholar 

  • Khoury B, Musallam KM, Abi-Habib R, Bazzi L, Ward Z, Succar J, Halawi R, Hankir A, Koussa S, Taher AT (2012) Prevalence of depression and anxiety in adult patients with ß-thalassemia major and intermedia. Int J Psychiatry Med 44:291–303

    PubMed  Google Scholar 

  • Kim J, Wessling-Resnick M (2014) Iron and mechanisms of emotional behavior. J Nutr Biochem 25:1101–1107

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koutelekos J, Haliasos N (2013) Depression and thalassemia in children, adolescents and adults. Health Sci J 7:239–246

    Google Scholar 

  • Kovacs M (1992) Children’s depression inventory manual. Multi-health Systems, New York

    Google Scholar 

  • Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C (2005) Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Ann N Y Acad Sci 1054:445–450

    PubMed  Google Scholar 

  • Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36:764–785

    CAS  PubMed  Google Scholar 

  • Liaska A, Petrou P, Georgakopoulos CD, Diamanti R, Papaconstantinou D, Kanakis MG et al (2016) β-Thalassemia and ocular implications: a systematic review. BMC Ophthalmol 16:102

    PubMed  PubMed Central  Google Scholar 

  • Libani IV, Guy EC, Melchiori L, Schiro R, Ramos P, Breda L, Scholzen T, Chadburn A, Liu Y, Kernbach M, Baron-Lühr B, Porotto M, de Sousa M, Rachmilewitz EA, Hood JD, Cappellini MD, Giardina PJ, Grady RW, Gerdes J, Rivella S (2008) Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia. Blood 112:875–885

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lombardi G, Matera R, Minervini MM, Cascavilla N, D’Arcangelo P, Carotenuto M et al (1994) Serum levels of cytokines and soluble antigens in polytransfused patients with beta-thalassemia major: relationship to immune status. Haematologica 79:406–412

    CAS  PubMed  Google Scholar 

  • Maes M, Carvalho AF (2018) The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol Neurobiol 55:8885–8903

    CAS  PubMed  Google Scholar 

  • Maes M, Bosmans E, Suy E, Vandervorst C, DeJonckheere C, Raus J (1991) Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production. Acta Psychiatr Scand 84:379–386

    CAS  PubMed  Google Scholar 

  • Maes M, Stevens WJ, Declerck LS, Bridts CH, Peeters D, Schotte C, Cosyns P (1993) Significantly increased expression of T-cell activation markers (interleukin-2 and HLA-DR) in depression: further evidence for an inflammatory process during that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 17:241–255

    CAS  Google Scholar 

  • Maes M, Van de Vyvere J, Vandoolaeghe E, Bril T, Demedts P, Wauters A et al (1996) Alterations in iron metabolism and the erythron in major depression: further evidence for a chronic inflammatory process. J Affect Disord 40:23–33

    CAS  PubMed  Google Scholar 

  • Maes M, Bosmans E, Scharpé S, Hendriks D, Cooremans W, Neels H, de Meyer F, D'Hondt P, Peeters D (1997) Components of biological variation in serum soluble transferrin receptor: relationships to serum iron, transferrin and ferritin concentrations, and immune and haematological variables. Scand J Clin Lab Invest 57:31–41

    CAS  PubMed  Google Scholar 

  • Maes M, Fišar Z, Medina M, Scapagnini G, Nowak G, Berk M (2012) New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology 20:127–150

    CAS  PubMed  Google Scholar 

  • Magalhaes PV, Jansen K, Stertz L, Ferrari P, Pinheiro RT, da Silva RA, Kapczinski F (2014) Peripheral eotaxin-1 (CCL11) levels and mood disorder diagnosis in a population-based sample of young adults. J Psychiatr Res 48:13–15

    PubMed  Google Scholar 

  • Manara R, Ponticorvo S, Tartaglione I, Femina G, Elefante A, Russo C et al (2019) Brain iron content in systemic iron overload: a beta-thalassemia quantitative MRI study. Neuroimage Clin 24:102058

    PubMed  PubMed Central  Google Scholar 

  • Maras JS, Das S, Sharma S, Sukriti S, Kumar J, Vyas AK, Kumar D, Bhat A, Yadav G, Choudhary MC, Sharma S, Kumar G, Bihari C, Trehanpati N, Maiwall R, Sarin SK (2018) Iron-overload triggers ADAM-17 mediated inflammation in severe alcoholic hepatitis. Sci Rep 8:10264. https://doi.org/10.1038/s41598-018-28483-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McLaren CE, Li KT, Gordeuk VR, Hasselblad V, McLaren GD (2001) Relationship between transferrin saturation and iron stores in the African American and US Caucasian populations: analysis of data from the third National Health and Nutrition Examination Survey. Blood 98:2345–2351

    CAS  PubMed  Google Scholar 

  • Messina G, Colombo E, Cassinerio E, Ferri F, Curti R, Altamura C et al (2008) Psychosocial aspects and psychiatric disorders in young adult with thalassemia major. Intern Emerg Med 2008:339–343

