Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Pathophysiology of the sideroblastic anemias

Sylvia S Bottomley, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD


Sideroblastic anemias feature congenital or acquired defects affecting the biosynthesis of heme, iron-sulfur (Fe-S) cluster generation, or mitochondrial protein synthesis within red cell precursors. The diverse circumstances under which these disorders are encountered, and the continuing discovery of molecular defects associated with the phenotype, underscore a broad spectrum of causes [1-4]. Yet, in a large proportion of patients the underlying mechanism remains undefined [1,4-6]. A conventional classification of the sideroblastic anemias provides an inclusive reference for their discussion and diagnosis (table 1).

In order to maintain a continual replacement of senescent red cells, approximately 85 percent of body heme is generated within the erythron. Heme synthesis is directly impaired in the two common forms of congenital sideroblastic anemia: the X-linked form because of deficient erythroid 5-aminolevulinate synthase (ALAS2), and the autosomal recessive disorder because of defects in the erythroid mitochondrial transporter SLC25A38. In the other congenital and most acquired forms, the production of heme is impaired secondarily (eg, when defects disrupt Fe-S cluster biogenesis), or the pathogenesis of the ring sideroblast abnormality is not defined. (See "Causes of congenital and acquired sideroblastic anemias".)

Deranged heme synthesis in the developing red cell leads to decreased hemoglobin production with the formation of hypochromic and microcytic red cells and other misshaped erythrocytes (picture 1). These red cells are the progeny of the ring sideroblasts that constitute the diagnostic hallmark of any sideroblastic anemia and are detected in the Prussian blue stained smear of the marrow aspirate, as shown in the upper panel (picture 2). The ultrastructure of the iron-positive cytoplasmic granules of ring sideroblasts is indicated by electron dense deposits within mitochondria, as shown in the lower panel (picture 2), reflecting accumulated iron, in a unique mitochondrial ferritin [7,8], that has been delivered to the developing erythroblast normally, but cannot be utilized. In those sideroblastic anemias in which cellular hemoglobin production does not appear to be affected, the red cell morphology is normocytic or macrocytic.

This topic review will address the physiologic consequences of defective heme production, namely the ineffective erythropoiesis and the associated iron overload. The molecular pathology of recognized genetic defects leading to impaired heme synthesis and other abnormalities in the sideroblastic anemias are discussed separately. (See "Causes of congenital and acquired sideroblastic anemias".) The clinical manifestations, diagnosis, and treatment of these disorders are also discussed separately. (See "Sideroblastic anemias: Diagnosis and management".)


