Sideroblastic

Overview of Sideroblastic Anemias

Definition: A group of heterogeneous hematologic disorders characterized by ineffective erythropoiesis and the presence of ringed sideroblasts in the bone marrow
Pathophysiology:
- Impaired ability of the bone marrow to incorporate iron into hemoglobin
- Iron accumulates in the mitochondria of erythroblasts, forming ringed sideroblasts
- Ineffective erythropoiesis leads to anemia
Classification:
- Hereditary Sideroblastic Anemias
- Acquired Sideroblastic Anemias
  - Reversible
  - Irreversible

Etiology and Classification

Hereditary Sideroblastic Anemias
- X-Linked Sideroblastic Anemia (XLSA):
  - Most common form of hereditary sideroblastic anemia
  - Caused by mutations in the ALAS2 gene, which encodes erythroid-specific 5-aminolevulinate synthase (ALAS2), a key enzyme in heme synthesis
- Autosomal Recessive Sideroblastic Anemias:
  - Rare disorders caused by mutations in genes involved in heme synthesis, mitochondrial function, or iron metabolism
  - Examples: Mutations in the ABCB7, GLRX5, HSPA9, and SLC25A38 genes
- Mitochondrial Myopathy with Sideroblastic Anemia (MLASA):
  - Associated with mutations in mitochondrial DNA (mtDNA) or nuclear genes that affect mitochondrial function
Acquired Sideroblastic Anemias
- Reversible Acquired Sideroblastic Anemias:
  - Caused by exposure to certain drugs, toxins, or nutritional deficiencies
  - Examples:
    - Alcohol-induced sideroblastic anemia: Alcohol interferes with heme synthesis
    - Drug-induced sideroblastic anemia: Isoniazid, pyrazinamide, chloramphenicol, and linezolid
    - Copper deficiency: Copper is required for iron transport and incorporation into heme
    - Vitamin B6 (Pyridoxine) deficiency: Vitamin B6 is a cofactor for ALAS2
- Irreversible Acquired Sideroblastic Anemias:
  - Associated with myelodysplastic syndromes (MDS):
    - A group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a risk of progression to acute myeloid leukemia (AML)
    - Refractory Anemia with Ring Sideroblasts (RARS): A subtype of MDS characterized by anemia and increased ring sideroblasts in the bone marrow
  - Associated with Myeloproliferative Neoplasms (MPN):
    - A group of disorders characterized by the overproduction of one or more blood cell lines in the bone marrow

Pathophysiology

Impaired Heme Synthesis:
- Mutations or deficiencies affecting enzymes involved in heme synthesis lead to a buildup of porphyrin precursors and impaired iron incorporation into protoporphyrin
- In XLSA, mutations in ALAS2 result in decreased production of δ-aminolevulinic acid (ALA), the first committed step in porphyrin synthesis
Mitochondrial Dysfunction:
- Defects in mitochondrial function impair iron-sulfur cluster synthesis and other mitochondrial processes essential for heme synthesis
- Iron accumulates in the mitochondria, leading to the formation of ringed sideroblasts.
Ringed Sideroblasts:
- Erythroblasts with iron-laden mitochondria encircling the nucleus
- The presence of ≥15% ring sideroblasts in the bone marrow is a key diagnostic criterion for sideroblastic anemia
Ineffective Erythropoiesis:
- Accumulation of iron and dysfunctional mitochondria in erythroblasts leads to cellular damage and apoptosis (programmed cell death)
- Results in decreased red blood cell production and anemia

Clinical Manifestations

Symptoms of Anemia:
- Fatigue
- Weakness
- Pallor (pale skin)
- Shortness of breath
- Dizziness
Iron Overload:
- In hereditary sideroblastic anemias and MDS-associated sideroblastic anemias, chronic anemia and ineffective erythropoiesis lead to increased iron absorption
- Frequent blood transfusions can also contribute to iron overload
- Iron accumulates in various organs, leading to:
  - Liver damage (cirrhosis)
  - Heart failure
  - Endocrine dysfunction (diabetes, hypothyroidism)
  - Skin pigmentation (bronze diabetes)
Other Symptoms:
- Splenomegaly (enlarged spleen)
- Hepatomegaly (enlarged liver)
- Neurological symptoms (in some mitochondrial disorders)

