Sideroblastic Anemia Flashcards
What is the underlying defect in sideroblastic anemias?
Sideroblastic anemias have an impaired biosynthesis of heme in the erythroid cells of the bone marrow.
This impairment can be due to either impaired production of protoporphyrin (δ-aminolevulinic acid synthase) or defective insertion of iron into protoporphyrin (ferrochelatase/heme synthetase)
How does iron accumulation occur in sideroblastic anemias?
In sideroblastic anemias, iron delivery to the erythroid is not downregulated despite the impaired heme synthesis. Iron continues to be transported normally to the mitochondria. However, since it cannot be incorporated into heme synthesis, it accumulates in a ring form around the nucleus of the erythroid cells. This leads to the characteristic ring sideroblast appearance when stained with Perl’s Prussian Blue Stain.
How are ring sideroblasts identified in sideroblastic anemias?
Ring sideroblasts are identified using the Perl’s Prussian Blue Stain. To make a diagnosis of sideroblastic anemia, at least 15% of the normoblasts must be ring sideroblasts.
How are sideroblastic anemias classified?
Sideroblastic anemias are typically classified as hereditary or acquired.
Acquired sideroblastic anemias can be further classified as idiopathic (referring to refractory anemia with ring sideroblasts, RARS) or secondary to drugs or toxins.
What is the pathophysiology of hereditary sideroblastic anemia?
patients with hereditary sideroblastic anemia have decreased δ-aminolevulinic acid synthase (ALA-S) activity, which is the first enzyme in the porphyrin and heme synthesis pathway. This decrease in ALA-S activity impairs the condensation of glycine and succinyl CoA, leading to impaired heme synthesis.
What are the clinical manifestations and physical findings of hereditary sideroblastic anemia?
Hereditary sideroblastic anemia is usually evident during infancy. Patients typically display signs and symptoms of anemia. Additionally, patients may also exhibit manifestations of iron overload.
What are the laboratory findings in hereditary sideroblastic anemia?
• The peripheral blood analysis shows severe anemia with a very low average hemoglobin (Hb) level of 6.0g/dl.
- MCV, MCH, MCHC are all decreased
- RDW ⬆️
Red cell morphology reveals anisocytosis, poikilocytosis with a microcytic, hypochromic picture, target cells and occasional siderocytes. Basophilic stippling is also observed but the number of circulating reticulocytes is not elevated (it is either N or slightly increased).
In milder cases, erythrocyte dimorphism is common including: microcytic hypochronic cells and normocytic normochromic cells.
• Bone marrow
1. Erythroid hyperplasia, with ineffective erythropoiesis.
2. ⬆️ iron stored in macrophages due to ineffective erythropoiesis and ⬆️ iron absorption from the intestines. (low hepcidin as opposed to ACD)
3. ~ 40% ring sideroblasts, most typically observed in the late non dividing
erythroblasts.
• Chemistry
1. Ferritin levels are high, consistent with the large amounts of stored iron.
2. In addition, serum iron is high, as is transferrin saturation (> 80%) indicating that iron is being delivered effectively to the developing erythrocytes in the bone marrow; however it is not utilized in hemoglobin synthesis and so it piles up in the mitochondria, creating the ring sideroblasts.
3. TIBC is normal/low
What is the treatment for hereditary Sideroblastic anemia?
- Pyridoxine typically is the treatment of choice, but only in some patients (1/3 of patients), a remarkable response is observed. Unfortunately, in most cases, pyridoxine produces only a slight improvement or produces no improvement. So the prognosis is variable and depends on the patient’s response to pyridoxine therapy.
- Transfusions in severe cases.
- Some measures like iron chelating could be taken to remove excess accumulated iron to reduce the risk of problems related to iron overload.
What is idiopathic acquired sideroblastic anemia (IASA)?
Idiopathic acquired sideroblastic anemia (IASA) is also known as Refractory Anemia with Ring Sideroblasts (RARS). It is classified as a subtype of Myelodysplastic Syndromes (MDS) according to the French-American-British (FAB) group. IASA is a clonal disorder characterized by an abnormal proliferating erythroid cell line.
What is the pathophysiology and etiology of IASA?
The exact mechanism leading to the development of IASA/RARS is not clear. However, decreased activity of δ-aminolevulinic acid synthase (ALA-S) has been consistently found in many patients. In some individuals with IASA, low levels of heme synthase (ferrochelatase) have also been documented.
What is the clinical presentation and physical findings of IASA?
IASA commonly occurs in individuals older than 50 years. The disease has an insidious onset, and it is often discovered during routine examinations. Some patients may experience typical symptoms of anemia.
What is the laboratory diagnosis for IASA?
IASA is usually a moderate anemia (as opposed to Hereditary which is severe) with Hb in the range of 8-10g/dl and a Hct in the range of 25-35%.
In most patients with this disorder, the MCV is > 100 fl and may be as high as 130fl.
Examination of the PB smear shows:
- Anisocytosis and poikilocytosis
-The RBC(s) are normocytic normochromic or macrocytic normochromic, and some cells are microcytic hypochromic. (Dimorphism is evident in these patients, as in the hereditary form of the disease, although the population of microcytic hypochromic cells may be small.)
- Target cells, siderocytes and heavily stippled, hypochromic cells may be seen.
- Erythroblasts with coarse basophillic stippling and megaloblastoid nucleus
- HJB can be detected
Bone marrow
1. Examination of the bone marrow reveals significant erythroid hyperplasia. Although mild dyserythropoiesis (multinuclearity, nuclear budding) and megaloblastoid changes are present, both myelopoiesis and megakoryopoiesis are usually normal.
- Iron stains also show increased amounts of stored iron in macrophages (due to ineffective erythropoiesis, and ⬆️ iron absorption, and repeated transfusions).
- As many as 95% of the normoblasts are ring sideroblasts (in hereditary only 40%). In contrast to hereditary sideroblastic anemia, ring sideroblasts are evident at all stages or erythroid maturation.
Chemistry
Iron studies show:
1. An ⬆️ serum iron
2. Very high Tf saturation levels
3. ⬆️ in the serum ferritin level
Cytogenetic studies
In approximately 50% of cases, chromosomal changes have been identified
Which index is the most useful for the diagnosis of Idiopathic Acquired Sideroblastic Anemia?
The MCV is the most consistent and useful erythrocyte index in the diagnosis of the anemia. (It is very high)
What are patients with IASA first suspected of having after presenting with macrocytosis?
As a result of the macrocytosis, some patients with IASA are initially diagnosed as having deficiency of Vit B12 or folate. They are treated with Vit B12 or folate but do not respond. The refractory behavior of their anemia soon becomes apparent.
What is the treatment for IASA or 1° acquired Sideroblastic anemia?
In a number of patients, no treatment is required because the anemia typically is non progressive.
A therapeutic trial of pyridoxine is usually given, but most patients do not respond.
Transfusions are necessary in many patients who have Hb levels of 8 g/dl or less. With transfusions, iron chelation therapy may be required to remove excess iron and prevent hemochromatosis.
