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Sideroblastic anemias: Diagnosis and management

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

INTRODUCTION

The sideroblastic anemias comprise a wide spectrum of relatively uncommon heritable and acquired erythropoietic disorders that are due to various abnormalities in heme synthesis and mitochondrial function (table 1).

In many of these disorders, the severity of the anemia is quite variable; it is uncommon for the peripheral blood findings to be characteristic. Thus, a sideroblastic anemia should be considered in all infants, children, and adults with anemia of any severity when it is unexplained by the patient’s history, clinical examination, and basic laboratory data.

The singular feature that typifies all forms of sideroblastic anemia is the presence of ring sideroblasts in the bone marrow aspirate.

The clinical course and management of these heterogeneous disorders are highly dependent on the underlying cause.

An approach to the patient with suspected sideroblastic anemia is discussed here, along with distinguishing clinical features, diagnostic evaluation, and management. Comprehensive discussions of the inherited and acquired sideroblastic anemias, including genetic defects and pathophysiology, are presented separately. (See "Pathophysiology of the sideroblastic anemias".)

                              

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Literature review current through: Nov 2016. | This topic last updated: Fri Oct 14 00:00:00 GMT 2016.
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References
Top
  1. Dobyns WB, Filauro A, Tomson BN, et al. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet A 2004; 129A:136.
  2. Sankaran VG, Ulirsch JC, Tchaikovskii V, et al. X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation. J Clin Invest 2015; 125:1665.
  3. Aivado M, Gattermann N, Rong A, et al. X-linked sideroblastic anemia associated with a novel ALAS2 mutation and unfortunate skewed X-chromosome inactivation patterns. Blood Cells Mol Dis 2006; 37:40.
  4. Bottomley SS, Wise PD, Wasson EG, et al. X-linked sideroblastic anemia in ten female probands due to ALAS2 mutations and skewed X chromosome inactivation. Am J Hum Genet 1998; 63:A352.
  5. Garçon L, Kannengiesser C. A double red cells population in a woman with a microcytic anemia. Blood 2014; 123:808.
  6. Cortesão E, Vidan J, Pereira J, et al. Onset of X-linked sideroblastic anemia in the fourth decade. Haematologica 2004; 89:1261.
  7. Rose C, Callebaut I, Pascal L, et al. Lethal ALAS2 mutation in males X-linked sideroblastic anaemia. Br J Haematol 2016.
  8. 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.
  9. Bekri S, Kispal G, Lange H, et al. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood 2000; 96:3256.
  10. Maguire A, Hellier K, Hammans S, May A. X-linked cerebellar ataxia and sideroblastic anaemia associated with a missense mutation in the ABC7 gene predicting V411L. Br J Haematol 2001; 115:910.
  11. Pagon RA, Bird TD, Detter JC, Pierce I. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder. J Med Genet 1985; 22:267.
  12. Allikmets R, Raskind WH, Hutchinson A, et al. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 1999; 8:743.
  13. Lichtenstein DA, Crispin AW, Sendamarai AK, et al. A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia. Blood 2016; 128:1913.
  14. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  15. Schmitt-Graeff AH, Teo SS, Olschewski M, et al. JAK2V617F mutation status identifies subtypes of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica 2008; 93:34.
  16. Broséus J, Alpermann T, Wulfert M, et al. Age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis. Leukemia 2013; 27:1826.