    Google Scholar 

  • Metafratzi Z, Argyropoulou MI, Kiortsis DN, Tsampoulas C, Chaliassos N, Efremidis SC (2001) T(2) relaxation rate of basal ganglia and cortex in patients with beta-thalassemia major. Br J Radiol 74:407–410

    CAS  PubMed  Google Scholar 

  • Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M (2001) Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol 11:203–208

    CAS  PubMed  Google Scholar 

  • Moris W, Verhaegh P, Jonkers D, Deursen CV, Koek G (2019) Hyperferritinemia in nonalcoholic fatty liver disease: iron accumulation or inflammation? Semin Liver Dis 39:476–482

    CAS  PubMed  Google Scholar 

  • Morris G, Berk M, Carvalho AF, Maes M, Walker AJ, Puri BK (2018) Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiolaogy of neuroprogressive diseases. Behav Brain Res 341:154–175

    CAS  PubMed  Google Scholar 

  • Nnah IC, Wessling-Resnick M (2018) Brain iron homeostasis: A focus on microglial iron. Pharmaceuticals 11:129

    CAS  PubMed Central  Google Scholar 

  • O’Brien-Ladner AR, Nelson SR, Murphy WJ, Blumer BM, Wesselius LJ (2000) Iron is a regulatory component of human IL-1 β production: Support for regional variability in the lung. Am J Respir Cell Mol Biol 23:112–119

    CAS  PubMed  Google Scholar 

  • Premawardhena A, Ranawaka U, Pilapitiya T, Weerasinghe G, Hapangama A, Hettiarachchi S (2019) Headache: an important symptom possibly linked to white matter lesions in thalassaemia. Br J Haematol 185(3):541–548

    PubMed  Google Scholar 

  • Qiu D, Chan GC, Chu J, Chan Q, Ha SY, Moseley ME, Khong PL (2014) MR quantitative susceptibility imaging for the evaluation of iron loading in the brains of patients with β-thalassemia major. AJNR Am J Neuroradiol 35(6):1085–1090

    CAS  PubMed  Google Scholar 

  • Ricerca BM, DiGirolamo A, Rund D (2009) Infections in thalassemia and hemoglobinopathies: focus on therapy-related complications. Mediterr J Hematol Infect Dis 1:e2009028

    PubMed  PubMed Central  Google Scholar 

  • Richardson AC, Heath AM, Haszard JJ, Polak MA, Houghton LA, Conner TS (2015) Higher body iron is associated with greater depression symptoms among young adult men but not women: observational data from the daily life study. Nutrients 7:6055–6072

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ringle CM, Wende S, Becker J-M (2015) SmartPLS 3. SmartPLS, Bönningstedt Retrieved from http://www.smartpls.com

    Google Scholar 

  • Russo AG, Ponticorvo S, Tartaglione I, Caiazza M, Roberti D, Elefante A et al (2019) No increased cerebrovascular involvement in adult beta-thalassemia by advanced MRI analyses. Blood Cells Mol Dis 78:9–13

    PubMed  Google Scholar 

  • Rybka J, Kędziora-Kornatowska K, Banaś-Leżańska P, Majsterek I, Carvalho LA, Cattaneo A, Anacker C, Kędziora J (2013) Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression. Free Radic Biol Med 63:187–194

    CAS  PubMed  Google Scholar 

  • Sari TT, Gatot D, Akib AA, Bardosono S, Hadinegoro SR, Harahap AR, Idjradinata PS (2014) Immune response of thalassemia major patients in Indonesia with and without splenectomy. Acta Med Indones 46:217–225

    PubMed  Google Scholar 

  • Schneider SA, Bhatia KP (2013) Excess iron harms the brain: The syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA). J Neural Transm 120:695–703

    CAS  PubMed  Google Scholar 

  • Shafiee A, Nazari S, Jorjani S, Bahraminia E, Sadeghi-Koupaei M (2014) Prevalence of depression in patients with β-thalassemia as assessed by the Beck’s depression inventory. Hemoglobin 38:289–291

    CAS  PubMed  Google Scholar 

  • Shah FT, Sayani F, Trompeter S, Drasar E, Piga A (2019) Challenges of blood transfusions in β-thalassemia. Blood Rev 100588:100588. https://doi.org/10.1016/j.blre.2019.100588

    Article  Google Scholar 

  • Sherief LM, Abd El-Salam SM, Kamal NM, El-Safy O, Almalky MA, Azab SF et al (2014) Nutritional biomarkers in children and adolescents with Beta-thalassemia-major: an Egyptian center experience. Biomed Res Int 2014:261761

    PubMed  PubMed Central  Google Scholar 

  • Siesjö B, Agardh CD, Bengtsson F (1989) Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1(3):165–211

