Anemia:- Part 9 – Sideroblastic Anemia, and Anemia Due To Chronic Diseases

August 1, 2021HematologyLab Tests

Sideroblastic anemia:

Definition:

1. The sideroblastic anemia indicates a group of disorders with the presentation of:
   1. Anemia.
   2. Ineffective erythropoiesis.
   3. Increased serum, and tissue iron.
   4. Increased number of ringed sideroblastic RBCs in the bone marrow aspirate (at least 20%).
      1. Sideroblasts are normoblasts with abnormal stainable iron in the cytoplasm that form a ring around the nucleus.
         

         Sideroblastic cells

2. These anemias are due to abnormalities of heme synthesis.
3. To qualify the sideroblastic anemia, >15% of ringed sideroblasts are to be found.
   1. This may be:
      1. Congenital (inherited).
         1. This includes sex-linked congenital sideroblastic anemia.
         2. Autosommal recessive sideroblastic anemia.
      2. Acquired (drug-induced).
         1. Primary or idiopathic.
            1. Myelodysplasia.
         2. Secondary.
            1. Lead.
            2. Alcohol.
            3. Drugs including isoniazid, and chloramphenicol.
            4. This may be seen in malignancies or malabsorption.

Pathophysiology:

1. The pathogenesis is incompletely understood.
2. Several investigators found the enzyme’s deficiency, including the deficiency of ALA synthase and uroporphyrinogen decarboxylase in these patients.
   1. Irrespective of the etiology, there is the abnormal deposition of iron or siderotic granules in normoblast mitochondria. The mitochondria are present around the nucleus.
   2. There is an adequate amount of iron in the body, but it cannot incorporate into hemoglobin.
   3. The iron (Fe) enters the developing RBCs but accumulates in the normoblast’s perinuclear mitochondria in primary sideroblastic anemia.
      

      Sideroblast in bone marrow smear

3. Classification of sideroblastic anemia:
   1. Inherited:
      1. This is rare and is sex-linked.
      2. Sex-linked (X-linked) anemia is more common than Autosomal recessive sideroblastic anemia.
      3. The responsible gene is ALAS2, found on the sex chromosomes X.
         1. Pyridoxine-responsive.
         2. Pyridoxine-refractory.
         3. Autosomal, pyridoxine-refractory.
      4. These sideroblastic anemias are usually present in childhood.
      5. MCV is usually low, and RDW is usually high.
   2. Acquired type:
      1. Primary (idiopathic).
      2. Secondary:
         1. Associated with myeloproliferative disorders like leukemia and polycythemia vera.
         2. Pyridoxine deficiency (responsive anemia):
            1. Alcoholism.
            2. Drugs induced like INH, and cycloserine, chloramphenicol, and chemotherapy.
            3. Vitamin B12 deficiency.
         3. Hemoglobin synthesis defects:
            1. Deficiency of vitamin B12 and folic acid.
            2. Erythropoietic porphyria.
            3. Lead poisoning.
         4. Radiation.
         5. Other diseases are, e.g., rheumatoid arthritis, carcinoma, megaloblastic,  hemolytic anemia, hemolytic anemia, and malabsorption.
         6. A special acquired rare form of Pearson syndrome has sideroblastic anemia, pancreatic insufficiency, and copper deficiency.
   3. Pyridoxine-responsive anemia:
      1. Classical type.
      2. Variant forms.

Signs and symptoms:

1. Typically anemia appears early, usually within the first few months or years of life.
2. The patients will show pallor and splenomegaly in the sideroblastic anemia.

Lab findings are:

1. The diagnostic feature is nucleated RBCs with iron granules called ringed sideroblasts, present in the bone marrow and dimorphic picture in the peripheral blood smear.
   1. Peripheral blood smears show hypochromic anemia, which is microcytic, normochromic, or macrocytic (dimorphic picture).
      1. The dimorphic picture is seen in the primary type. It is prominent anisopoikilocytosis.
      2. The microcytic form is seen mostly in the inherited form of sideroblastic anemia. In comparison, the macrocytic form is seen in the acquired form.
      3. There may be seen iron-containing Papenheimer bodies and may look like basophilic stippling.
   2. Hemoglobin is low.
      1. MCV is variable and may be low, normal, or increased.
      2. MCH and MCHC are often low but may be normal.
      3. White blood cells may show abnormality.
      4. RDW is increased.
   3. Serum iron is usually more than normal.
      1. Transferrin% saturation is high.
   4. The serum ferritin level is markedly raised.
   5. The serum B12 and folic acid levels are normal.
   6. Raised bilirubin level.
   7. LDH is raised.
   8. Decreased serum haptoglobin.
2. Peripheral blood smears show a dimorphic picture with the presence of normocytic (normal RBCs) and as well as microcytic and hypochromic RBCs (small size RBCs). Occasional macrocytes are seen.
3. Microcytosis is more common in the inherited form of sideroblastic anemia.
   

   Sideroblastic cells in the peripheral blood smear

4. Bone marrow shows erythroid hyperplasia, but circulating reticulocytes are not increased (ineffective erythropoiesis).
   1. There are sideroblasts in the bone marrow aspirate. and these are >15%.
   2. Cytogenetics study shows a chromosomal anomaly in 25% to 50% of the cases.
   3. There are increased or normal iron stores.
      

