sideroblastic anemia

Lecture 12.sideroblastic anemia

1. Sideroblastic Anaemia

2. Abnormal Accumulation Sideroblasts   ( sidero - + -blast) are atypical, abnormal nucleated erythroblasts (precursors to mature red blood cells) with granules of iron accumulated in the mitochondria surrounding the nucleus . Pappenheimer bodies are abnormal granules of iron found inside red blood cells on routine blood stain. They are a type of inclusion body formed by phagosomes that have engulfed excessive amounts of iron  . Basophilic stippling   : Coarse  basophilic stippling indicates impaired hemoglobin synthesis, probably due to the instability of RNA in the young cell .

3. R efractory anemias : There are less than 5% blasts found in the bone marrow. This subtype of MDS does not often turn into AML.  Refractory anemia  with ringed sideroblasts (RARS). People with this subtype of MDS have  anemia , similar to those with RA, except more than 15% of the red blood cells are sideroblasts .

4. Sideroblastic anemias Sideroblastic anemias are a rare heterogeneous group of refractory anemias characterized by Presence of ring sideroblasts in the bone marrow aspirate. A dimorphic peripheral blood picture. Microcytic hypochromic red cells in hereditary form and macrocytic in the acquired forms of the disease mixed with normochromic cells. Tiny iron-containing inclusions called as Pappenheimer bodies in the red blood cells (stain positively by Prussian blue staining). Increased serum iron concentration and markedly increased storage iron . Ineffective erythropoiesis due to non-viable sideroblasts

5. Sideroblastic anemia   A nemia  is a disease in which the bone marrow produces ringed sideroblasts rather than healthy RBCs (erythrocytes). Caused either by:- genetic disorder   myelodysplastic syndrome , Can evolve into  hematological malignancies  (especially  acute myelogenous leukemia ). the body has iron available but cannot incorporate it into  hemoglobin , which RBCs need to transport oxygen efficiently. Sideroblasts  are atypical, abnormal  nucleated   erythroblasts with granules of iron accumulated in perinuclear  mitochondria . Sideroblasts are seen in aspirates of  bone marrow . Ring sideroblast  are named because of the arrangement of the iron granules in a ring form around the nucleus.

6. Morphology of sideroblasts Grouped on Morphology 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.

7. Classification Sideroblastic anemia is typically divided into subtypes based on its cause. Hereditary C ongenital Sideroblastic anemia may be X-linked or autosomal.

8. HEREDITARY SIDEROBLASTIC ANEMIAS Hereditary sideroblastic anemias comprise a clinically, genetically and hematologically heterogeneous group of rare disorders. It may be inherited as X-linked or an autosomal (dominant or recessive) disorder. patients generally have low levels of δ- aminolevulinic acid synthase (ALAS) enzyme in the normoblasts leading to defective synthesis of hemoglobin.

9. Clinical Features Sex: It predominantly affects males . Anemia : It may not manifest until adolescence . Iron overload may result in : Hepatomegaly Splenomegaly Impaired growth and development Cardiac arrhythmias

10. Symptoms Skin paleness , fatigue, dizziness , enlarged spleen and liver . Heart disease, liver damage , and kidney failure can result from iron buildup in these organs.

11. Causes Drug-induced:  ethanol ,  isoniazid ,  chloramphenicol ,  cycloserine ,  Linezolid ,  oral contraceptives Nutritional:  pyridoxine (Vitamin B6)  or  copper  deficiency Diseases: Rheumatoid arthritis or multiple myeloma Genetic: ALA synthase deficiency ( X-linked , associated with  ALAS2 )

12. Causes failure to completely form  heme  molecules in the  mitochondrion lead to deposits of iron in the  mitochondria  that form a ring around the  nucleus  of the developing  RBC . Sometimes the disorder represents a stage in evolution of a generalized bone marrow disorder that may ultimately terminate in acute leukemia. Toxins:  lead ,  copper , or  zinc  poisoning

13. Laboratory Findings Peripheral Blood Red cell indices:  MCV : Decreased MCH: Decreased • Peripheral smear  RBCs: Red cells show dimorphic blood picture with moderate degree of anisopoikilocytosis . There are microcytic hypochromic red cells mixed with normocytic normochromic red cells. Few red cells may show basophilic stippling. Occasional nucleated RBC may be found.  WBCs and platelets: Usually normal. However, leucopenia and thrombocytopenia may develop due to hypersplenism . Reticulocyte count: 0.2-1%.

