A Ring Sideroblast visualized by Prussian blue stain
|Classification and external resources|
|OMIM||301310 206000 300751|
Sideroblastic anemia or sideroachrestic anemia is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can evolve into hematological malignancies (especially acute myelogenous leukemia).
Sideroblasts (sidero- + -blast) are atypical, abnormal nucleated erythroblasts (precursors to mature red blood cells) with granules of iron accumulated in perinuclear mitochondria. Normally, Sideroblasts are present in the bone marrow, and enter the circulation after maturing into a normal erythrocyte.
Ring sideroblasts are so named so because iron-laden mitochondria form a ring around the nucleus. To count a cell as a ring sideroblast, the ring must encircle a third or more of the nucleus and contain five or more iron granules, according to the 2008 WHO classification of the tumors of the hematopoietic and lymphoid tissues.
The WHO International Working Group on Morphology of MDS (IWGM-MDS) defined three types of sideroblasts:
- Type 1 sideroblasts: fewer than 5 siderotic granules in the cytoplasm
- Type 2 sideroblasts: 5 or more siderotic granules, but not in a perinuclear distribution
- Type 3 or ring sideroblasts: 5 or more granules in a perinuclear position, surrounding the nucleus or encompassing at least one third of the nuclear circumference.
Sideroblastic anemia is typically divided into subtypes based on its cause.
- Hereditary or congenital sideroblastic anemia may be X-linked or autosomal.
|300751||X-linked sideroblastic anemia (XLSA)||ALAS2|
|301310||sideroblastic anemia with spinocerebellar ataxia (ASAT)||ABCB7|
|205950||pyridoxine-refractory autosomal recessive sideroblastic anemia||SLC25A38|
|206000||pyridoxine-responsive sideroblastic anemia||(vitamin B6 deficiency; pyridoxal phosphate required for heme synthesis)|
- Acquired, or secondary, sideroblastic anemia develops after birth and is divided according to its cause.
Symptoms of sideroblastic anemia include skin paleness, fatigue, dizziness, and enlarged spleen and liver. Heart disease, liver damage, and kidney failure can result from iron buildup in these organs.
Causes of sideroblastic anemia can be categorized into three groups: congenital sideroblastic anemia, acquired clonal sideroblastic anemia, and acquired reversible sideroblastic anemia. All cases involve dysfunctional heme synthesis or processing. This leads to granular deposition of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell. Congenital forms often present with normocytic or microcytic anemia while acquired forms of sideroblastic anemia are often normocytic or macrocytic.
- Congenital sideroblastic anemia
- X-linked sideroblastic anemia: This is the most common congenital cause of sideroblastic anemia and involves a defect in ALAS2, which is involved in the first step of heme synthesis. Although X-linked, approximately one third of patients are women due to skewed X-inactivation.
- Autosomal recessive sideroblastic anemia involves mutations in the SLC25A38 gene. The function of this protein is not fully understood, but it is involved in mitochondrial transport of glycine. Glycine is a substrate for ALAS2 and necessary for heme synthesis. The autosomal recessive form is typically severe in presentation.
- Genetic syndromes: Rarely, sideroblastic anemia may be part of a congenital syndrome and present with associated findings, such as ataxia, myopathy, and pancreatic insufficiency.
- Acquired clonal sideroblastic anemia
- Clonal sideroblastic anemias fall under the broader category of myelodysplastic syndromes (MDS). Three forms exist and include refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). These anemias are associated with increased risk for leukemic evolution.
- Acquired reversible sideroblastic anemia
- Causes include excessive alcohol use (the most common cause of sideroblastic anemia), pyridoxine deficiency, lead poisoning, and copper deficiency. Excess zinc can indirectly cause sideroblastic anemia by decreasing absorption and increasing excretion of copper. Antimicrobials that may lead to sideroblastic anemia include isoniazid, chloramphenicol, cycloserine, and linezolid.
Ringed sideroblasts are seen in the bone marrow.
The anemia is moderate to severe and dimorphic. Microscopic viewing of the red blood cells will reveal marked unequal cell size and abnormal cell shape. Basophilic stippling is marked and target cells are common. Pappenheimer bodies are present in the red blood cells. The mean cell volume is commonly decreased (i.e., a microcytic anemia), but MCV may also be normal or even high. The RDW is increased with the red blood cell histogram shifted to the left. Leukocytes and platelets are normal. Bone marrow shows erythroid hyperplasia with a maturation arrest.
In excess of 40% of the developing erythrocytes are ringed sideroblasts. Serum iron, percentage saturation and ferritin are increased. The total iron-binding capacity of the cells is normal to decreased. Stainable marrow hemosiderin is increased.
- Serum Iron: High
- Increased ferritin levels
- Normal total iron-binding capacity
- High transferrin saturation
- Hematocrit of about 20-30%
- The mean corpuscular volume or MCV is usually normal or low for congenital causes of sideroblastic anemia but normal or high for acquired forms.
- With lead poisoning, see coarse basophilic stippling of red blood cells on peripheral blood smear
- Specific test: Prussian blue stain of RBC in marrow shows ringed sideroblasts. Prussian blue staining involves a non-enzymatic reaction of ferrous iron with ferrocyanide forming ferric-ferrocyanide, which is blue in color. A counterstain may be used to provide better visualization.
Occasionally, the anemia is so severe that support with transfusion is required. These patients usually do not respond to erythropoietin therapy. Some cases have been reported that the anemia is reversed or heme level is improved through use of moderate to high doses of pyrodoxine (Vitamin B6). In severe cases of SBA, bone marrow transplant is also an option with limited information about the success rate. Some cases are listed on MedLine and various other medical sites. In the case of isoniazid-induced sideroblastic anemia, the addition of B6 is sufficient to correct the anemia. Desferrioxamine, a chelating agent, is used to treat iron overload from transfusions. Therapeutic phlebotomy can be used to manage iron overload. Bone marrow transplant (BMT) can be considered in severe cases.
Course and prognosis
Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B6.
1- Congenital: 80% are responsive, though the anemia does not completely resolve.
2- Acquired clonal: 40% are responsive, but the response may be minimal.
3- Acquired reversible: 60% are responsive, but course depends on treatment of the underlying cause.
Severe refractory sideroblastic anemias requiring regular transfusions and/or that undergo leukemic transformation (5-10%) significantly reduce life expectancy.
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