What is sideroblastic anemia and its pathophysiology?

Sideroblastic Anemia: Definition and Pathophysiology

Sideroblastic anemia is a heterogeneous group of inherited and acquired disorders characterized by defective heme synthesis leading to iron accumulation in erythroblast mitochondria, forming pathognomonic ring sideroblasts in the bone marrow, with resultant ineffective erythropoiesis and microcytic anemia. 1, 2

Core Pathophysiologic Mechanism

The fundamental defect in sideroblastic anemia involves disrupted heme biosynthesis within erythroid precursors, which prevents proper incorporation of iron into protoporphyrin IX to form heme 1, 3. This leads to:

• Mitochondrial iron accumulation in perinuclear distribution, creating the characteristic ring sideroblasts visible on Perls' stain 3, 4
• Ineffective erythropoiesis as defective erythroblasts undergo apoptosis before maturation 1, 2
• Paradoxical iron overload despite anemia, due to increased intestinal iron absorption driven by ineffective erythropoiesis and low hepcidin levels 5

Genetic and Molecular Basis

X-Linked Sideroblastic Anemia (XLSA) - Most Common Inherited Form

ALAS2 gene mutations (encoding erythroid-specific δ-aminolevulinate synthase) represent the most common genetic cause 5, 2, 3. The pathophysiology involves:

• Defective pyridoxal phosphate (vitamin B6) cofactor binding in most cases, impairing the first enzymatic step of heme synthesis 5
• Decreased protoporphyrin synthesis with subsequent reduced iron incorporation 5
• Mitochondrial iron loading that exacerbates anemia through decreased pyridoxine sensitivity 5
• Heme deficiency-induced ineffective erythropoiesis, followed by increased intestinal iron uptake and systemic iron accumulation 5

Autosomal Recessive Forms

SLC25A38 mutations cause severe congenital sideroblastic anemia by disrupting mitochondrial glycine import or ALA exchange across the inner mitochondrial membrane, essential for heme synthesis 5, 2. This results in:

• Severe transfusion-dependent microcytic anemia presenting in childhood 5
• Marked iron overload even before transfusions begin 5

ABCB7 mutations disrupt Fe-S cluster export from mitochondria, causing both sideroblastic anemia and cerebellar ataxia through impaired iron metabolism 5

GLRX5 mutations impair Fe-S cluster biosynthesis, leading to:

• Increased cytosolic IRP1 activity, creating a cellular "low-iron state" 5
• Repression of ALAS2 and other target genes, reducing heme synthesis 5
• Increased ferrochelatase turnover with mitochondrial iron accumulation 5

Iron Metabolism Defects

SLC11A2 (DMT1) mutations cause defective enterocyte and erythroid iron uptake, yet paradoxically lead to systemic iron loading, likely through alternative heme absorption pathways or low hepcidin levels 5

STEAP3 mutations impair ferroreductase activity, preventing Fe³⁺ to Fe²⁺ reduction in erythroblast endosomes, resulting in severe microcytic anemia 5

Acquired Sideroblastic Anemia Pathophysiology

SF3B1 mutations (present in >90% of refractory anemia with ring sideroblasts) alter RNA splicing machinery 2. This causes:

• Misrecognition of 3' splice sites in downstream genes 2
• Truncated gene products and decreased expression through nonsense-mediated RNA decay 2
• Multifactorial pathogenesis explaining the ineffective erythropoiesis in myelodysplastic syndrome with ring sideroblasts 2, 6

Clinical Consequences of Pathophysiology

The disrupted heme synthesis and iron metabolism lead to:

• Microcytic hypochromic anemia due to reduced hemoglobin synthesis 5, 1
• Variable severity: from mild anemia in XLSA to severe transfusion-dependent anemia in SLC25A38 defects 5, 2
• Systemic iron overload affecting liver, heart, and endocrine organs despite anemia 5
• Increased TSAT and ferritin reflecting the iron loading despite impaired erythroid iron utilization 5

Key Pathophysiologic Distinction

A critical pitfall: Unlike iron deficiency anemia where iron stores are depleted, sideroblastic anemia features paradoxical iron overload with microcytic anemia because iron cannot be properly utilized for heme synthesis despite adequate or excessive body iron stores 5, 1. This explains why iron supplementation is contraindicated in most forms and why phlebotomy can actually improve anemia in mild cases like XLSA 5.