      Sideroblastic anemia showing sideroblast in bone marrow smear

5. Treatment:
   1. Treat the cause. Some patients respond when alcohol and drugs are stopped.
   2. In primary type, these are unresponsive to various vitamins, especially pyridoxine (another reference says some patient responds to pyridoxine).
   3. Folic acid may be given in case of folate deficiency.

Anemia due to chronic diseases

Definition:

1. 1. This anemia occurs mostly in chronic inflammatory and malignant diseases.
   2. The anemia is present for several months following chronic diseases (which is present for several months).
   3. These are commonly associated with infections, malignant neoplasm, and autoimmune disorders.

Pathogenesis

1. 1. The basic defect is in the iron utilization for erythropoiesis.
      1. It looks that there is a block of the iron delivery from the reticuloendothelial system to RBCs.
      2. Chronic disease state blocks the transfer of storage iron to maturing erythroid precursors within the bone marrow.
      3. This will lead to a deficiency of iron in RBCs, while the stores have abundant iron.
         

         Anemia of chronic diseases

   2. There is a decreased release of the iron from the macrophages to plasma.
   3. RBCs life span is reduced.
   4. Inadequate erythropoietin response to anemia is caused by the effect of cytokines like IL-1 and tumor necrosis factor (TNF) on erythropoiesis.
   5. Hepcidin, released by the liver in response to inflammation, will inhibit macrophages’ release of iron and absorption.
   6. The anemia will respond to successful treatment of the cause, but no response to iron therapy.
   7. Anemia due to chronic diseases may be due to:
      1. Decreased Erythropoietin response by the RBCs.
      2. Decreased RBCs survival.
      3. Defective iron absorption.
      4. Cytokines blocking the release of iron from the reticuloendothelial system for the development of RBCs.

Causes

1. 1. This is seen in collagen diseases (autoimmune diseases).
      1. Systemic lupus erythematosus.
      2. Rheumatoid arthritis.
      3. Sarcoidosis.
   2. Inflammatory chronic conditions.
      1. Tuberculosis.
      2. Chronic osteomyelitis.
      3. Fungal infection.
   3. Malignancies.
      1. Carcinoma.
      2. Lymphomas.
      3. Multiple myeloma.
         Causes of anemia due to chronic diseases:

         Groups of the diseases	Causes of the chronic diseases
         Infections	Tuberculosis Chronic osteomyelitis Fungal infections Bronchiectasis Lung abscess Empyema Infective endocarditis Brucellosis
         Autoimmune diseases	Systemic lupus erythematosus (SLE) Sarcoidosis Rheumatoid arthritis Inflammatory bowel disease Vasculitis
         Malignancies	Lymphomas Multiple myeloma Carcinomas
         Other causes	Chronic liver disease Chronic adrenal insufficiency Hypothyroidism

Signs and symptoms:

1. Anemia appears for several months after the chronic disease.
2. Anemia usually presents 1 to 3 months following the onset of chronic disease.

Lab findings:

1. 1. There is Low hemoglobin (7 to 11 g/dL).
   2. MCV is normal.
   3. RBCs may be normal or microcytic and hypochromic RBCs. This microcytosis is not as severe as in iron deficiency anemia.
      1. Usually normocytic RBCs with normal MCV, rarely  MCV is <75 fl.
      2. In some cases, we may see hypochromic or normochromic RBCs.
         

         Anemia of chronic diseases

   4. Decreased Serum iron.
   5. TIBC is normal or decreased.
   6. The serum ferritin is normal or increased.
   7. There is a decreased % saturation.
   8. Normal to increased serum ferritin level.
   9. It needs to differentiate from iron deficiency anemia.
   10. Decreased sideroblastic cells (rare to absent ringed sideroblast.

Table showing findings in various anemias

Characteristic findings in various Anemias

Classification of anemia based on RDW:

Abnormalities of RBCs and their etiology

Type of RBCs abnormality	Etiology for the abnormality
Microcytic Sickle cell Hb structure	Iron-deficiency anemia Thalassemia Sideroblastic anemia Lead poisoning
Macrocytic	Megaloblastic anemia Liver diseases Myelodysplastic syndrome Increased reticulocyte count
Spherocytes	Hereditary spherocytosis Hemolytic anemia Post transfusion
Target cells RBC target cell	Thalassemia Liver diseases Sideroblastic anemia Hemoglobinopathies
Teardrop cells	Severe anemia Pernicious anemia Myeloproliferative anemia
Elliptocytes	Hereditary elliptocytosis Thalassemia Iron-deficiency anemia
Sickle cells	Sickle cell anemia Sickle-thalassemia
Stomatocytes	Malignant tumors Acute alcoholism
Burr cells	Renal diseases Liver diseases Bleeding gastric ulcer Severe burns
Acanthocytes	Alcohol intoxication Postsplenectomy Vitamin E deficiency Congenital abetalipoproteinemia
Hemet cells	G-6-PD deficiency Pulmonary emboli
Schistocytes	Hemolytic uremic syndrome Thrombotic idiopathic thrombocytopenia (ITP) Disseminated intravascular coagulopathy (DIC)

Summary of lab findings in various anemias:

Various forms of red blood cells