Diagnostic Evaluation

Complete Blood Count (CBC):
- Hemoglobin (HGB): Decreased (anemia)
- Hematocrit (HCT): Decreased
- Mean Corpuscular Volume (MCV): Usually microcytic (low), but can be normocytic or macrocytic in some cases
- Red Cell Distribution Width (RDW): Increased (anisocytosis)
Peripheral Blood Smear:
- Microcytes, hypochromia (in some cases)
- Dimorphic red cell population (mixture of normal and abnormal RBCs)
- Pappenheimer bodies (iron-containing inclusions in RBCs)
- Basophilic stippling
Reticulocyte Count:
- Low or normal (inappropriately low for the degree of anemia)
Iron Studies:
- Serum Iron: Increased
- Total Iron-Binding Capacity (TIBC): Decreased or normal
- Transferrin Saturation: Increased
- Ferritin: Increased (often markedly elevated)
Bone Marrow Aspiration and Biopsy:
- Hypercellular marrow with erythroid hyperplasia
- Ringed sideroblasts (erythroblasts with iron-laden mitochondria encircling the nucleus)
- Prussian blue stain: Highlights iron deposits in the bone marrow
- Cytogenetic analysis: To detect chromosomal abnormalities in MDS
Other Tests:
- Vitamin B6 level: To rule out pyridoxine deficiency
- Copper level: To rule out copper deficiency
- Alcohol history and liver function tests: To assess for alcohol-induced sideroblastic anemia
- Drug history: To identify potential drug-induced causes
- Genetic testing: To identify mutations in genes associated with hereditary sideroblastic anemias (e.g., ALAS2, ABCB7, GLRX5, SF3B1)

Differential Diagnosis

Iron Deficiency Anemia: Low serum iron and ferritin, high TIBC
Anemia of Chronic Disease: Low serum iron, normal or low TIBC, normal or high ferritin
Thalassemia: Microcytic anemia with normal or elevated iron studies, abnormal hemoglobin electrophoresis
Lead Poisoning: Basophilic stippling and elevated lead levels

Treatment and Management

Reversible Acquired Sideroblastic Anemias:
- Identify and remove the causative agent (e.g., alcohol, drugs, toxins)
- Correct nutritional deficiencies (e.g., copper, vitamin B6)
Hereditary Sideroblastic Anemias:
- Pyridoxine (Vitamin B6) Supplementation:
  - Some patients with XLSA respond to high doses of pyridoxine
  - Trial of pyridoxine is recommended in all patients with suspected sideroblastic anemia
- Blood Transfusions:
  - To manage severe anemia
  - Iron chelation therapy is necessary to prevent iron overload
- Iron Chelation Therapy:
  - Deferoxamine (intravenous or subcutaneous)
  - Deferasirox or Deferiprone (oral)
- Hematopoietic Stem Cell Transplantation (HSCT):
  - Potentially curative option for severe cases
MDS-Associated Sideroblastic Anemias:
- Supportive Care:
  - Blood transfusions to manage anemia
  - Erythropoiesis-stimulating agents (ESAs) to stimulate red blood cell production (may be effective in some patients)
- Hypomethylating Agents (e.g., Azacitidine, Decitabine):
  - Used to improve hematopoiesis and reduce the risk of progression to AML
- Luspatercept:
  - A recombinant fusion protein that binds to TGF-β superfamily ligands, promoting erythroid maturation and reducing transfusion burden in RARS-T patients (MDS with ring sideroblasts and thrombocytosis)
- Lenalidomide:
  - Used in patients with MDS with deletion 5q
- Hematopoietic Stem Cell Transplantation (HSCT):
  - Potentially curative option for younger patients with high-risk MDS

Key Laboratory Findings

Complete Blood Count (CBC):
- Anemia (low HGB and HCT)
- MCV may be low, normal, or high
Peripheral Blood Smear:
- Dimorphic red cell population
- Pappenheimer bodies
- Basophilic stippling
Iron Studies:
- High serum iron
- Low or normal TIBC
- High transferrin saturation
- High ferritin
Bone Marrow Examination:
- Hypercellular marrow with erythroid hyperplasia
- Ringed sideroblasts (≥15% of erythroblasts)
Genetic Testing:
- To identify specific gene mutations associated with hereditary sideroblastic anemias

Key Terms

Sideroblastic Anemia: Anemia characterized by ringed sideroblasts in the bone marrow
Ringed Sideroblasts: Erythroblasts with iron-laden mitochondria encircling the nucleus
ALAS2: Erythroid-specific 5-aminolevulinate synthase, a key enzyme in heme synthesis
MDS: Myelodysplastic syndromes, a group of clonal hematopoietic stem cell disorders
Ineffective Erythropoiesis: Premature destruction of red blood cell precursors in the bone marrow
Pappenheimer Bodies: Iron-containing inclusions in red blood cells
Iron Chelation Therapy: Treatment to remove excess iron from the body

Thalassemias

Porphyria