(See also Overview of Decreased Erythropoiesis Overview of Decreased Erythropoiesis Anemia, a decrease in the number of red blood cells (RBCs), hemoglobin (Hb) content, or hematocrit (Hct), can result from decreased RBC production (erythropoiesis), increased RBC destruction... read more .)
Sideroblastic anemias may be
Acquired sideroblastic anemia is frequently associated with the myelodysplastic syndrome Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more (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 (splicing factor 3b subunit 1), commonly occur. Acquired sideroblastic anemia occurs in adulthood.
Less common causes include
Deficiency of vitamin B6 (pyridoxine) or copper (possibly caused by zinc ingestion, which prevents absorption of copper in the gastrointestinal tract)
Drugs (eg, chloramphenicol, cycloserine, isoniazid, linezolid, pyrazinamide)
Toxins (including ethanol and lead)
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 X-Linked Dominant Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more form caused by a germline mutation in ALAS2 (5'-aminolevulinate synthase 2), 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 General reference 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... read more ).
RBCs are usually microcytic and hypochromic, but this is not always the case.
1. Ducamp S, Fleming MD: The molecular genetics of sideroblastic anemia. Blood 133:59–69, 2019. doi: 10.1182/blood-2018-08-815951
Diagnosis of Sideroblastic Anemias
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 Iron Deficiency Anemia Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more ).
The peripheral smear Peripheral smear Anemia is a decrease in the number of red blood cells (RBCs) as measured by the red cell count, the hematocrit, or the red cell hemoglobin content. In men, anemia is defined as any of the following... read more 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 Myelodysplasia and Iron-Transport Deficiency Anemia In myelodysplastic syndrome, anemia is commonly prominent. The anemia is usually normocytic or macrocytic, and a dimorphic (large and small) population of circulating cells can be present. ... read more , such as cytopenias and dysplasia, may be evident.
Serum lead is measured if sideroblastic anemia has an unknown cause.
Treatment of Sideroblastic Anemias
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 high doses of recombinant EPO. Cases that are refractory to EPO supplementation can be treated with luspatercept, which promotes differentiation of red cell precursors (1 Treatment reference 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... read more ).
1. Fenaux P, Platzbecker U, Mufti GJ, et al:Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med 382(2): 140–151, 2020. doi: 10.1056/NEJMoa1908892
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.