    PubMed  Google Scholar 

  • Simon NM, McNamara K, Chow CW, Maser RS, Papakostas GI, Pollack M, Nierenberg AA, Fava M, Wong KK (2008) A detailed examination of cytokine abnormalities in major depressive disorder. Eur Neuropsychopharmacol 18:230–233

    CAS  PubMed  Google Scholar 

  • Stockings E, Degenhardt L, Lee YY, Mihalopoulos C, Liu A, Hobbs M, Patton G (2015) Symptom screening scales for detecting major depressive disorder in children and adolescents: a systematic review and meta-analysis of reliability, validity and diagnostic utility. J Affect Disord 174:447–463

    PubMed  Google Scholar 

  • Suriapperuma T, Peiris R, Mettananda C, Premawardhena A, Mettananda S (2018) Body iron status of children and adolescents with transfusion dependent β-thalassaemia: trends of serum ferritin and associations of optimal body iron control. BMC Res Notes 11:547

    PubMed  PubMed Central  Google Scholar 

  • Taher AT, Saliba AN (2017) Iron overload in thalassemia: different organs at different rates. Hematol Am Soc Hematol Educ Program 2017:265–271

    Google Scholar 

  • Tartaglione I, Caiazza M, Di Concilio R, Ciancio A, De Michele E, Maietta C et al (2019) Headache in beta-thalassemia: an Italian multicenter clinical, conventional MRI and MR-angiography case-control study. Blood Cells Mol Dis 81:102403

    PubMed  Google Scholar 

  • Thein SL (2013) The molecular basis of β-thalassemia. Cold Spring Harb Perspect Med 3:a011700

    PubMed  PubMed Central  Google Scholar 

  • Tietz NW, Rinker AD, Morrison SR (1994) When is a serum iron really a serum iron? The status of serum iron measurements. Clin Chem 40:546–551

    CAS  PubMed  Google Scholar 

  • Wahidiyat PA, Sastroasmoro S, Fucharoen S, Setianingsih I, Putriasih S (2018) Applicability of a clinical scoring criteria for disease severity of ß-thalassemia/ hemoglobin E in Indonesia. Med J Indones 27:26–32

    Google Scholar 

  • Walker EM, Walker SM (2000) Effects of iron overload on the immune system. Ann Clin Lab Sci 30:354–365

    CAS  PubMed  Google Scholar 

  • Wessling-Resnick M (2010) Iron homeostasis and the inflammatory response. Annu Rev Nutr 30:105–122

    CAS  PubMed  PubMed Central  Google Scholar 

  • Witzleben CL, Wyatt JP (1961) The effect of long survival on the pathology of thalassæmia major. J Pathol Bacteriol 82:1–12

    CAS  PubMed  Google Scholar 

  • Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26:165–176

    CAS  PubMed  Google Scholar 

  • Yang H, Yang M, Guan H, Liu Z, Zhao S, Takeuchi S, Yanagisawa D, Tooyama I (2013) Mitochondrial ferritin in neurodegenerative diseases. Neurosci Res 77:1–7

    CAS  PubMed  Google Scholar 

  • Yengil E, Acipayam C, Kokacya MH, Kurhan F, Oktay G, Ozer C (2014) Anxiety, depression and quality of life in patients with beta thalassemia major and their caregivers. Int J Clin Exp Med 7:2165–2172

    PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Que K, Zhang Z, Yi ZJ, Zhao PX, You Y, Gong J, Liu Z (2018) Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl-p53 pathway. Cancer Med 7:4012–4022

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank the staff of the Thalassemia Unit at Al-Zahra’a Teaching Hospital-Najaf city-Iraq for their help in the collection of samples. We also acknowledge the work of the highly skilled staff of the Asia Laboratory in measuring the biomarkers.

Author information

Authors and Affiliations

  1. Department of Chemistry, College of Science, University of Kufa, Najaf, Iraq

    Hussein Kadhem Al-Hakeim & Asawer Hassan Najm

  2. College of Medicine, University of Kufa, Kufa, Iraq

    Arafat Hussein Al-Dujaili

  3. Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand

    Michael Maes

  4. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  5. IMPACT Strategic Research Centre, Deakin University, PO Box 281, Geelong, VIC, 3220, Australia

    Michael Maes

Authors
  1. Hussein Kadhem Al-Hakeim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asawer Hassan Najm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arafat Hussein Al-Dujaili
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the contributing authors have participated in the preparation of the manuscript.

Corresponding author

Correspondence to Michael Maes.

Ethics declarations

The study was approved by the IRB of University of Kufa number 487/2018.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Hakeim, H.K., Najm, A.H., Al-Dujaili, A.H. et al. Major Depression in Children with Transfusion-Dependent Thalassemia Is Strongly Associated with the Combined Effects of Blood Transfusion Rate, Iron Overload, and Increased Pro-inflammatory Cytokines. Neurotox Res 38, 228–241 (2020). https://doi.org/10.1007/s12640-020-00193-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-020-00193-1

Keywords

Search

Navigation