Snapshot A 69-year-old man is brought to the emergency department by police after being found stumbling in the middle of the street at night. He smells strongly of whiskey and is found to have a blood alcohol content level of 0.23%. Laboratory studies are ordered, and the patient is found to have a hemoglobin of 7 g/dL and a hematocrit of 21%. Iron studies show an increase in free iron levels. A peripheral blood smear is obtained and shows the finding seen in the image. Introduction Overview sideroblastic anemias are a group of inherited and acquired anemias in which iron accumulates in the mitochondria of erythrocyte precursors ringed sideroblasts (iron-laden erythrocytes with Prussian-blue stained mitochondria) seen on bone marrow aspirate Genetics inheritance pattern X-linked (inherited sideroblastic anemia) mutations ALAS2 gene encodes for ALA synthase Epidemiology Incidence rare Demographics X-linked recessive type of inherited sideroblastic anemia occurs more commonly in males median age of occurence of primary acquired sideroblastic anemia is 74 years Risk factors alcoholism vitamin B6 deficiency lead poisoning copper deficiency ETIOLOGY Pathophysiology mitochondrial pathways in erythrocyte precursors are disrupted, leading to accumulation of iron in the mitochondria excessive iron deposits in erythroblasts form a ring around the nucleus, making a ringed sideroblast heme synthesis is impaired, leading to ↓ heme production and abnormal RBCs X-linked sideroblastic anemia mutation in ALAS2 gene which encodes ALA synthase, the first enzyme of the heme synthesis pathway vitamin B6 (pyridoxine) is a necessary cofactor for ALA synthase isoniazid disrupts conversion of vitamin B6 (pyridoxine) to its active cofactor chronic alcohol use impairs vitamin B6 metabolism toxic effects on mitochondrial protein synthesis lead poisoning inhibits several enzymes involved in heme synthesis ALA dehydratase ferrochelatase Presentation Symptoms general symptoms of anemia fatigue weakness dyspnea on exertion lack of coordination (cerebellar symptoms) diarrhea Physical exam growth delay in children ataxia ↓ deep-tendon reflexes incoordination dyspnea muscular weakness Studies Serum labs ↑ serum iron and ferritin ↓ TIBC ↓ or normal MCV Histology peripheral blood smear hypochromic RBCs Pappenheimer bodies in RBCs abnormal basophilic granules of iron low reticulocyte count bone marrow stained with Prussian blue ringed sideroblasts diagnostic hallmark of all sideroblastic anemias Differential Iron deficiency anemia key distinguishing factor ↓ serum iron and ferritin Megaloblastic anemia key distinguishing factor megaloblastic changes seen on peripheral blood smear and bone marrow rather than ringed sideroblasts Treatment Medical pyridoxine (vitamin B6) supplementation Prognosis Highly variable depending on cause anemia due to reversible causes (i.e., alcohol, drugs) do not have long-term sequelae Secondary hemochromatosis (from transfusions) and leukemia are major causes of death