The presence of ineffective erythropoiesis is suspected on morphologic grounds when anemia is associated with erythroid hyperplasia in the bone marrow in the absence of a reticulocyte response in the peripheral blood. In this situation, erythroid progenitor cells are intact, and erythropoietin production in response to anemic hypoxia is appropriately increased. However, cellular maturation involving either nuclear (DNA synthesis) or cytoplasmic (hemoglobin production) processes is disrupted, giving rise to faulty erythroblasts, many of which are destroyed within the bone marrow (ie, intramedullary hemolysis) via mechanisms that include apoptosis [9,10].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jan 2017. | This topic last updated: Wed Jul 24 00:00:00 GMT+00:00 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Bottomley SS. Sideroblastic anemias. In: Wintrobe's Clinical Hematology, 13th ed, Greer JP, Arber DA, Glader B, et al. (Eds), Lippincott, Williams and Wilkins, Philadelphia 2014. p.643.
  2. Fleming MD. Congenital sideroblastic anemias: iron and heme lost in mitochondrial translation. Hematology Am Soc Hematol Educ Program 2011; 2011:525.
  3. Camaschella C. Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol 2008; 143:27.
  4. Cazzola M, Invernizzi R. Ring sideroblasts and sideroblastic anemias. Haematologica 2011; 96:789.
  5. Bergmann AK, Campagna DR, McLoughlin EM, et al. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer 2010; 54:273.
  6. Ducamp S, Kannengiesser C, Touati M, et al. Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. Hum Mutat 2011; 32:590.
  7. Levi S, Corsi B, Bosisio M, et al. A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 2001; 276:24437.
  8. Cazzola M, Invernizzi R, Bergamaschi G, et al. Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood 2003; 101:1996.
  9. Matthes TW, Meyer G, Samii K, Beris P. Increased apoptosis in acquired sideroblastic anaemia. Br J Haematol 2000; 111:843.
  10. Hellström-Lindberg E, Schmidt-Mende J, Forsblom AM, et al. Apoptosis in refractory anaemia with ringed sideroblasts is initiated at the stem cell level and associated with increased activation of caspases. Br J Haematol 2001; 112:714.
  11. Tehranchi R, Invernizzi R, Grandien A, et al. Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes. Blood 2005; 106:247.
  12. Schmidt-Mende J, Tehranchi R, Forsblom AM, et al. Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts. Leukemia 2001; 15:742.
  13. Tehranchi R, Fadeel B, Forsblom AM, et al. Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors. Blood 2003; 101:1080.
  14. Finch CA, Deubelbeiss K, Cook JD, et al. Ferrokinetics in man. Medicine (Baltimore) 1970; 49:17.
  15. Barrett PV, Cline MJ, Berlin NI. The association of the urobilin "early peak" and erythropoiesis in man. J Clin Invest 1966; 45:1657.
  16. Cotter PD, May A, Fitzsimons EJ, et al. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest 1995; 96:2090.
  17. White JM, Ali MA. Globin synthesis in sideroblastic anaemia. II. The effect of pyridoxine, -aminolaevulinic acid and haem, in vitro. Br J Haematol 1973; 24:481.
  18. Chen JJ. Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood 2007; 109:2693.
  19. Bottomley SS. The spectrum and role of iron overload in sideroblastic anemia. Ann N Y Acad Sci 1988; 526:331.
  20. May A, de Souza P, Barnes K, et al. Erythroblast iron metabolism in sideroblastic marrows. Br J Haematol 1982; 52:611.
  21. Lill R. Function and biogenesis of iron-sulphur proteins. Nature 2009; 460:831.
  22. Rouault TA. Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease. Dis Model Mech 2012; 5:155.
  23. Ye H, Rouault TA. Erythropoiesis and iron sulfur cluster biogenesis. Adv Hematol 2010; 2010.
  24. Ye H, Jeong SY, Ghosh MC, et al. Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 2010; 120:1749.
  25. Nikpour M, Scharenberg C, Liu A, et al. The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts. Leukemia 2013; 27:889.
  26. Bottomley SS. Iron overload in sideroblastic and other non-thalassemic anemias. In: Hemochromatosis. Genetics, Pathophysiology, Diagnosis and Treatment, Barton JC, Edwards CQ (Eds), Cambridge University Press, Cambridge 2000. p.442.
  27. Peto TE, Pippard MJ, Weatherall DJ. Iron overload in mild sideroblastic anaemias. Lancet 1983; 1:375.
  28. Marcus RE. Iron overload in mild sideroblastic anaemia. Lancet 1983; 1:1276.
  29. Bottomley SS. Sideroblastic anemia: Death from iron overload. Hosp Pract 1991; 26(suppl 3):55.
  30. Heller T, Höchstetter V, Basler M, Borck V. [Vitamin B6-sensitive hereditary sideroblastic anemia]. Dtsch Med Wochenschr 2004; 129:141.
  31. Cazzola M, Barosi G, Bergamaschi G, et al. Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias. Br J Haematol 1983; 54:649.
  32. Yaouanq J, Grosbois B, Jouanolle AM, et al. Haemochromatosis Cys282Tyr mutation in pyridoxine-responsive sideroblastic anaemia. Lancet 1997; 349:1475.
  33. Cotter PD, May A, Li L, et al. Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis. Blood 1999; 93:1757.
  34. Nearman ZP, Szpurka H, Serio B, et al. Hemochromatosis-associated gene mutations in patients with myelodysplastic syndromes with refractory anemia with ringed sideroblasts. Am J Hematol 2007; 82:1076.
  35. Pootrakul P, Kitcharoen K, Yansukon P, et al. The effect of erythroid hyperplasia on iron balance. Blood 1988; 71:1124.
  36. Papanikolaou G, Tzilianos M, Christakis JI, et al. Hepcidin in iron overload disorders. Blood 2005; 105:4103.
  37. Nemeth E. Iron regulation and erythropoiesis. Curr Opin Hematol 2008; 15:169.
  38. Tanno T, Miller JL. Iron Loading and Overloading due to Ineffective Erythropoiesis. Adv Hematol 2010; 2010:358283.
  39. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med 2011; 62:347.
  40. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13:1096.
  41. Tanno T, Noel P, Miller JL. Growth differentiation factor 15 in erythroid health and disease. Curr Opin Hematol 2010; 17:184.
  42. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 2009; 114:181.
  43. Bottomley SS, Wasson EG, Wise PD. Role of the hemochromatosis HFE gene mutation(s) in the iron overload of hereditary sideroblastic anemia (abstract). Blood 1997; 90:11b.
  44. Beris P, Samii K, Darbellay R, et al. Iron overload in patients with sideroblastic anaemia is not related to the presence of the haemochromatosis Cys282Tyr and His63Asp mutations. Br J Haematol 1999; 104:97.
  45. French TJ, Jacobs P. Sideroblastic anaemia associated with iron overload treated by repeated phlebotomy. S Afr Med J 1976; 50:594.
  46. Jensen PD, Heickendorff L, Pedersen B, et al. The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol 1996; 94:288.
  47. Hofmann WK, Kaltwasser JP, Hoelzer D, et al. Successful treatment of iron overload by phlebotomies in a patient with severe congenital dyserythropoietic anemia type II. Blood 1997; 89:3068.