Macrocytic Anemia

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Reticulocytes

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-occur after extrusion of nucleous from orthochromic normoblast
-remainsin marrow approx 3 days
-released into circulation- remodeled with loss of water and mambrane
-normal retics are macrocytic

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Icreased erythropoietic drive causes

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reticulocytes to be released early

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Alcohol and retics

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mech unknown, acetaldehyde can induce membrane changes and interfere with cellular division

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Liver Disease

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mechanism of macrocytosis is unclear, maybe caused by incr in lipid deposition in red cell membranes
-Target cells on smear

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Thyroid Disease

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Mechanism of macrocytosis is unknown, autoimmune thyroiditis assoc with antiparietal cell antibodies

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Spurious Macrocytosis

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Artifacts that can occur to normal size rbcs. Clumps are counted as single cells by automated counter

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Myelodysplastic Syndromes

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group of diseases where bone marrow does not make enough healthy blood cells, AKA preleukemia and smoldering leukemia.
-hypolobulated or hypogranular neutropils, lg and/or abnormally granulated plts, monocytosis, occasional blast forms

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Megaloblastic anemia

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anemia, often with pancytopenia with macrocytic rbcs adn hyperseg'd neutrophils due to impairment in DNA synth. Inadequate conversion of deoxyuridate to thymidylate. Slows DNA synth, delayed nuclear maturation. Neclear cytoplasmic dyssynchrony ( immature nucl and mature cyto)

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Interference with DNA synthesis can be caused by

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Folate def, Cobalmin def, Drugs

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Megaloblastic Anemias

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Characterized by defect in DNA synth resulting in unbalanced cell growth and implaired division. Immature appearing nucl but mature cyto and large cells. Most common causes are B12 and folate def.

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Coblamin dependant enzymes

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L-methylmethionyl CoA mutase (methylmalonic acid metabolism) and methionine synthase (metabolism of homocysteine).

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Increases in homocysteine levels and MMA are indicative of :

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Cobalmin Deficiency.
Homocysteine alone: folate deficiency

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Cobalmins and folate affect DNA synthersis by being directly involved in the synthesis of what?

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Purines

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Sources of B12

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Fish, eggs, poultry, fortified cereals

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Sources of folate

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fortified breakfast cereals, beef, liver, spinach, norhtern beans

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Stages of cobalmin metabolism

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-intake solely via food
-hapto corrin and gastric secretions (HCL and pepsin), IF, pancreatic and biliary secretions, enterohepatic cycle.
- Absorption brings into play IF and Cubilin
- Transport by transcobalmins
-Intracellualr enzymes.

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causes of coblamin deficiency

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vegetarian diet, gastrectomy, pernicious anemia, food-conbalmin malabsorption, ileal resection, deficiency in transcobalmin II, deficiency in intracellular enzymes. Achlorhydria

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Serum Findings in B12 Deficiency

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- Low Cobalmin
-normal folate
-High MMA
-High Homocysteine

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Serum Findings in Folate Deficiency

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-normal cobalmin
-low folate
-normal MMA
-high Homocysteine

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Peripheral Blood findings in Cobalamin or Folate Deficiency

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Hyperseg'd neutrophils, oval macrocytosis (with or without anemia) Hi MCV, thrombocytopenia or leukopenia w/ immature forms, basophilic stippling.

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Bone Marrow Abnormalities in Coblamin of Folate Deficiency

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Hypercelluar, giant bands and metamyelocytes, N:C dyssynchrony, open and immature nuclear chromatin pattern, Karyorrhexis.

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Karyorrhexis

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stage of cellular necrosis in which the fragments of the nucleus fragments and its chromatin are distributed irregularly throughout the cytoplasm

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Blood Chemistry in Cobalamin or Folate Deficiency

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Incr indirect Bili
Incr LDH

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Which cells exhibit megaloblastosis?

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All proliferating cells, but megaloblastic changes are most striking in the blood and bone marrow

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Other Clinical Manifestations of Cobalamin and Folate Deficiency

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Glossitis, secondary malabsorption caused by megaloblastic GI changes, weight loss/growth failure, infertility, thrombosis, hyperpigmentation, immune deficiency

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Pernicous Anemia

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B12 deficiency caused by malabsrption due to immune attack on IF or loss of parietal cells.
-peripheral neuropathies, Dorsal Column involvement ( loss of propri and vibr sense, ataxia), subacute combined degeneration of spinal cord, psych Sx like dementia or psychosis

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Management of Cobalamin Deficiency Using Cobalamin Rx

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Parenteral-1000 micro grams IM weekly x 8wks Maintenance dose is 1000 a month
Oral- 1000/day for a month. Maintenance is 125-500 for intake deficiency, 1000/day for pernicious anemia

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Folate supplementation

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1 mg PO daily.
**folate repletion without B12 repletion can normalize MCV and Hgb but allow neuro Sx to persist

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Schilling Test

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Measures Cobalamin Absorption.
Part 1: Give radioactive B12 by mouth. After 1 ht, give injection of unlabeled cobalamin (flushing dose) to saturate plasma B12 binders so labeled B12 will be exreted.
-Measure amount of labeled B12 in ureine. Pernicious anemia will have lost little to none to absorption. Amt of labeled B12 in urine would be less than normal
Part 2: give exogenous IF with labeled B12. In pts w/ penicious anemia this should correct the absorption and increae secretion into the normal range. If still abnormal, SI cant absorb B12 IF complex.

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Diagnostic Tests for Pernicious Anemia

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Anti Parietal cell anitbodies
Anti If antibodies
Low Serum Pepsinogen
High serum gastrin
Schilling test
endoscopy

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Causes of Folate Deficiency

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diet, Alcoholism, Sprue, Crohn's disease, hemodialysis, incr cellular propliferation (pregnancy, skin diseases, hemolysis, malignancies), drugs: antifolates and anticonvulsants.

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Most common cause of megaloblastic anemia

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Pernicous Anemia