Sideroblastic Anemia

Sideroblastic anemias are a heterogeneous group of bone marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors. The accumulated iron appears as granules in a ringlike distribution around the nucleus, giving rise to the characteristic morphological feature of a ring sideroblast. Sideroblastic anemias may be due to inherited defects in heme synthesis or can be acquired through alcoholism, lead poisoning, medications, or vitamin deficiencies. The anemia is commonly microcytic with low to normal reticulocyte count. Serum iron levels are typically elevated. A bone marrow examination showing ring sideroblasts establishes the diagnosis. Management involves treating the underlying condition, avoiding causative medication and/or toxins, and phlebotomy in cases of iron overload.

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Overview

Definition

Sideroblastic anemias are a heterogeneous group of bone marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors.

The distribution of the iron is ringlike around the nucleus, manifested by the precursors (ring sideroblasts) in the bone marrow.

Epidemiology

  • A rare disease → incidence and prevalence not well characterized
  • Men > women
  • No racial predominance
  • Hereditary forms usually manifest before 30 years of age.
  • Acquired type is often seen at age 65 years or older.

Etiology

Congenital disorders:

  • Syndromic: with accompanying nonhematologic manifestations
  • Nonsyndromic: 
    • Present with anemia, no other clinical manifestations
    • Majority of cases

Acquired:

  • Clonal hematopoietic disorders:
    • Myelodysplastic syndromes (MDS)
    • Myeloproliferative neoplasms (MPN)
  • Reversible causes:
    • Alcohol 
    • Vitamin deficiencies (vitamin B6, cofactor for protoporphyrin synthesis)
    • Lead poisoning (inhibits the conversion of protoporphyrins)
    • Medications (isoniazid, chloramphenicol, linezolid)
    • Copper deficiency
    • Zinc poisoning
    • Hypothermia

Pathophysiology

Heme synthesis

  • Heme:
    • A porphyrin-containing compound, synthesized through an enzymatic pathway that takes place in the mitochondria and cytoplasm
    • Most production occurs in the bone marrow.
  • In the mitochondria:
    • Succinyl-CoA + glycine → aminolevulinic acid (ALA) 
    • Reaction is catalyzed by aminolevulinic acid synthase (ALAS2 in the erythrocytes).
    • ALA → exits to the cytoplasm
  • In the cytoplasm: 
    • 2 ALA molecules condense to produce porphobilinogen.
    • Porphobilinogen → uroporphyrinogen III → coproporphyrinogen III 
    • Coproporphyrinogen III is transported back to the mitochondria.
  • In the mitochondria:
    • Coproporphyrinogen III → protoporphyrinogen III, which then is converted to protoporphyrin IX
    • Ferrous iron is inserted into protoporphyrin IX (catalyzed by ferrochelatase), forming heme.
Heme synthesis

Heme synthesis:
Heme synthesis is a process that takes place in the mitochondria and cytoplasm.
In the mitochondria, succinyl-CoA combines with glycine to form aminolevulinic acid (ALA).
This reaction is catalyzed by aminolevulinic acid synthase (ALAS2 in the erythrocytes). The ALA exits to the cytoplasm, where 2 ALA molecules condense to produce porphobilinogen (PB). The subsequent steps lead to the formation of coproporphyrinogen III, which is transported back to the mitochondria. Oxidase facilitates conversion of coproporphyrinogen III to protoporphyrinogen IX, which then is converted to protoporphyrin IX. Ferrous iron is inserted into protoporphyrin IX, forming heme (catalyzed by ferrochelatase).

Image by Lecturio.

Pathogenesis

Defects in heme synthesis:

  • X-linked sideroblastic anemia (XLSA):
    • Mutations in ALAS2 gene, which encodes aminolevulinic acid synthase, the rate-limiting enzyme in heme synthesis
    • Frequently (> 50% of cases) responsive to B6 supplementation
  • Autosomal recessive sideroblastic anemia:
    • SLC25A38 mutation: impaired glycine transporter into mitochondria 
    • FECH mutation: impaired ferrochelatase
  • Acquired:
    • Isoniazid (INH): causes ALAS2 impairment
    • Alcohol

Defects in iron-sulfur cluster (ISC) biogenesis:

  • ISCs are involved in multiple biological functions including electron transport, iron regulation, and DNA repair.
  • Dysfunction in ISC transfer in and out of mitochondria disables erythropoiesis.
  • Seen in mutations such as:
    • ABCB7: associated with ataxia (syndromic)
    • HSPA9
    • GLRX5

Defects in mitochondrial protein synthesis:

  • Congenital etiologies affect multifunctional proteins, so these are associated with systemic signs (syndromic) such as:
    • Pearson marrow-pancreas syndrome
    • Myopathy, lactic acidosis, and sideroblastic anemia (MLASA)
    • TRNT1 mutation (immunodeficiency, recurrent fevers, developmental delay) 
  • Acquired:
    • Chloramphenicol
    • Linezolid

Dysfunction in erythropoiesis:

  • RBCs unable to mature
  • Leads to cell death in the marrow (intramedullary hemolysis)
  • ↑ Inappropriate iron absorption → iron overload
  • Seen in:
    • XLSA
    • SLC25A38 mutation
    • MDS/MPN

Clinical Presentation

Clinical presentation varies depending on the underlying disease.

