Sideroblastic Anemia: Types, Causes & Pathophysiology

• Sideroblastic anemia is a refractory condition characterized by hypochromic cells in the peripheral blood and increased marrow iron.
• It is specifically defined by the presence of pathological ring sideroblasts in the bone marrow, resulting from a defect in heme synthesis.

Classification of Sideroblastic Anemia

• Hereditary: Sex-linked, occurring predominantly in males, rarely in females.
• Acquired:
  • Primary: Myelodysplasia.
  • Secondary: Associated with malignant marrow diseases like myelofibrosis and leukemia.
  • Secondary: Induced by drugs and chemicals such as antituberculous drugs, lead, and ethanol.
  • Secondary: Linked to benign conditions like hemolytic anemia and rheumatoid arthritis.

Pathophysiology

• Heme synthesis is disrupted due to disturbances in regulating enzymes, with decreased erythropoietic ALA synthetase in hereditary sex-linked forms.
• Ringed sideroblasts form as non-ferritin iron accumulates in the mitochondria, circling the normoblast nucleus.
• Mitochondria eventually rupture as they overload with iron.
• Iron stains reveal blue punctate deposits across the nucleus.

Siderocyte

• Red blood cells contain granules of non-heme iron and show a positive Prussian blue reaction.
• Siderocytes are not typically found in peripheral blood in healthy individuals, except in small numbers post-splenectomy.

Sideroblast

• Erythroblasts have Prussian blue positive iron granules in their cytoplasm.
• Three classifications of sideroblasts exist, one normal and two abnormal.
• The sideroblasts are classified based on the number, size, and distribution of siderotic granules.

Type 1 Sideroblasts

• Seen in normal bone marrow, representing iron not utilized for hemoglobin synthesis.
• Features granules that are few, small, difficult to see, scattered throughout the cytoplasm, and not localized in the preinuclear zone.
• Approximately 30-40% of erythroblasts are normally sideroblasts.
• Not observed in iron deficiency anemia (IDA).

Type 2 Sideroblasts

• Abnormal, found when transferrin saturation is increased, such as in dyserythropoiesis or hemolysis.
• Features granules that are large and more scattered throughout the cytoplasm.

Type 3 Sideroblasts

• Found where heme synthesis is disturbed, such as in idiopathic and secondary sideroblastic anemia.
• Features granules that are larger and more numerous than type 2, forming a complete or partial ring around the nucleus, known as ring sideroblasts.

Clinical Signs and Symptoms

• Pallor
• Dizziness
• Fatigue
• Liver disease
• Enlarged liver or spleen
• Cardiac arrhythmia
• Renal failure

Lab Diagnosis (Complete Blood Count)

• Hemoglobin (Hb) level: Low
• Packed Cell Volume (PCV): Low
• Red Blood Cell count (RBCs): Low
• Reticulocyte count: Low
• Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), and Mean Corpuscular Hemoglobin Concentration (MCHC): May be normal in the presence of a dimorphic blood picture.
• White cell count: Normal
• Platelets count: Normal

Peripheral Blood Picture

• Anemia severity is moderate to severe, and dimorphic (macrocyte, microcyte) with marked anisocytosis and poikilocytosis
• Basophilic stippling is marked, and target cells are common, as are Nucleated Red Blood Cells (NRBCs).
• Pappenheimer bodies present with Prussian blue stain.
• Differential Leukocyte Count (DLC): Normal
• Platelets (Pltls): Normal

Bone Marrow Aspiration

• Displays erythroid hyperplasia with maturation arrest.
• Sideroblastic anemia detected when over 40% of marrow erythroblasts are ring sideroblasts, visualized with Prussian Blue stain.

Biochemical Tests

• Serum iron: High
• Serum Ferritin: High
• Percentage of saturation: High
• Total Iron Binding Capacity (TIBC): Normal or low

Diagnostic Tests

• Free erythrocyte protoporphyrin (FEP) levels in X-linked sideroblastic anaemia are reduced.
• Molecular studies: Mutations are common in the aminolevulinate synthase (ALAS2) gene.

Differential Diagnosis

Treatment

• Treatment approach will vary based on the cause of sideroblastic anemia.
• Acquired sideroblastic anemia requires removing the offending agent.
• Underlying inflammatory conditions, like rheumatoid arthritis, should be treated.
• Vitamin B6 (50-200 mg/day) may reverse anemia.
• Whole red blood cell transfusion may be needed in extreme cases.

Prognosis and Complications

• Iron overload accompanies sideroblastic anemia.
  • Repeated whole red blood cell transfusions exacerbate existing iron burden when needed to treat anemia.
  • Patients may require chelation therapy.
• Leukemia can develop in patients with acquired sideroblastic anemia.

Lead Poisoning Effects

• Lead inhibits both heme and globin synthesis.
• Interferes with RNA breakdown by inhibiting pyrimidine-5-nucleotidase.
• Causes accumulation of denatured RNA in red cells, leading to basophilic stippling on Romanowsky stains.
• Can cause hypochromic or hemolytic anemia.
• Bone marrow may show ring sideroblasts.
• Free erythrocyte protoporphyrin is raised.

Lead Poisoning Symptoms

• Poor appetite
• Abdominal pain (with or without vomiting)
• Sleeplessness
• Headaches
• Constipation

Explore sideroblastic anemia, a refractory condition marked by hypochromic cells and increased marrow iron. Learn about hereditary and acquired classifications, including primary myelodysplasia and secondary causes like drugs and chemicals, plus the pathophysiology of disrupted heme synthesis.