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What is the DNA-related biochemical abnormality that result from B12 and fotalte deficiency and what are the results of this abnormality?
- Thymidine triphosphate (TTP) is needed for normal DNA synthesis
- Decrease in TTP synthesis from uridine monophosphoate (UMP) results in abnormal DNA synthesis
- Results
- Defective nuclear maturation and megaloblastic morphology
- immature nuclear proteins
- *note-essentially DNA maturation lags behind cell development
- early hemoglobinization of RBCs
- fragmentation of nucleus and early destruction of RBCs (too big, broken apart in transit)
- Macrocytic anemia
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What are the clinical features of macrocytic anemia (B12 deficiency, folate deficiency)
- Fatigue
- Weakness
- Shortness of breath
- Lightheadedness
- Some jaundice in severe cases due to increased bilirubin
- Congestive heart failure possible in severe cases
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Describe the bone marrow of a patient with macrocytic anemia
- Ineffective hematopoiesis in RBCs, WBCs, and platelets
- Hypercellular marrow (overcorrecting)
- M:E ratio can be from 1:1 to 1:3
- Asynchronous development between the nucleus and cytoplasm
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What are the stages of megaloblastic erythrocyte maturation?
- Promegaloblast
- Basophilic megaloblast
- Polychromatic megaloblast
- Orthochromatic megaloblast
- Diffusely basophilic macrocyte
- Macrocyte
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Describe the peripheral blood findings of a patient with macrocytic anemia (blood smear, standard RBC tests, morphology, other special tests)
- Macrocytic, normochromic
- RBC count: 1-3x106/μL
- Hgb: 6-9 g/dL
- Hct: 20-30%
- MCV: 100-160fL
- MCH: increased
- MCHC: normal
- morphology: macrocytes, macroovalocytes, anisocytosis, poikilocytosis, decreased reticulocyte count, RBC inclusion
- Hypersegmented neutrophils (5+ segments)
- Decreased platelets
- Elevated Lactate dehydrogenase (LDH)
- Bilirubin and urobilinogen
- Decreased free haptoglobin
- Increased free iron
- Increased erythropoietin
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What are sources of B12? What are the nutritional requirements?
- Produced by microorganisms and fungi
- Liver, fish, poultry, meat, eggs
- Intake 5-30μg/day, 1-5μg/day absorbed
- dependent on body's needs
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Describe B12 absorption and transport
- B12 enters stomach and couples with IF (intrinsic factor)
- Decouples in/near the ileum, and B12 is absorbed (in the ileum)
- TCII (transcobalamin II) (carrier protein) transmits B12 through the blood stream to final destination (marrow, liver, other)
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How much B12 does the body store? What is the % loss each day? How long might it take to become deficient?
- 1-5mg Vit B12 is stored
- ~.1%/day is lost (stool)
- Takes years to become B12 deficient
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What is the etiology (various causes) of B12 deficiency?
- Dietary
- Poor diet
- mothers who are strict vegetarian may have children who are deficient
- Malabsorption
- pernicious anemia (decreased IF due to parietal cell atrophy)
- gastrectomy, ileal diseases
- fish tapeworm
- HIV and AIDSAlcohol
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Clinical features of B12 deficiency?
- Typical megaloblastic picture in bone marrow and blood
- Neurological problems: degeneration of peripheral nerves, degeneration of spinal cord
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What are the sources of Folic Acid?
- Water-soluble vitamin
- Green, leafy vegetables
- Fruits, dairy products, cereals
- Liver, kidney
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What are the nutritional requirements for folic acid?
- 400-600μg/day in the average diet
- 50-100μg/day recommended intake
- dependent on body's needs
- *note-overcooking foods destroys folic acid and causes deficiency
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Describe folic acid absorption and transportation
- Polyglutamic acid enters the stomach and is moved to the duodenum and jejunum
- It is converted to monoglutamate then methyl tetrahydrofolate (CH3THF) in the duodenum and jejunumCH3THF is coupled with a protein transporter and then delivered to the tissues
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How much folic acid is stored in the body? How long would it take to become deficient?
- Body stores 5-10mg in many tissues
- Takes only a few months to become deficient
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Describe the etiology (causes) of folate deficiency
- Dietary
- poverty
- aging
- alcoholism
- Malabsorption
- Tropical sprue syndrome
- Increased requirement
- pregnancy
- infancy
- cancer
- Drugs
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What are the clinical features of folate deficiency
- Typical megaloblastic picture in bone marrow and blood
- Neurological problems: not as severe as B12 deficiency
- Depression and dementia in some cases
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What laboratory tests differentiate between B12 and Folate deficiencies?
- Serum B12 levels
- Serum and RBC folate levels
- Antibodies to intrinsic factor
- Schillings test (evaluates B12 absorption from GI tract)
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Describe the treatments for B12 and for folate deficiencies
- B12: oral therapy, injections
- Folate: oral therapy
- *note- Effectiveness monitored by increase in reticulocyte count and hematocrit
- *note- may take only a few weeks to respond
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What are non-megaloblastic causes of macrocytosis?
- Chronic liver disease
- Alcoholism
- Acute hemorrhage
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