  17. Malcovati L, Karimi M, Papaemmanuil E, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood 2015; 126:233.
  18. Gattermann N, Aul C, Schneider W. Two types of acquired idiopathic sideroblastic anaemia (AISA). Br J Haematol 1990; 74:45.
  19. Germing U, Gattermann N, Aivado M, et al. Two types of acquired idiopathic sideroblastic anaemia (AISA): a time-tested distinction. Br J Haematol 2000; 108:724.
  20. Halfdanarson TR, Kumar N, Hogan WJ, Murray JA. Copper deficiency in celiac disease. J Clin Gastroenterol 2009; 43:162.
  21. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc 2006; 81:1371.
  22. Prodan CI, Bottomley SS, Vincent AS, et al. Copper deficiency after gastric surgery: a reason for caution. Am J Med Sci 2009; 337:256.
  23. Sonu RJ, Rashidi HH. Concurrent copper and iron deficiency in a gastric bypass patient: a great mimicker of MDS. Blood 2015; 125:2582.
  24. von Drygalski A, Andris DA. Anemia after bariatric surgery: more than just iron deficiency. Nutr Clin Pract 2009; 24:217.
  25. Choi EH, Strum W. Hypocupremia-related myeloneuropathy following gastrojejunal bypass surgery. Ann Nutr Metab 2010; 57:190.
  26. Gregg XT, Reddy V, Prchal JT. Copper deficiency masquerading as myelodysplastic syndrome. Blood 2002; 100:1493.
  27. Vilter RW, Bozian RC, Hess EV, et al. Manifestations of copper deficiency in a patient with systemic sclerosis on intravenous hyperalimentation. N Engl J Med 1974; 291:188.
  28. Takeuchi M, Tada A, Yoshimoto S, Takahashi K. [Anemia and neutropenia due to copper deficiency during long-term total parenteral nutrition]. Rinsho Ketsueki 1993; 34:171.
  29. Banno S, Niita M, Kikuchi M, et al. [Anemia and neutropenia in elderly patients caused by copper deficiency for long-term enteral nutrition]. Rinsho Ketsueki 1994; 35:1276.
  30. Nagano T, Toyoda T, Tanabe H, et al. Clinical features of hematological disorders caused by copper deficiency during long-term enteral nutrition. Intern Med 2005; 44:554.
  31. Pirruccello E, Luu HS, Chen W. Haematogone hyperplasia in copper deficiency. Br J Haematol 2016; 173:335.
  32. Fiske DN, McCoy HE 3rd, Kitchens CS. Zinc-induced sideroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome. Am J Hematol 1994; 46:147.
  33. Irving JA, Mattman A, Lockitch G, et al. Element of caution: a case of reversible cytopenias associated with excessive zinc supplementation. CMAJ 2003; 169:129.
  34. Broun ER, Greist A, Tricot G, Hoffman R. Excessive zinc ingestion. A reversible cause of sideroblastic anemia and bone marrow depression. JAMA 1990; 264:1441.
  35. Hassan HA, Netchvolodoff C, Raufman JP. Zinc-induced copper deficiency in a coin swallower. Am J Gastroenterol 2000; 95:2975.
  36. Kumar A, Jazieh AR. Case report of sideroblastic anemia caused by ingestion of coins. Am J Hematol 2001; 66:126.
  37. Pawa S, Khalifa AJ, Ehrinpreis MN, et al. Zinc toxicity from massive and prolonged coin ingestion in an adult. Am J Med Sci 2008; 336:430.
  38. Nations SP, Boyer PJ, Love LA, et al. Denture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology 2008; 71:639.
  39. Hedera P, Peltier A, Fink JK, et al. Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin II. The denture cream is a primary source of excessive zinc. Neurotoxicology 2009; 30:996.
  40. Perry AR, Pagliuca A, Fitzsimons EJ, et al. Acquired sideroblastic anaemia induced by a copper-chelating agent. Int J Hematol 1996; 64:69.
  41. Cousins RJ. Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol Rev 1985; 65:238.
  42. Prodan CI, Holland NR, Wisdom PJ, et al. CNS demyelination associated with copper deficiency and hyperzincemia. Neurology 2002; 59:1453.
  43. Prodan CI, Holland NR, Wisdom PJ, Bottomley SS. Myelopathy due to copper deficiency. Neurology 2004; 62:1655.
  44. Kumar N, Gross JB Jr, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004; 63:33.
