1) Macrocytic anemias are characterized by large red blood cells (RBCs) and can be megaloblastic or non-megaloblastic. Megaloblastic anemias involve defective DNA synthesis leading to abnormal RBC maturation.
2) The most common causes of megaloblastic anemia are vitamin B12 and folic acid deficiencies, which prevent the conversion of dUMP to dTMP needed for DNA synthesis. Neurological symptoms occur only in B12 deficiency due to propionyl CoA accumulation.
3) Laboratory findings show macrocytic anemia, hypersegmented neutrophils, and Howell-Jolly bodies on smear. The Schilling test
1) Macrocytic anemias are characterized by large red blood cells (RBCs) and can be megaloblastic or non-megaloblastic. Megaloblastic anemias involve defective DNA synthesis leading to abnormal RBC maturation.
2) The most common causes of megaloblastic anemia are vitamin B12 and folic acid deficiencies, which prevent the conversion of dUMP to dTMP needed for DNA synthesis. Neurological symptoms occur only in B12 deficiency due to propionyl CoA accumulation.
3) Laboratory findings show macrocytic anemia, hypersegmented neutrophils, and Howell-Jolly bodies on smear. The Schilling test
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1) Macrocytic anemias are characterized by large red blood cells (RBCs) and can be megaloblastic or non-megaloblastic. Megaloblastic anemias involve defective DNA synthesis leading to abnormal RBC maturation.
2) The most common causes of megaloblastic anemia are vitamin B12 and folic acid deficiencies, which prevent the conversion of dUMP to dTMP needed for DNA synthesis. Neurological symptoms occur only in B12 deficiency due to propionyl CoA accumulation.
3) Laboratory findings show macrocytic anemia, hypersegmented neutrophils, and Howell-Jolly bodies on smear. The Schilling test
Copyright:
Attribution Non-Commercial (BY-NC)
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Download as PPT, PDF, TXT or read online from Scribd
Macrocytic anemias are characterized by large RBCs with a normal
hemoglobin content. The biochemical basis for this is as follows: Megaloblastic dyspoiesis (abnormal synthesis) occurs when the DNA synthesis in the hematopoietic system is disrupted. Other rapidly proliferating cells in the body are also affected. Administration of drugs that interfere with DNA metabolism can be the cause of a megaloblastic anemia. Macrocytic anemias are classified as either megaloblastic or non- megaloblastic Megaloblastic anemias are associated with defective DNA synthesis and therefore, abnormal RBC maturation in the bone marrow (a nuclear maturation defect). In megaloblastic anemias, the granulocytic and megakaryocytic
maturation are also affected and this leads to pancytopenia
Megaloblastic anemias However, the primary defect in DNA replication is usually due to depletion of thymidine triphosphate which leads to retarded mitosis, and therefore retarded nuclear maturation. The depletion of thymidine triphosphate is usually due to a
deficiency of vitamin B12 or folic acid.
Vitamin B 12 deficiency is usually due to a deficiency of a factor necessary for B12 absorption while a folic acid deficiency is usually due to an inadequate dietary intake. When B12 is released from the mucosal cell, it binds to transport proteins in the bloodstream (transcobalamine I→III). Type II is the primary transport protein. Therefore a congenital deficiency in type II can lead to a megaloblastic anemia. B 12 is transported to the bone marrow for use or to the liver for storage. How is B12 involved in DNA synthesis? Decreased vitamin B12 therefore results in no conversion of N5-methyl THF to THF. Thus, the net result is that dTMP for DNA synthesis is not made. Megaloblastic anemias Folic acid (pteroyl glutamic acid) Is found in most foods, including eggs, milk, yeast, and liver. Is abundant in green, leafy vegetables and is synthesized by many microorganisms. Is destroyed by heat Absorption occurs in the small intestine Therefore, with decreased folic acid, the net result is the same as that for decreased vitamin B12 – there is decreased conversion of dUMP to dTMP, and thus, dTTP which is required for DNA synthesis. Defective DNA synthesis may occur when dUTP gets used in place of dTTP because there is a great increase in erroneous DNA copying where dUTP is put in place of dTTP. Megaloblastic anemias Clinical manifestations occur in two categories – those found in folic acid or vitamin B12 deficiency, and those only found in B12 deficiency In both types of deficiency the symptoms include pallor, weakness, lightheadedness, a smooth,sore tongue, and diarrhea alternating with constipation In vitamin B12 deficiency only, there are neurological disturbances including numbness and tingling of extremities, gait abnormalities, and mental disturbances. This is due to a defect in the degradation of
propionyl CoA to succinyl CoA leading to an
accumulation of propionyl CoA: Megaloblastic anemias When there is a build up of propionyl CoA (3 carbons), it is used in place of acetyl CoA (2 carbons) as a primer for fatty acid synthesis. Fatty acids with odd numbers of carbons get incorporated into neural membranes This leads to disruption of membrane function with subsequent demyelination of nerve fibers. Lab findings Macrocytic, normochromic anemia (MCV=100-140, MCHC is normal)) MCH is increased (due to increased cell size) Megaloblastic anemias On a peripheral smear, a triad of things is commonly seen: oval macrocytes, Howell Jolly bodies (nuclear DNA fragments), and hypersegmented neutrophils (5 or more lobes). In addition: Anisocytosis is usually moderate
Poikilocytosis is striking with nucleated RBCs,
polychromatophilia, and cabot rings (spindle
remnants). RBC dimorphism is seen with concomitant IDA.
The absolute reticulocyte count is decreased
because of ineffective erythropoiesis.
Megaloblastic anemias The bone marrow will show hypercellularity, yet there are decreased numbers of all cell types in the peripheral blood because ineffective hematopoiesis is occurring and many cells are dying prematurely in the bone marrow. In folic acid deficiency – there will be decreased serum and RBC folate In B12 deficiency – there will be decreased serum vitamin B12 Specific tests for PA Gastric analysis – if there is no free HCl after
histamine stimulation, this may indicate PA since
the same cells that secrete HCl, also secrete intrinsic factor (IF) Megaloblastic anemias Schilling test – is the definative test for the diagnosis of PA. The test measures the amount of an oral dose of radioactively labeled B12 that is absorbed in the gut and excreted in the urine. This is followed by an injection of unlabeled vitamin B12 to saturate all vitamin B12 receptors in the tissue and plasma. Thus any amount absorbed in the gut will be in excess, and will be filtered in the kidneys to appear in the urine. If there is no radioactivity in the urine, this means that there is either malabsorption or PA. The test is repeated, but this time the radioactively labeled B12 is accompanied by a dose of IF. If absorption is now normal, this means that the patient has PA Schilling test Schilling test results Non-megaloblastic macrocytic anemia Non-megaloblastic macrocytic anemia Note that the macrocytic RBCs are not oval, but are round. There are no hypersegmented neutrophils or Howell-Jolly bodies Differential diagnosis with increased MCV Differential diagnosis with a high MCV Lab results of megaloblastic vs non- megaloblastic macrocytosis