Chapter 4: Megaloblastic Anemias (macrocytic anemias) Flashcards
What are macrocytic anemias?
Anemias in which cells have a MCV greater than 95.
What is megaloblastic anemia?
Anemia characterized by cells with nuclei that are immature compared with the cytoplasm.
What is the underlying cause of megaloblastic anemia?
Megaloblastic anemia is usually caused by defective DNA synthesis. (commonly the result of B12 or folate deficiency.
What is cobalamin (55)?
Cobalamin is Vitamin B12.
Where is B12 created (55)?
B12 is created by microorganisms.
What is the structure of B12 (55)?
B12 (cobalamin) is composed of a cobalt atom at the center of a corrin ring
How is B12 absorbed(56)?
B12 binds to intrinsic factor (IF) forming a complex that binds the receptor cubilin. the new complex then binds a second protein called amnionless which then endocytoses the B12.
What happens to B12 in the blood stream (56)?
B12 in the blood stream binds to either transcobalamin or haptocorrin. However, only transcobalamin is able to deliver B12 to the bone marrow.
What binds more B12 haptocorrin or transcobalamin (57)?
Haptocorrin binds most of the B12.
What are the two biochemical functions of B12 (57)?
(1) B12 is a cofactor for methionine synthase in the synthesis of methionine
(2) B12 helps to convert methylmalonyl CoA to succinyl CoA.
How is B12 deficiency tested for (57)?
levels of homocysteine or methylmalonic acid are assayed.
How is Folate absorbed(58)?
Folate is converted to THF to be absorbed by enterocytes. The enterocytes then convert THF to folate polyglutamates.
What is the function of folate(58)?
Folate functions in single carbon unit transfer. (synthesis of glycine or purine etc.)
Why does folate deficiency cause megaloblastic anemia(58)?
Folate deficiency causes megaloblastic anemia because folate is necessary for the synthesis of thymidylate (a precursor of thymine).
How is dihydrofolate converted to tetrahydrofolate during thymidylate synthesis(59)?
It is converted by dihydrofolate reductase?
What drugs inhibit dihydrofolate reductase(59)?
(1) Methotrexate (antineoplastic)
(2) pyrimethamine (anti malarial)
(3) Trimethoprim (antimicrobial)
What are the most common causes of B12 deficiency in western culture (59)?
(1) Addisonian pernicious anemia
(2) Veganism (it is found in meat)
(3) Gastrectomy or small intestinal lesions.
(4) Nitrous oxide may inactivate B12.
What causes pernicious anemia(59)?
Pernicious anemia is caused by an autoimmune attack that causes atrophy of the gastric mucosa. (commonly initiated by helicobacter pylori infection)
What is the epidemiology of pernicious anemia(59)?
(1)Pernicious anemia is most common in females. (2)Peak age of onset is 60. (3) Occurs most in northern europeans. (4) 2-3% of patients develop carcinoma of the stomach.
What antibodies are present in pernicious anemia(60)?
(1) Parietal cell antibodies (against H/K ATPase) (90%) (also occurs in 16% for normal people over 60)
(2) Type 1 blocking antibody against IF (50%)
(3) Type 2 precipitating antibody against IF.
How long does it take for B12 deficiency to take effect (60)?
it takes 2 years for B12 stores to be depleted.
What are some secondary causes of B12 deficiency (60)?
(1) Congenital defect in B12 absorption complex
(2) inadequate intake
(3) atrophic gastritis (without IF antibodies) (helicobacter pylori)
What causes folate deficiency (60)?
Folate deficiency occurs when intake is not adequate for the level of folate utilization. Increased utilizaiton (pregnancy) or inadequate diet may be the cause.
What are the primary clinical features often seen in Megaloblastic anemia (60)?
Insidious with progressive onset
(1) Mild jaundice
(2) Glossitis
(3) Angular stomatitis
(4) Mild malabsorption and weight loss (epithelial abnormality)
(5) melanin pigmentation
What is vitamin B12 neuropathy (61)?
A symetrical neuropathy affecting the peripheral nerves that is caused by the buildup of adenosyl homocystein and adenosyl methionine in nervous tissue (B12 deficiency). May also cause psychiatric problems.
Why are B12 and folate levels extremely important in pregnancy (62)?
Because lower levels of B12 and folate are correlated with higher incidences of neural tube defects in newborns.
What secondary tissue abnormalities can occur in relation to folate or B12 deficiency (63)?
(1) Sterility
(2) Epithelial abnormalities
(3) reversible pigmantation
(4) reduced osteoblastic activity.
What are the serum lab findings in megaloblastic anemia (63)?
(1) MCV is increased
(2) Rdw is decreased
(3) WBC is moderately reduced
(4) Platlets are moderately reduced
(5) increased bilirubin
(6) LDH is increased.
What cellular morphological characteristics are associated with megaloblastic anemia (63)?
(1) Large oval erythrocytes
(2) Immature nuclei with normal cytoplasmic Hgb
(3) hypersegmented neutrophils
(4) giant metamyelocytes
How are folate and B12 deficiencies diagnosed (63)?
Serum B12, serum folate, and red cell folate are used to diagnose deficiency.
How is absorption tested as the cause of B12 deficiency (63)?
Absorption is tested by ingestion of radio labeled cyanocobalamin. This can differentiate between malabsorption and indadequate diet. When acitve IF is added gastric lesions can be differentiated from intestinal lesions. Schilling test for urinary excretion of labeled B12 is also used.
How can pernicious anemia be tested for (64)?
By testing for antibodies to gastric antigens.
How is a folate deficiency diagnosed (65)?
folate deficiency is diagnosed by dietary history.
How are folate and B12 deficiencies treated (65)?
treatment involves giving supplements of both vitamins unless B12 deficiency can be definitively ruled out. (Folic acid given with B12 deficiency can aggravate neuropathy.
What is the major concern with heart failure patients taking folate/B12 supplements (66)?
The concern is that hypokalemia may occur. Patients must be corrected with diuretics and potassium for 10 days.
What is the response to folate and B12 supplementation (66)?
(1) patient feels better in 24-48 hours
(2) Hgb should rise by 2-3 every 2 weeks
(3) Cell counts should return to normal in 7-10 days.
When is B12 given prophylactically (66)?
B12 is given prophylactically to patients who have had a total gastrectomy or ileal resection.
When is folic acid given prophylactically (66)?
(1) pregnancy
(2) Chronic dialysis
(3) hemolytic anemias
(4) chronic myelofibrosis
(5) premature babies
What are some secondary causes of Megaloblstic anemia (67)?
(1) congenital defects in B12 or folate metabolism
(2) repeated nitrous oxide anesthesia.
(3) Antifolate drugs (methotrexate)
Is cardiovascular disease linked to B12/folate deficiency (67)?
Yes increased levels of homocysteine are linked in mycocardial infarction.
Can megaloblastic anemia occur without B12 or folate deficiency (67)?
Yes
(1) enzymatic deficiency in purine/pyrimidine synthesis
(2) Drugs that inhibit purine or pyrimidine synthesis.
What can cause non-megaloblastic macrocytic anemias (67)?
(1) Lipid deposition in RBC membrane
(2) Alcohol increases MCV
(3) Hemolytic anemia (release of reticulocytes)
