Sideroblastic anemias

Chapter on pathogenesis and clinical features of sideroblastic anemias. Males with hereditary X-linked sideroblastic anemia may present in the first two decades of life with symptoms of anemia, or later with either anemia and/or symptoms and signs of parenchymal iron overload. Occasional patients, both men and women, may be diagnosed with this constitutional disease late in life. Distinctive features of XLSA are microcytic anemia with hypochromic red cells, increased RDW, and parenchymal iron overload. Patients with acquired refractory anemia with ringed sideroblasts (RARS) have a median age of about 65 years and present with isolated anemia. The anemia is typically macrocytic; leukocyte and platelet counts are generally normal at diagnosis, and most patients have some evidence of iron overload, as indicated by increased serum iron, transferrin saturation and serum ferritin. Bone marrow examination is crucial to the diagnosis in showing dyserythropoiesis and ≥ 15% ring sideroblasts. After Prussian blue staining, ring sideroblasts are identified as immature red cells in which 10 or more blue granules representing iron-loaded mitochondria form a ring around the nucleus. XLSA is caused by mutations in the erythroid-specific ALA synthase gene (ALAS2). Any subject who is suspected as having XLSA or belongs to a family with XLSA should have DNA or reticulocyte RNA tested for ALAS2 mutations, irrespective of sex and age. Management of XLSA involves treatment of anemia, prevention and treatment of iron overload, family studies to identify additional at-risk individuals, and genetic counseling. Most patients with XLSA are to some extent responsive to pyridoxine: the initial dosage is 75-150 mg/day. In XLSA, response to pyridoxine supplementation is greatly influenced by body iron status, and iron overload may suppress pyridoxine responsiveness. Reversal of iron overload by phlebotomy generally results in higher hemoglobin concentrations during pyridoxine supplementation. Most patient with iron overload can safely undergo mild phlebotomy programs under pyridoxine supplementation. Supportive therapy is the only therapy currently available for patients with refractory anemia with ring sideroblasts. Patients with refractory anemia with ring sideroblasts with a regular need for blood transfusion should receive iron chelation therapy with desferrioxamine.