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Sideroblastic Anemias

By

Evan M. Braunstein

, MD, PhD, Johns Hopkins School of Medicine

Last full review/revision Mar 2020| Content last modified Mar 2020
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Sideroblastic anemias are a diverse group of anemias characterized by the presence of increased serum iron, ferritin, and transferrin saturation as well as ringed sideroblasts (erythroblasts with perinuclear iron-engorged mitochondria). Symptoms are those of anemia and include fatigue and lethargy. Diagnosis is with complete blood count, reticulocyte count, and peripheral blood smear as well as iron studies and bone marrow examination. Treatment requires stopping causative substances and giving vitamin supplements and erythropoietin.

Sideroblastic anemias may be

  • Acquired

  • Congenital

Acquired sideroblastic anemia is frequently associated with myelodysplastic syndrome (but may be caused by drugs or toxins) and causes a macrocytic anemia.

Congenital sideroblastic anemia is caused by one of numerous X-linked or autosomal mutations and is usually a microcytic, hypochromic anemia.

Sideroblastic anemias are iron-utilization anemias, which are characterized by inadequate marrow utilization of iron for heme synthesis despite the presence of adequate or increased amounts of iron. Sideroblastic anemias are sometimes characterized by the presence of polychromatophilia (indicative of an increased number of reticulocytes) and stippled red blood cells (siderocytes) containing iron-laden granules (Pappenheimer bodies).

In both acquired and congenital sideroblastic anemia, heme synthesis is impaired due to the inability to incorporate iron into protoporphyrin IX, leading to the formation of ringed sideroblasts.

Acquired sideroblastic anemia

Most often, acquired sideroblastic anemias are part of a

Somatic mutations in genes involved in RNA splicing, most frequently SF3B1, commonly occur. Acquired sideroblastic anemia occurs in adulthood.

Less common causes include

  • Drugs (eg, chloramphenicol, cycloserine, isoniazid, linezolid, pyrazinamide)

  • Toxins (including ethanol and lead)

  • Deficiency of vitamin B6 (pyridoxine) or copper (possibly caused by zinc ingestion, which prevents absorption of copper in the gastrointestinal tract)

Deficient reticulocyte production, intramedullary death of red blood cells (RBCs), and bone marrow erythroid hyperplasia (and dysplasia) occur. Although hypochromic RBCs are produced, other RBCs may be large, producing normocytic or macrocytic indices; if so, variation in RBC size (dimorphism) usually produces a high RBC distribution width (RDW).

Congenital sideroblastic anemia

Inherited forms of sideroblastic anemia are less common than acquired forms and usually occur in infancy or early childhood. The most common congenital sideroblastic anemia is an X-linked form caused by a germline mutation in ALAS2, a gene involved in heme biosynthesis. Vitamin B6 (pyridoxine) is an essential cofactor for the enzyme produced by ALAS2, thus patients may respond to pyridoxine supplementation.

Numerous other X-linked, autosomal and mitochondrial forms have been identified with mutations in genes involved in heme synthesis or other mitochondrial enzymatic pathways (1).

RBCs are usually microcytic and hypochromic, but this is not always the case.

Reference

  • 1. Ducamp S, Fleming MD: The molecular genetics of sideroblastic anemia. Blood 133:59–69, 2019. doi: 10.1182/blood-2018-08-815951

Diagnosis

  • Complete blood count (CBC), reticulocyte count, and peripheral blood smear

  • Iron studies (serum iron, serum ferritin, and transferrin saturation)

  • Bone marrow examination

  • Genetic testing for a suspected inherited or acquired mutation

Sideroblastic anemia is suspected in patients with microcytic anemia or a high RDW anemia, particularly with increased serum iron, serum ferritin, and transferrin saturation (see Iron Deficiency Anemia).

The peripheral smear shows RBC dimorphism. RBCs may appear stippled.

Bone marrow examination is necessary and reveals erythroid hyperplasia. Iron staining reveals the pathognomonic iron-engorged perinuclear mitochondria in developing RBCs (ringed sideroblasts). Other features of myelodysplasia, such as cytopenias and dysplasia, may be evident.

Serum lead is measured if sideroblastic anemia has an unknown cause.

Treatment

  • Stopping causative substances

  • Vitamin or mineral supplementation

  • Recombinant erythropoietin (EPO)

Elimination of a toxin or drug (especially alcohol or zinc ingestion), or mineral/vitamin supplementation (copper or pyridoxine) can lead to recovery.

Congenital cases may respond to pyridoxine 50 mg orally 3 times a day, but usually incompletely.

Acquired cases will frequently respond to recombinant EPO.

Key Points

  • Sideroblastic anemia can be acquired or congenital.

  • Ringed sideroblasts on a bone marrow biopsy are pathognomic.

  • Anemia is usually microcytic in congenital sideroblastic anemia and macrocytic in acquired sideroblastic anemia.

  • Serum iron, ferritin, and transferrin are typically increased.

  • Treat the underlying disorder and consider pyridoxine in congenital cases or recombinant erythropoietin in acquired cases.

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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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