  45. Willis MS, Monaghan SA, Miller ML, et al. Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 2005; 123:125.
  46. Rowin J, Lewis SL. Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation. J Neurol Neurosurg Psychiatry 2005; 76:750.
  47. Kumar N, Elliott MA, Hoyer JD, et al. "Myelodysplasia," myeloneuropathy, and copper deficiency. Mayo Clin Proc 2005; 80:943.
  48. Greenberg SA, Briemberg HR. A neurological and hematological syndrome associated with zinc excess and copper deficiency. J Neurol 2004; 251:111.
  49. Prodan CI, Bottomley SS, Holland NR, Lind SE. Relapsing hypocupraemic myelopathy requiring high-dose oral copper replacement. J Neurol Neurosurg Psychiatry 2006; 77:1092.
  50. Roberts PD, Hoffbrand AV, Mollin DL. Iron and folate metabolism in tuberculosis. Br Med J 1966; 2:198.
  51. Piso RJ, Kriz K, Desax MC. Severe isoniazid related sideroblastic anemia. Hematol Rep 2011; 3:e2.
  52. Demiroglu H, Dündar S. Vitamin B6 responsive sideroblastic anaemia in a patient with tuberculosis. Br J Clin Pract 1997; 51:51.
  53. Bottomley SS. Sideroblastic anaemia. In: Iron in Biochemistry and Medicine II, Jacobs A, Worwood M (Eds), Academic Press, London 1980. p.363.
  54. Haden HT. Pyridoxine-responsive sideroblastic anemia due to antituberculous drugs. Arch Intern Med 1967; 120:602.
  55. Hines JD, Love DS. Determination of serum and blood pyridoxal phosphate concentrations with purified rabbit skeletal muscle apophosphorylase b. J Lab Clin Med 1969; 73:343.
  56. Standal BR, Kao-Chen SM, Yang GY, Char DF. Early changes in pyridoxine status of patients receiving isoniazid therapy. Am J Clin Nutr 1974; 27:479.
  57. Beck EA, Ziegler G, Schmid R, Lüdin H. Reversible sideroblastic anemia caused by chloramphenicol. Acta Haematol 1967; 38:1.
  58. SCOTT JL, FINEGOLD SM, BELKIN GA, LAWRENCE JS. A CONTROLLED DOUBLE-BLIND STUDY OF THE HEMATOLOGIC TOXICITY OF CHLORAMPHENICOL. N Engl J Med 1965; 272:1137.
  59. Kloss P, Xiong L, Shinabarger DL, Mankin AS. Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center. J Mol Biol 1999; 294:93.
  60. Montpetit MC, Shammo JL, Loew J, et al. Sideroblastic anemia due to linezolid in a patient with a left ventricular assist device. J Heart Lung Transplant 2004; 23:1119.
  61. Saini N, Jacobson JO, Jha S, et al. The perils of not digging deep enough--uncovering a rare cause of acquired anemia. Am J Hematol 2012; 87:413.
  62. Vial T, Grignon M, Daumont M, et al. Sideroblastic anaemia during fusidic acid treatment. Eur J Haematol 2004; 72:358.
  63. Condamine L, Hermine O, Alvin P, et al. Acquired sideroblastic anaemia during treatment of Wilson's disease with triethylene tetramine dihydrochloride. Br J Haematol 1993; 83:166.
  64. Kandola L, Swannell AJ, Hunter A. Acquired sideroblastic anaemia associated with penicillamine therapy for rheumatoid arthritis. Ann Rheum Dis 1995; 54:529.
  65. Colucci G, Silzle T, Solenthaler M. Pyrazinamide-induced sideroblastic anemia. Am J Hematol 2012; 87:305.
  66. Savage D, Lindenbaum J. Anemia in alcoholics. Medicine (Baltimore) 1986; 65:322.
  67. Eichner ER, Hillman RS. The evolution of anemia in alcoholic patients. Am J Med 1971; 50:218.
  68. 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.
  69. 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.
  70. Liu G, Guo S, Kang H, et al. Mutation spectrum in Chinese patients affected by congenital sideroblastic anemia and a search for a genotype-phenotype relationship. Haematologica 2013; 98:e158.
  71. 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.
  72. Bottomley SS, Fleming MD. Sideroblastic anemia: diagnosis and management. Hematol Oncol Clin North Am 2014; 28:653.
  73. MOLLIN DL. SIDEROBLASTS AND SIDEROBLASTIC ANAEMIA. Br J Haematol 1965; 11:41.
  74. Bottomley SS. Sideroblastic anaemia. Clin Haematol 1982; 11:389.
