Introduction:

• It is a disorder in which hemoglobin synthesis is reduced because of failure to incorporate heme into protoporphyrin to form hemoglobin.
• Accumulation of iron occurs in mitochondria, leading to formation of ringed sideroblasts.

Etiology:

• Hereditary
  • Deficiency of erythropoietic  delta ALA synthase, whose gene is located at chromosome X p 21- q 21
    • X- linked inheritance
    • Mutations usually affect promoter regions of gene
    • Promoter function can be rescued to a variable degree by pyridoxal phosphate (which is a cofactor for ALA S2)
  • Abnormalities in the ATP binding cassette transporter gene (ABC7) on chromosome Xq 13.3
    • X- linked inheritance
    • It is refractory to pyridoxine
    • Associated with early onset of non progressive cerebellar ataxia
    • Diagnostic distinction – RBCs contain increased zinc protoporphyrin despite of adequate iron stores. (It is low / normal in case of abnormality of ALA S2)
  • Mitochondrial DNA Mutations (Pearson marrow- pancreas syndrome)
    • Associated with deletion / duplication of mitochondrial DNA
    • It is a syndrome consist ofsideroblastic anemia, pancreatic exocrine dysfunction and lactic acidosis.
    • They present with failure to thrive and persistent diarrhea
    • Peripheral smear  – Microcytic anemia
    • Bone marrow- Prominent vacuoles in cells of both myeloid and erythroid lineage
    • Heteroplasmy – As many different mitochondria are present within cells, there is coexistence of both normal and abnormal species, the proportion of which varies in different tissues.
  • Abnormalities of high affinity transporter of thiamine (Thiamine responsive megaloblastic anemia / Roger’s syndrome)
    • SLC 19A2 gene on chromosome 1q 23.3 is affected
    • Autosomal recessive  inheritance
    • Presents with DIDMOAD – Diabetes insipidus, Diabetes mellitus, Optic atrophy, Deafness
    • Treatment – pharmacological doses of thiamine
  • Autosomal recessive pyridoxine refractory sideroblastic anemia: Associated with mutations in following genes 
    • SLC25A38- Located on chromosome 3, encodes mitochondrial carrier protein, exchagesglycine for 5-ALA
    • GLRX5- Encodes mitochondrial protein- Glutaredoxin 5
  • MLASA gene mutation: Presents with myopathy, lactic acidosis and sideroblastic anemia
• Acquired
  • Secondary to drugs and toxins
    • They interfere with activity of heme synthetic enzymes
    • Isoniazid, cycloserine, chloramphenicol, cyclophosphamide, alcohol, lead, chemotherapeutic agents, zinc, penicillamine etc
  • Alcoholism
    • Alcohol inhibits ferrochelatase
    • Sideroblastic anemia is seen in alcoholics who have poor nutrition
    • MCV is high
    • Vacuolation of RBC precursors is noted
  • Hematological disorders – Myelofibrosis, polycythemia vera, acute leukemia, multiple myeloma, lymphoma, hemolytic anemia, malignant histiocytosis, MDS – RARS etc.
  • Miscellaneous – carcinoma, myxedema, malabsorption, rheumatoid arthritis, SLE, Copper deficiency (macrocytic anemia with variable thrombocytopenia), Pyridoxine deficiency (It is needed in initial steps of hemoglobin synthesis), Erythropoietic  protoporphyria

Pathogenesis:

• Iron is avidly taken up by mitochondria even when synthesis of protoporphyrin IX is suppressed, but it is not utilized for synthesis of hemoglobin.
• Lack of heme as negative feedback regulator plays important role in mitochondrial iron accumulation.

Investigations:

• Hemogram
  • Microcytic hypochromic anemia
  • Sometimes dimorphic picture with normochromic and hypochromic cells
  • Siderocytes – RBCs containing granules of non heme iron which gives a positive Prussian blue reaction(Iron is stored in mitochondria)
  • Pappenheimer bodies – Granules of iron appearing as basophilic inclusions on Romonwasky stains.(Reticulocyte count should be done with care, as these bodies also take up supravital stains)
  • Poikilocytosis is seen with occasional target cells
  • WBCs and platelets are normal
• Bone marrow examination
  • Marked erythroid hyperplasia with marked dyserythropoiesis.
  • Normoblasts are microcytic with poorly hemoglobinized, scanty, vacuolated, frayed cytoplasm.
  • Prussian blue Stain shows ringed sideroblasts constitute about 40% of normoblasts (> 15% type 3 sideroblasts is the criteria for diagnosis)
  • 3 Types of sideroblasts  

• Bone marrow macrophages contain increased amount of storage iron.
• Erythrocyte protoporphyrin levels – Elevated
• Reticulocyte production index – less than 2
• Iron studies
  • Serum iron – Elevated
  • TIBC – Normal / Decreased
  • Serum ferritin – Increased
  • Transferrin saturation – Increased

Prognosis:

• Mean survival – 5 – 10years

Treatment:

• High dose Pyridoxine
  • Dose- 200mg – OD
  • Give for 3 months in patients who respond and continue in lower doses for lifetime
  • If no response at 3 months- Stop
  • Especially useful in INH induced sideroblastic anemia
• Folic acid- 5mg- OD
• RBC transfusion- For pyridoxine unresponsive cases
• Iron chelation to prevent end organ damage
• Phlebotomy- If anemia is mild
• Bone marrow transplant
  • It is a curative option
  • Useful in congenital cases
• Treatment of cause in secondary forms of sideroblastic anemia
• Splenectomy is contraindicated 

Recent Advances:

Luspatercept as Potential Treatment for Congenital Sideroblastic Anemia 

This is an interesting case report. In a transfusion-dependent 51-year-old man with X-linked sideroblastic anemia, the use of the TGF-β ligand blocker luspatercept led to a 30% increase in hemoglobin levels and a decreased need for transfusion. 

https://doi.org/10.1056/NEJMc2216213