Sideroblastic anemia

Description, Causes and Risk Factors: Alternative Name: Refractory anaemia with ringed sideroblasts (RARS). Abbreviation: SA. The sideroblastic anemias are disorders of ineffective erythropoiesis, collectively characterized by abnormal Prussian blue-positive granules (i.e., iron-stuffed mitochondria) that encircle marrow erythroblast nuclei to form ringed sideroblast cells. There are three categories of sideroblastic anemias: inherited, acquired, and idiopathic. The etiology, epidemiology, pathophysiology and treatment of these conditions differ vastly. The mitochondrion is the nexus of sideroblastic anemia, however. Disturbed mitochondrial metabolism is at the center of all sideroblastic anemias in which a cause has been determined. SAs are usually acquired, but occasionally congenital. While the causes of the common acquired forms of SA remain largely unknown, the molecular genetics of several of the inherited forms of SA is now well understood. For instance, X-linked SA is often associated with germline mutations in the erythroid-specific isoform of 5-aminolevulinate synthase gene (ALAS2), and several mitochondrial metabolic defects have also been linked to inherited SAs. However, there are still many congenital SA cases of unknown molecular origin. Thirteen different ALAS2 mutations were identified in 16 out of 29 probands with sideroblastic anemia. One third of the patients were females with a highly skewed X-chromosome inactivation. The identification of seven novel mutations in the ALAS2 gene, six missense mutations, and one deletion in the proximal promoter extends the allelic heterogeneity of XSLA. Most of the missense mutations were predicted to be deleterious and ten of them, without any published functional characterization, were expressed in E. coli. ALAS2 activities were assayed in vitro. Five missense mutations resulted in decreased enzymatic activity under standard conditions, and two other mutated proteins had decreased activity when assayed in the absence of exogenous pyridoxal phosphate and increased thermosensitivity. Although most amino-acid substitutions result in a clearly decreased enzymatic activity in vitro, a few mutations have a more subtle effect on the protein that is only revealed by in vitro tests under specific conditions. The precise relationship between SA and erythropoietic protoporphyria (EPP) is unclear. A substantial fraction of patients with EPP have anemia (48% of women and 33% of men in the largest series), which is usually mild and associated with diminished iron stores. Ferrochelatase, the enzyme deficient in EPP, is encoded by the FECH locus at 18q21.3 and catalyzes the final step in heme biosynthesis: addition of ferrous iron to the protoporphyrin ring. In one analysis of EPP patients, scattered ringed sideroblasts were observed by light microscopy in the bone marrows of 7 patients, while mitochondrial electron energy-loss spectroscopy (EELS) indicated SA-like iron compounds in all 9 samples. Additionally, a 1973 report described a case of EPP with fatal liver disease associated with SA-like features. Despite these observations, most idiopathic acquired SA cases do not have FECH mutations, even though modest elevations of erythrocyte protoporphyrin levels are common in this group. Other secondary causes may include:
  • Systemic lupus erythematosus (SLE).
  • Inflammatory conditions such as rheumatoid arthritis.
  • Chronic infections.
  • Drug toxicity.
  • Chronic alcoholism.
  • Hemolytic anaemia.
  • Malabsorption syndromes.
  • Myxedema.
  • Lead poisoning.
  • Pregnancy.
Symptoms: The signs and symptoms can range from mild to severe, and include fatigue, breathing difficulties, and weakness. Enlargement of the liver or spleen may also occur. In severe cases, the increased levels of iron in the blood may lead to heart disease, liver damage, and kidney failure. Diagnosis:
  • Diagnosis is made from bone marrow examination demonstrating the presence of ring sideroblasts with a generalized increase in iron stores.
  • A full blood count (FBC) usually shows a moderate anemia.
  • The mean corpuscular volume (MCV) is normal or increased, but can be low.
  • High serum iron and transferring saturation also occur.
  • The blood film shows a dimorphic population of both normal and hypochromic red blood cells.
Treatment: General measures:
  • Treatment is mainly supportive.
  • Red cell transfusion is given for symptomatic anemia.
  • Iron chelation with deferoxamine should be considered after 20-25 units of red cells have been received.
  • Avoid alcohol and vitamin C as these increase iron absorption.
Pharmacological Options:
  • The use of erythropoietin plus or minus granulocyte colony-stimulating factor has been demonstrated to reduce the need for red cell transfusion in some patients with myelodysplastic syndrome but the studies were small.
  • Patients with hereditary sideroblastic anemia may respond to pyridoxine.
  • Cyclosporin A has been shown to give a response rate (i.e. alteration of disease progression or remission) of 62.5% in patients with myelodysplastic syndromes including sideroblastic anaemia.
  • New therapies are emerging, approved by the United States FDA in 2004. There are two DNA methyltransferase inhibitors (azacitidine and decitabine) and an immunomodulatory agent (lenalidomide).
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.  


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