  75. Bottomley SS, Muller-Eberhard U. Pathophysiology of heme synthesis. Semin Hematol 1988; 25:282.
  76. Urban C, Binder B, Hauer C, Lanzer G. Congenital sideroblastic anemia successfully treated by allogeneic bone marrow transplantation. Bone Marrow Transplant 1992; 10:373.
  77. González MI, Caballero D, Vázquez L, et al. Allogeneic peripheral stem cell transplantation in a case of hereditary sideroblastic anaemia. Br J Haematol 2000; 109:658.
  78. Ayas M, Al-Jefri A, Mustafa MM, et al. Congenital sideroblastic anaemia successfully treated using allogeneic stem cell transplantation. Br J Haematol 2001; 113:938.
  79. Medeiros BC, Kolhouse JF, Cagnoni PJ, et al. Nonmyeloablative allogeneic hematopoietic stem cell transplantation for congenital sideroblastic anemia. Bone Marrow Transplant 2003; 31:1053.
  80. Meo A, Ruggeri A, La Rosa MA, et al. Iron burden and liver fibrosis decrease during a long-term phlebotomy program and iron chelating treatment after bone marrow transplantation. Hemoglobin 2006; 30:131.
  81. Wiseman DH, May A, Jolles S, et al. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood 2013; 122:112.
  82. Urban CH, Deutschmann A, Kerbl R, et al. Organ tolerance following cadaveric liver transplantation for chronic graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 2002; 30:535.
  83. Wood JC. Use of magnetic resonance imaging to monitor iron overload. Hematol Oncol Clin North Am 2014; 28:747.
  84. 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.
  85. Cox TC, Bottomley SS, Wiley JS, et al. X-linked pyridoxine-responsive sideroblastic anemia due to a Thr388-to-Ser substitution in erythroid 5-aminolevulinate synthase. N Engl J Med 1994; 330:675.
  86. Bergmann AK, Sahai I, Falcone JF, et al. Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update. J Pediatr 2009; 155:888.
  87. Bachmeyer C, Ferroir JP, Eymard B, et al. Coenzyme Q is effective on anemia in a patient with sideroblastic anemia and mitochondrial myopathy. Blood 2010; 116:3681.
  88. 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.
  89. Tanno T, Miller JL. Iron Loading and Overloading due to Ineffective Erythropoiesis. Adv Hematol 2010; 2010:358283.
  90. Marcus RE. Iron overload in mild sideroblastic anaemia. Lancet 1983; 1:1276.
  91. Peto TE, Pippard MJ, Weatherall DJ. Iron overload in mild sideroblastic anaemias. Lancet 1983; 1:375.
  92. Barton JC, Lee PL. Disparate phenotypic expression of ALAS2 R452H (nt 1407 G --> A) in two brothers, one with severe sideroblastic anemia and iron overload, hepatic cirrhosis, and hepatocellular carcinoma. Blood Cells Mol Dis 2006; 36:342.
  93. Cuijpers ML, van Spronsen DJ, Muus P, et al. Need for early recognition and therapeutic guidelines of congenital sideroblastic anaemia. Int J Hematol 2011; 94:97.
  94. Bottomley SS. The spectrum and role of iron overload in sideroblastic anemia. Ann N Y Acad Sci 1988; 526:331.
  95. Hines JD. Effect of pyridoxine plus chronic phlebotomy on the function and morphology of bone marrow and liver in pyridoxine-responsive sideroblastic anemia. Semin Hematol 1976; 13:133.
  96. BYRD RB, COOPER T. Hereditary iron-loading anemia with secondary hemochromatosis. Ann Intern Med 1961; 55:103.
  97. Aleali SH, Castro O, Spencer RP, Finch SC. Sideroblastic anemia with splenic abscess and fatal thromboemboli after splenectomy. Ann Intern Med 1975; 83:661.
  98. Bottomley SS. Sideroblastic anemia: Death from iron overload. Hosp Pract 1991; 26(suppl 3):55.
  99. Byrne MT, Bergman AK, Ruiz AI, et al. Postsplenectomy thromboembolic disease in congenital sideroblastic anaemia. BMJ Case Rep 2010; 2010.
  100. Kakourou G, Vrettou C, Kattamis A, et al. Complex preimplantation genetic diagnosis for beta-thalassaemia, sideroblastic anaemia, and human leukocyte antigen (HLA)-typing. Syst Biol Reprod Med 2016; 62:69.