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Sideroblastic anemia

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"sideroblastic anemia"[MeSH Terms]

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Sideroblastic Anemia

Definition

Sideroblastic anemia is a group of disorders defined by the presence of ringed sideroblasts on bone marrow examination - erythroid precursors in which iron-laden mitochondria form a perinuclear ring around the nucleus (by convention: ≥5 iron granules encircling at least one-third of the nuclear circumference on Prussian blue stain). The unifying pathophysiology is defective heme synthesis, leading to iron accumulating in mitochondria rather than being incorporated into hemoglobin.
Ringed sideroblasts on Prussian blue stain of bone marrow - erythroblasts with perinuclear rings of iron-laden mitochondria
Prussian blue stain of bone marrow showing ringed sideroblasts - erythroblasts with perinuclear rings of iron-laden mitochondria. (Goldman-Cecil Medicine)

Classification

1. Hereditary / Congenital Forms

TypeGene/DefectNotes
X-linked (XLSA) - most common (~40%)ALAS2 (Xp11.21) - encodes erythroid ALA synthase (ALA-S2), the rate-limiting enzyme in heme synthesisAffects males; onset can be infancy to adolescence; >120 loss-of-function mutations identified
Autosomal recessiveSLC25A38 (mitochondrial glycine importer)Rare
Autosomal recessiveGlutaredoxin 5 (GLRX5) - impairs ALAS2 translationRare
Mitochondrial (syndromic)Mitochondrial genome deletionsPearson syndrome (ring sideroblasts + pancreatic exocrine insufficiency + vacuolated marrow cells + variable marrow failure - typically macrocytic)
In XLSA, mutations may reduce the enzyme's affinity for its cofactor pyridoxal phosphate (PLP), which is why some patients respond to high-dose pyridoxine (B6).

2. Acquired Forms

Primary (clonal):
  • MDS with ring sideroblasts (MDS-RS) - most common acquired cause; ≥15% of erythroblasts are ring sideroblasts; most harbor somatic SF3B1 mutations (splicing factor), leading to aberrant mRNA splicing; presents with dimorphic anemia (hypochromic-microcytic + macrocytic cells), elevated MCV
  • MDS/MPN with ring sideroblasts (MDS/MPN-RS) - overlapping myeloproliferative features
Secondary (reversible):
  • Alcohol - most common reversible cause; acts via decreased pyridoxal phosphate levels, inhibition of ALA dehydratase and ferrochelatase, and possible mitochondrial protein synthesis inhibition; ring sideroblasts disappear within days of abstinence
  • Anti-TB drugs - isoniazid (INH), pyrazinamide, cycloserine (interfere with pyridoxine metabolism)
  • Chloramphenicol - inhibits mitochondrial protein synthesis
  • Linezolid - similar mechanism to chloramphenicol
  • Lead poisoning - blocks ALAS, ALA dehydratase, and heme synthase; raises urine ALA and coproporphyrin
  • Copper deficiency - from inadequate intake, malabsorption, or zinc overload (zinc competes with copper absorption); also causes neutropenia and myelopathy
  • Zinc toxicity - high zinc ingestion -> copper deficiency -> sideroblastic anemia
  • Penicillamine (high doses) - copper chelation

Pathophysiology

The central defect is disruption of heme biosynthesis, which occurs in mitochondria. When heme synthesis is impaired:
  • Iron taken up by developing erythroblasts cannot be incorporated into protoporphyrin IX to form heme
  • Iron accumulates in mitochondria, forming the characteristic perinuclear ring
  • This leads to ineffective erythropoiesis - red cell precursors die in the marrow before maturing

Clinical Features

  • Inherited forms: typically microcytic anemia in younger patients; XLSA presents with weakness, pallor, secondary hypersplenism, and progressive iron overload (hemosiderosis) despite no external iron source
  • Acquired forms: presentation varies - blood film shows a dimorphic picture (mixed microcytic/hypochromic + normocytic or macrocytic cells); MDS-RS tends toward macrocytic
  • Copper deficiency: neurologic manifestations (myelopathy) accompany the anemia
  • Ineffective erythropoiesis markers: elevated bilirubin, elevated LDH, low haptoglobin

Peripheral Blood & Bone Marrow Findings

Peripheral smear:
  • Hypochromic, often microcytic RBCs (inherited) or dimorphic picture (acquired)
  • Bimodal RBC volume distribution (especially in inherited forms)
  • Basophilic stippling
  • Pappenheimer bodies (iron-containing granules visible on Romanowsky stain)
  • Anisocytosis, poikilocytosis, polychromasia in XLSA
Bone marrow:
  • Ringed sideroblasts (Prussian blue stain)
  • Erythroid hyperplasia with dyserythropoiesis
  • Markedly increased iron stores
  • Megaloblast-like changes occasionally (without true B12/folate deficiency)
Laboratory:
  • Elevated serum iron, very high transferrin saturation, elevated ferritin (iron-loading pattern - similar to hereditary hemochromatosis)
  • Decreased TIBC
  • Elevated bilirubin, LDH; low haptoglobin (due to ineffective erythropoiesis and intramedullary hemolysis)

Diagnosis

  1. Bone marrow biopsy with Prussian blue iron stain - demonstrates ringed sideroblasts (diagnostic)
  2. Exclude secondary causes - review medications, alcohol history, serum copper/ceruloplasmin, blood lead level
  3. Cytogenetics + molecular testing - SF3B1 mutation for MDS-RS; ALAS2 sequencing for XLSA (>120 mutations identified)
  4. In XLSA: ALA-S2 activity is decreased in bone marrow; urine porphyrin precursors are normal (distinguishes from porphyrias)

Treatment

SituationTreatment
Secondary (drug/toxin)Remove offending agent - most resolve rapidly (e.g., alcohol-induced sideroblasts clear within days)
Copper deficiencyCopper repletion
XLSA / pyridoxine-responsivePyridoxine (B6) 50-200 mg/day - effective when mutation disrupts PLP binding site; may reduce or eliminate transfusion need
Pyridoxine-unresponsive inheritedTransfusion support + iron chelation therapy to manage iron overload; stem cell transplant in selected cases
MDS-RS / MDS-MPN-RSLuspatercept (TGF-β ligand trap) - FDA-approved for anemia in MDS-RS and MDS/MPN-RS; treatment of underlying MDS

Key Associations to Remember

  • Pearson syndrome = sideroblastic anemia + pancreatic insufficiency + marrow vacuolation (mitochondrial deletion)
  • XLSA = ALAS2 mutation, X-linked recessive, responds to pyridoxine in some cases
  • MDS-RS = acquired, SF3B1 mutation, macrocytic/dimorphic, treated with luspatercept
  • Alcohol = most common reversible cause; resolves with abstinence and nutrition
  • Isoniazid = inhibits pyridoxal phosphate; give prophylactic B6 with prolonged INH therapy
  • All forms cause iron overload despite anemia - do not give iron supplements
Sources: Goldman-Cecil Medicine 26e, p. 1035 | Henry's Clinical Diagnosis and Management by Laboratory Methods | Harrison's Principles of Internal Medicine 22e (2025) | Quick Compendium of Clinical Pathology 5e | Washington Manual of Medical Therapeutics
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