What is sideroblastic anemia?

Sideroblastic Anemia

Sideroblastic anemia is a group of inherited and acquired disorders characterized by the presence of ring sideroblasts in the bone marrow, resulting from disrupted heme biosynthesis and pathological iron accumulation in the mitochondria of erythroid precursors. The hallmark feature of sideroblastic anemia is the presence of ring sideroblasts, which are erythroblasts containing excessive deposits of non-heme iron in perinuclear mitochondria, creating a characteristic ring appearance in bone marrow samples. 1, 2

Types and Etiology

Congenital Sideroblastic Anemia

• X-linked Sideroblastic Anemia (XLSA)

  • Most common inherited form
  • Caused by mutations in ALAS2 gene (encodes erythroid-specific δ-aminolevulinate synthase)
  • Results in decreased protoporphyrin synthesis and reduced heme synthesis
  • Typically presents with mild to moderate hypochromic, microcytic anemia and systemic iron overload
  • Often responsive to pyridoxine (vitamin B6) supplementation 1, 3

• Autosomal Recessive Sideroblastic Anemia

  • SLC25A38 mutations - severe, often transfusion-dependent anemia presenting in childhood
  • GLRX5 mutations - rare, associated with iron overload and ineffective erythropoiesis
  • STEAP3 mutations - affects iron reduction in erythroblasts 1, 4

• X-linked Sideroblastic Anemia with Ataxia (XLSA/A)

  • Caused by mutations in ABCB7 gene
  • Presents with mild microcytic anemia and cerebellar ataxia 1, 5

Acquired Sideroblastic Anemia

• Primary

  • Myelodysplastic syndrome (MDS) with ring sideroblasts (previously known as refractory anemia with ring sideroblasts or RARS)
  • Associated with somatic mutations in SF3B1 gene in over 90% of cases
  • Characterized by ineffective erythropoiesis 1, 6

• Secondary/Reversible Causes

  • Medications (antimicrobials, anticonvulsants, chelating agents)
  • Alcohol abuse
  • Lead poisoning
  • Copper deficiency
  • Zinc toxicity 7, 2

Clinical Presentation

• Symptoms of anemia (fatigue, weakness, pallor)
• Microcytic, hypochromic anemia on complete blood count
• Normal or elevated serum ferritin and transferrin saturation
• Iron overload manifestations (in hereditary forms and transfusion-dependent cases)
• Variable severity from mild to transfusion-dependent anemia
• May have associated neurological symptoms in certain genetic forms 1, 7

Diagnostic Approach

1. Laboratory Evaluation

   • Complete blood count (typically shows microcytic, hypochromic anemia)
   • Peripheral blood smear
   • Iron studies (ferritin, transferrin saturation)
   • Bone marrow examination (essential for diagnosis - shows ring sideroblasts) 7

2. Exclude Reversible Causes

   • Medication review
   • Alcohol history
   • Copper levels
   • Lead levels 7, 2

3. Genetic Testing

   • For suspected congenital forms
   • Based on clinical presentation, family history, and inheritance pattern
   • Sequencing of ALAS2, SLC25A38, ABCB7, GLRX5, and other relevant genes 1, 4

Treatment Approaches

Congenital Sideroblastic Anemia

• Pyridoxine (Vitamin B6)

  • First-line for XLSA
  • Initial doses: 50-200 mg daily
  • Maintenance: 10-100 mg daily (long-term)
  • Not all patients are responsive 1, 7

• Management of Iron Overload

  • Phlebotomy for mild anemia
  • Iron chelation therapy for transfusion-dependent cases
  • Important to normalize iron stores before declaring pyridoxine non-response 1, 7

• Supportive Care

  • Red blood cell transfusions for symptomatic anemia
  • Erythropoiesis-stimulating agents in selected cases 7, 6

• Curative Approach

  • Hematopoietic stem cell transplantation for severe cases (particularly SLC25A38 mutations)
  • Reported disease-free survival in selected patients 1, 2

Acquired Sideroblastic Anemia

• Medication-induced

  • Discontinuation of causative medication
  • Pyridoxine supplementation (50-100 mg daily) 7

• MDS with Ring Sideroblasts

  • Erythropoiesis-stimulating agents
  • Luspatercept (erythroid maturation agent) for transfusion-dependent cases
  • Red blood cell transfusions
  • Iron chelation for transfusion-dependent patients 7, 6

Monitoring and Follow-up

• Complete blood count every 2-4 weeks until stabilization
• Iron studies to monitor for iron overload
• Repeat bone marrow examination after 2-3 months to confirm resolution (in reversible cases)
• Avoid excessive iron supplementation unless true iron deficiency is confirmed 7

Clinical Pitfalls and Caveats

• Misdiagnosis: Sideroblastic anemia can be misdiagnosed as iron deficiency anemia due to microcytic, hypochromic presentation, but iron studies show normal or elevated iron stores
• Inappropriate Iron Supplementation: Can worsen iron overload in patients with already elevated iron stores
• Delayed Recognition of Genetic Forms: Particularly important in children and young adults with unexplained microcytic anemia
• Inadequate Pyridoxine Trial: Patients should not be considered pyridoxine-refractory until iron stores are normalized
• Missing Secondary Causes: Thorough evaluation for medications, alcohol, and nutritional deficiencies is essential 1, 7