14. Diagnosis Ringed sideroblasts are seen in the bone marrow. The anemia is moderate to severe Dimorphic with marked  anisocytosis  and  poikilocytosis . Basophilic stippling  is marked and target cells are common.  Pappenheimer bodies  are present. MCV  is decreased (i.e., a  microcytic anemia ). RDW  is increased with the  red blood cell histogram shifted to the left. 

15. Bone Marrow Bone Marrow • Cellularity: Hypercellular • Erythropoiesis: Erythroid hyperplasia but is ineffective. The reaction may be normoblastic or micronormoblastic . Iron: Moderate to marked increase in bone marrow iron. Ring sideroblasts with partial/ complete perinuclear ring of iron granules are characteristically present Other Findings • Serum ferritin, serum iron and transferrin saturation are increased.

16. Diagnosis 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  TIBC  is normal to decreased. Stainable marrow hemosiderin is increased.

17. ACQUIRED IDIOPATHIC SIDEROBLASTIC ANEMIA • The term primary or idiopathic is applied when other causes of sideroblastic anemia cannot be identified. • Acquired idiopathic sideroblastic anemia (AISA) constitutes a subgroup of the myelodysplastic syndromes refractory anemia with ring sideroblasts (RARS). Majority present after 40 years of age. The dimorphic anemia has both hypochromic-microcytic and macrocytic red blood cells, and the MCV is usually high . At least 15% or more of erythroblasts (early and late forms) in bone marrow are ring sideroblasts .

18. Secondary (drug- or toxin-induced) Sideroblastic Anemia This form of sideroblastic anemia is secondary to various agents that interfere with heme synthesis. Antituberculous drugs: Long-term therapy with isoniazid, cycloserine and pyrazinamide. Lead poisoning: Lead interferes with heme synthesis by blocking the enzymes ALA synthase, ALA dehydratase and heme synthetase . • Chloramphenicol: Sideroblastic anemia results probably due to inhibition of mitochondrial protein synthesis. Copper deficiency or zinc overload: This results in sideroblastic anemia and neutropenia. Copper chelators in large doses, such as penicillamine , can produce sideroblastic anemia . • Ethanol-induced anemia : This is perhaps the most common of the reversible sideroblastic anemias . Folate deficiency, hypomagnesemia and hypokalemia are concomitant findings. • Primary pyridoxine deficiency: It is often associated with malnutrition, is occasionally associated with sideroblastic anemia.

19. Laboratory findings Increased   ferritin  levels Normal  total iron-binding capacity Hematocrit  of about 20-30% Serum Iron: High High  transferrin saturation MCV is usually normal or low. With  lead poisoning , see coarse basophilic stippling of RBCs on peripheral blood smear Specific test: Prussian Blue stain of RBC in marrow. Shows ringed sideroblasts . Can also cause microcytic hypochromic anemia.

20. CONGENITAL DYSERYTHROPOIETIC ANEMIA ( CDA) Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and marrow erythroid multinuclearity . Three common types are recognized. Ring sideroblasts with partial perinuclear ring of iron granules CDA-I is characterized by macrocytic anemia . Bone marrow shows megaloblastic erythropoiesis with internuclear chromatin bridges. CDA-II is the most common form and presents with normocytic normochromic anemia . Bone marrow shows normoblastic hyperplasia with binuclear and multinuclear normoblasts . CDA-II is distinguished from the others because it has a positive acidified serum test and a negative sucrose hemolysis test. It is also known as hereditary erythroblastic multinuclearity with positive acidified serum test (HEM-PAS ). CDA-III has giant erythroid precursors, with more pronounced multinuclearity ( gigantoblasts ) and a macrocytic anemia . In contrast to CDA-I and CDA-II, which are autosomal recessive, CDA-III has autosomal dominant inheritance.

21. Treatment anemia is so severe that support with transfusion is required. Patients usually do not respond to erythropoietin therapy. improved heme level by moderate to high doses of Vitamin Severe cases of SBA, bone marrow transplant with limited information about the success rate. In the case of  isoniazid -induced sideroblastic anemia, the addition of B 6  is sufficient to correct the anemia.  Desferrioxamine  is used to treat iron overload from transfusions. Bone Marrow Transplant (BMT) is the last possible treatment.