The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterised by anaemia of varying severity and the presence of ring sideroblasts in the bone marrow. Sideroblastic anaemia is characterised by isolated erythroid dysplasia with <5% blasts and at least 15% ringed sideroblasts in the bone marrow.The International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) has recommended that ring sideroblasts be defined as erythroblasts in which there is a minimum of five siderotic granules covering at least one third of the circumference of the nucleus.
The sideroblasts form due to reduced haemoglobin synthesis, resulting in the accumulation of iron within red blood cell precursors. Cases may be congenital or acquired. Cases are more often acquired and sometimes represent a stage in the development of myelodysplastic syndromes (MDS).
Refractory anaemia with ringed sideroblasts (RARS) may account for 5-15% of all MDS cases.
- The most common inherited sideroblastic anaemia is X-linked sideroblastic anaemia (XLSA) caused by mutations of the erythroid-specific delta-aminolevulinic acid synthase 2 gene (ALAS2). Sideroblastic anaemia due to SLC25A38 gene mutations is the next most common inherited sideroblastic anaemia.[6, 7]
- Congenital causes of sideroblastic anaemia also include Wolfram's syndrome. There are two types, each caused by a genetic error on a different chromasome. Wolfram's syndrome 1 is characterised by DIDMOAD (= Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness). Wolfram's syndrome 2 is characterised by early optic atrophy, diabetes mellitus, deafness, decreased lifespan but not diabetes insipidus.
In addition to MDS, sideroblastic anaemia can also occur in other bone marrow diseases including:
- Polycythaemia rubra vera
Secondary causes include:
- Inflammatory conditions - eg, rheumatoid arthritis.
- Systemic lupus erythematosus.
- Chronic infections.
- Drug toxicity - eg, chloramphenicol, cycloserine, antituberculous agents.
- Chronic alcoholism.
- Haemolytic anaemia.
- Nutritional deficiencies - eg, copper, vitamin B6; malabsorption syndromes.
- Lead poisoning.
- Zinc overdose.
- Clinical features are those related to anaemia in general. Symptoms reflect the cytopenias, ie anaemia, infection, bruising and haemorrhage.
- There are no specific signs or symptoms related to sideroblastic anaemia alone.
Diagnosis is made from bone marrow examination demonstrating the presence of ring sideroblasts with a generalised increase in iron stores.
- FBC usually shows a moderate degree of anaemia.
- The mean corpuscular volume (MCV) is normal or increased, but can be low.
- High serum iron and transferrin saturation also occur.
- The blood film shows a dimorphic population of both normal and hypochromic red blood cells.
- Treatment is mainly supportive.
- Red cell transfusion is given for symptomatic anaemia.
- Iron chelation with desferrioxamine should be considered after 20-25 units of red cells have been received.
- Avoid alcohol and reduce vitamin C intake, as these increase iron absorption.
- The use of recombinant erythropoietin (EPO) and granulocyte colony-stimulating factor has been demonstrated to reduce symptoms and may also increase survival.
- Patients with hereditary sideroblastic anaemia may respond to pyridoxine.
- Ciclosporin has been shown to give a response rate (ie alteration of disease progression or remission) of 62.5% in patients with MDS including sideroblastic anaemia.
- Emerging therapies include the use of the hypomethylating agents decitabine and azacitidine and the immunomodulatory drugs lenalidomide and azacitidine.
- Allogenic peripheral stem cell transplantation has been used with success in pyridoxine-refractory hereditary sideroblastic anaemia. Few patients are eligible for transplant.
- The prognosis is very variable.
- Reversible causes (eg, alcohol or drugs) appear to have no long-term effects if the underlying cause is successfully treated or removed.
- Patients continuing to need regular blood transfusions, those who have conditions unresponsive to treatment, and those with MDS often have a much worse prognosis.
- Patients with idiopathic sideroblastic anaemia and MDS have a median survival of 38 months. Those with pure sideroblastic anaemia (abnormal erythropoiesis only) have a median survival of 60 months.
- Favourable prognostic indicators include thrombocytosis and needing fewer blood transfusions.
- Causes of death include haemochromatosis, resulting from transfusions, and leukaemia.
Further reading and references
Kaneko K, Furuyama K, Fujiwara T, et al; Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia. Haematologica. 2014 Feb99(2):252-61. doi: 10.3324/haematol.2013.085449. Epub 2013 Aug 9.
Chiabrando D, Mercurio S, Tolosano E; Heme and erythropoieis: more than a structural role. Haematologica. 2014 Jun99(6):973-83. doi: 10.3324/haematol.2013.091991.
Cazzola M, Invernizzi R; Ring sideroblasts and sideroblastic anemias. Haematologica. 2011 Jun96(6):789-92.
Sideroblastic Anaemia; Royal College of Pathologists of Australasia, 2015
Mufti GJ, Bennett JM, Goasguen J, et al; Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts. Haematologica. 2008 Nov93(11):1712-7. Epub 2008 Oct 6.
Refractory anemia with ringed sideroblasts (RARS); Atlas of Genetics and Cytogenetics in Oncology and Haematology
Anemia, Sideroblastic, X-linked, XLSA; Online Mendelian Inheritance in Man (OMIM)
Camaschella C; Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol. 2008 Sep143(1):27-38. Epub 2008 Jul 14.
Harigae H, Furuyama K; Hereditary sideroblastic anemia: pathophysiology and gene mutations. Int J Hematol. 2010 Oct92(3):425-31. Epub 2010 Sep 17.
Rigoli L, Di Bella C; Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr. 2012 Aug24(4):512-7. doi: 10.1097/MOP.0b013e328354ccdf.
Mir MA et al; Sideroblastic Anemias, Medscape, Nov 2015
Knovich MA, Storey JA, Coffman LG, et al; Ferritin for the clinician. Blood Rev. 2009 May23(3):95-104. doi: 10.1016/j.blre.2008.08.001. Epub 2008 Oct 2.
Ascorbic acid; Pubchem, 2011 (updated 2015).
Newman K, Maness-Harris L, El-Hemaidi I, et al; Revisiting use of growth factors in myelodysplastic syndromes. Asian Pac J Cancer Prev. 201213(4):1081-91.
Chen S, Jiang B, Da W, et al; Treatment of myelodysplastic syndrome with cyclosporin A. Int J Hematol. 2007 Jan85(1):11-7.
Loiseau C, Ali A, Itzykson R; New therapeutic approaches in myelodysplastic syndromes: Hypomethylating agents and lenalidomide. Exp Hematol. 2015 Aug43(8):661-72. doi: 10.1016/j.exphem.2015.05.014. Epub 2015 Jun 27.
Palmer SR, Tefferi A, Hanson CA, et al; Platelet count is an IPSS-independent risk factor predicting survival in refractory anaemia with ringed sideroblasts. Br J Haematol. 2008 Mar140(6):722-5. Epub 2008 Jan 29.
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