Sideroblastic Anemia

Snapshot

• A 35-year-old man presents to the clinic for follow-up for treatment of latent tuberculosis. He is a recent immigrant to the United States from Mexico and started taking isoniazid 2 months ago after he was diagnosed with latent tuberculosis at an occupational health visit. Physical examination is notable for decreased sensation to pinprick in his lower extremities. A bone marrow aspirate is obtained and after staining with Prussian blue, the finding in the image is observed. 

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 
• 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 of age
  • risk factors
    • alcoholism
    • vitamin B6 deficiency
    • lead poisoning
    • copper deficiency
• Pathophysiology
  • 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 (see Heme Metabolism)  
      • 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
• Genetics
  • inheritance pattern
    • X-linked (inherited sideroblastic anemia)
  • mutations
    • ALAS2 gene
      • encodes for ALA synthase
• Prognosis
  • highly variable depending on cause
    • anemia due to reversible causes (i.e., alcohol and drugs) do not have long-term sequelae
• secondary hemochromatosis (from transfusions) and leukemia are major causes of death

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