General features of anemia:

  • Growth retardation in children 
  • Fatigue and muscle weakness
  • Hypothermia
  • Photosensitivity

Patients with vitamin B6 deficiency may have:

  • Peripheral neuropathy
  • Ataxia
  • Dermatitis
  • Glossitis

Patients with lead poisoning may have:

  • Abdominal pain
  • Dental lead lines
  • Peripheral neuropathy (adults)
  • Ataxia
  • Encephalopathy
  • Mental and growth retardation (children)

Others:

  • Pink-stained urine from porphyrins
  • Those with syndromic sideroblastic anemias will have other nonhematologic manifestations.

Diagnosis

Medical history

  • Family history of anemia
  • Presence of concurrent clinical features (in syndromic forms)
  • Possibilities of copper deficiency:
    • History of gastrointestinal surgery 
    • Enteral or parenteral nutrition without copper 
    • Excessive zinc intake 
  • Alcohol use
  • History of exposure to lead
  • Medications 
  • Long-term dialysis

Laboratory findings

  • Complete blood count:
    • Microcytosis (MCV < 80)
    • ↑ RBC distribution width (RDW)
    • Clinical significance: In children, neither microcytic anemia with no iron deficiency nor thalassemia is suggestive of XLSA.
  • Normal to low reticulocyte count
  • Iron studies:
    • ↑ Serum iron 
    • ↑ Ferritin levels
    • Normal or ↓ total iron-binding capacity (TIBC)
    • ↑ Transferrin saturation
  • Abnormal peripheral blood smear:
    • Anisocytosis, poikilocytosis
    • Siderocytes: hypochromic erythrocytes with basophilic granules staining positive for iron
  • Diagnosis is based on bone marrow aspirate (in Prussian blue-stained smear): ring sideroblasts
Ring sideroblasts

Ring sideroblasts

Image: “Ringed sideroblasts” by S. Bhimji, MD. License: CC BY 4.0

Differentiating sideroblastic anemia from other microcytic anemias

Table: Differentiating sideroblastic anemia from other microcytic anemias (MCV < 80)
CBC findingDiagnosisIron levelFeatures or historical setting
Anemia with MCV < 80Sideroblastic anemia↑ Iron levelAlcoholic, MDS
Iron deficiency anemia↓ Iron levelBlood loss
ThalassemiaNormal iron levelVariant dependent (asymptomatic to severe anemia)
MDS: myelodysplastic syndromes

Additional tests

  • If indicated based on history:
    • Copper and ceruloplasmin levels
    • Lead level
  • Genetic testing:
    • Necessary to establish a specific diagnosis
    • Performed on leukocytes from the peripheral blood

Management

Goals

  • Prevent organ damage from subsequent iron overload. 
  • Control symptoms associated with anemia.

Treatment options

Treatment options depend on the etiology and include:

  • Drug induced: withdrawal of the medication
  • Alcohol or toxin induced: alcohol abstinence, removal of the toxic agents
  • Treatment of underlying condition, i.e., MDS/MPN 
  • In the case of INH intake: Co-administration of B6 is required.
  • For XLSA: vitamin B6 (pyridoxine) supplements 
  • For thiamine-responsive megaloblastic anemia: vitamin B1 
  • For symptomatic anemia: transfusion if indicated
  • Iron overload: phlebotomy, iron chelation
  • For some inherited sideroblastic anemias: possible allogeneic hematopoietic stem cell transplantation

Clinical Relevance

  • Lead poisoning: lead inhibits ferrochelatase and ALA dehydratase (enzymes in the heme synthesis pathway), resulting in decreased heme synthesis. Features include gastrointestinal symptoms and neurological manifestations. Laboratory findings include anemia, erythrocyte basophilic stippling in peripheral smear, and ringed sideroblasts in bone marrow. Diagnosis is by lead level measurement.
  • Myelodysplastic syndrome: a group of malignant myeloid stem cell disorders characterized by dysplastic and ineffective bone marrow myeloid line cell production and an increased risk of transformation to acute leukemia. Myelodysplastic syndrome usually presents in older patients, greater than 60 years of age. The syndrome manifests as thrombocytopenia, anemia, and neutropenia with dysfunctional granulocytes, despite a hypercellular bone marrow.
  • Vitamin B6 deficiency: caused by pyridoxine-inactivating drugs (e.g., isoniazid), protein-energy undernutrition, malabsorption, alcoholism, or excessive loss due to hemodialysis. Deficiency can cause peripheral neuropathy, seizures, seborrheic dermatitis, glossitis, cheilosis, and sideroblastic anemia.

References

  1. Ashorobi D, Chhabra A. (2020). Sideroblastic Anemia. StatPearls: StatPearls Publishing. Retrieved April 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK538287/
  2. Bottomley SS. (2021). Sideroblastic anemias: Diagnosis and management. UpToDate. Retrieved April 6, 2021, from https://www.uptodate.com/contents/sideroblastic-anemias-diagnosis-and-management
  3. Bottomley SS. (2021). Causes and pathophysiology of the sideroblastic anemias. UpToDate. Retrieved April 6, 2021, from https://www.uptodate.com/contents/causes-and-pathophysiology-of-the-sideroblastic-anemias
  4. Ducamp S, Fleming MD. (2019). The molecular genetics of sideroblastic anemia. https://pubmed.ncbi.nlm.nih.gov/30401706/
  5. Sticco KL, Yarrarapu, SNS, Al Obaidi NM. (2021) Refractory Anemia With Ring Sideroblasts. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Retrieved April 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK537073/

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