Chapter 4: Megaloblastic Anemias (macrocytic anemias)

Question 1

What are macrocytic anemias?

Answer 1

Anemias in which cells have a MCV greater than 95.

Question 2

What is megaloblastic anemia?

Answer 2

Anemia characterized by cells with nuclei that are immature compared with the cytoplasm.

Question 3

What is the underlying cause of megaloblastic anemia?

Answer 3

Megaloblastic anemia is usually caused by defective DNA synthesis. (commonly the result of B12 or folate deficiency.

Question 4

What is cobalamin (55)?

Answer 4

Cobalamin is Vitamin B12.

Question 5

Where is B12 created (55)?

Answer 5

B12 is created by microorganisms.

Question 6

What is the structure of B12 (55)?

Answer 6

B12 (cobalamin) is composed of a cobalt atom at the center of a corrin ring

Question 7

How is B12 absorbed(56)?

Answer 7

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.

Question 8

What happens to B12 in the blood stream (56)?

Answer 8

B12 in the blood stream binds to either transcobalamin or haptocorrin. However, only transcobalamin is able to deliver B12 to the bone marrow.

Question 9

What binds more B12 haptocorrin or transcobalamin (57)?

Answer 9

Haptocorrin binds most of the B12.

Question 10

What are the two biochemical functions of B12 (57)?

Answer 10

(1) B12 is a cofactor for methionine synthase in the synthesis of methionine
(2) B12 helps to convert methylmalonyl CoA to succinyl CoA.

Question 11

How is B12 deficiency tested for (57)?

Answer 11

levels of homocysteine or methylmalonic acid are assayed.

Question 12

How is Folate absorbed(58)?

Answer 12

Folate is converted to THF to be absorbed by enterocytes. The enterocytes then convert THF to folate polyglutamates.

Question 13

What is the function of folate(58)?

Answer 13

Folate functions in single carbon unit transfer. (synthesis of glycine or purine etc.)

Question 14

Why does folate deficiency cause megaloblastic anemia(58)?

Answer 14

Folate deficiency causes megaloblastic anemia because folate is necessary for the synthesis of thymidylate (a precursor of thymine).

Question 15

How is dihydrofolate converted to tetrahydrofolate during thymidylate synthesis(59)?

Answer 15

It is converted by dihydrofolate reductase?

Question 16

What drugs inhibit dihydrofolate reductase(59)?

Answer 16

(1) Methotrexate (antineoplastic)
(2) pyrimethamine (anti malarial)
(3) Trimethoprim (antimicrobial)

Question 17

What are the most common causes of B12 deficiency in western culture (59)?

Answer 17

(1) Addisonian pernicious anemia
(2) Veganism (it is found in meat)
(3) Gastrectomy or small intestinal lesions.
(4) Nitrous oxide may inactivate B12.

Question 18

What causes pernicious anemia(59)?

Answer 18

Pernicious anemia is caused by an autoimmune attack that causes atrophy of the gastric mucosa. (commonly initiated by helicobacter pylori infection)

Question 19

What is the epidemiology of pernicious anemia(59)?

Answer 19

(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.

Question 20

What antibodies are present in pernicious anemia(60)?

Answer 20

(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.

Question 21

How long does it take for B12 deficiency to take effect (60)?

Answer 21

it takes 2 years for B12 stores to be depleted.

Question 22

What are some secondary causes of B12 deficiency (60)?

Answer 22

(1) Congenital defect in B12 absorption complex
(2) inadequate intake
(3) atrophic gastritis (without IF antibodies) (helicobacter pylori)

Question 23

What causes folate deficiency (60)?

Answer 23

Folate deficiency occurs when intake is not adequate for the level of folate utilization. Increased utilizaiton (pregnancy) or inadequate diet may be the cause.

Question 24

What are the primary clinical features often seen in Megaloblastic anemia (60)?

Answer 24

Insidious with progressive onset

(1) Mild jaundice
(2) Glossitis
(3) Angular stomatitis
(4) Mild malabsorption and weight loss (epithelial abnormality)
(5) melanin pigmentation

Question 25

What is vitamin B12 neuropathy (61)?

Answer 25

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.

Question 26

Why are B12 and folate levels extremely important in pregnancy (62)?

Answer 26

Because lower levels of B12 and folate are correlated with higher incidences of neural tube defects in newborns.

Question 27

What secondary tissue abnormalities can occur in relation to folate or B12 deficiency (63)?

Answer 27

(1) Sterility
(2) Epithelial abnormalities
(3) reversible pigmantation
(4) reduced osteoblastic activity.

Question 28

What are the serum lab findings in megaloblastic anemia (63)?

Answer 28

(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.

Question 29

What cellular morphological characteristics are associated with megaloblastic anemia (63)?

Answer 29

(1) Large oval erythrocytes
(2) Immature nuclei with normal cytoplasmic Hgb
(3) hypersegmented neutrophils
(4) giant metamyelocytes

Question 30

How are folate and B12 deficiencies diagnosed (63)?

Answer 30

Serum B12, serum folate, and red cell folate are used to diagnose deficiency.

Question 31

How is absorption tested as the cause of B12 deficiency (63)?

Answer 31

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.

Question 32

How can pernicious anemia be tested for (64)?

Answer 32

By testing for antibodies to gastric antigens.

Question 33

How is a folate deficiency diagnosed (65)?

Answer 33

folate deficiency is diagnosed by dietary history.

Question 34

How are folate and B12 deficiencies treated (65)?

Answer 34

treatment involves giving supplements of both vitamins unless B12 deficiency can be definitively ruled out. (Folic acid given with B12 deficiency can aggravate neuropathy.

Question 35

What is the major concern with heart failure patients taking folate/B12 supplements (66)?

Answer 35

The concern is that hypokalemia may occur. Patients must be corrected with diuretics and potassium for 10 days.

Question 36

What is the response to folate and B12 supplementation (66)?

Answer 36

(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.

Question 37

When is B12 given prophylactically (66)?

Answer 37

B12 is given prophylactically to patients who have had a total gastrectomy or ileal resection.

Question 38

When is folic acid given prophylactically (66)?

Answer 38

(1) pregnancy
(2) Chronic dialysis
(3) hemolytic anemias
(4) chronic myelofibrosis
(5) premature babies

Question 39

What are some secondary causes of Megaloblstic anemia (67)?

Answer 39

(1) congenital defects in B12 or folate metabolism
(2) repeated nitrous oxide anesthesia.
(3) Antifolate drugs (methotrexate)

Question 40

Is cardiovascular disease linked to B12/folate deficiency (67)?

Answer 40

Yes increased levels of homocysteine are linked in mycocardial infarction.

Question 41

Can megaloblastic anemia occur without B12 or folate deficiency (67)?

Answer 41

Yes

(1) enzymatic deficiency in purine/pyrimidine synthesis
(2) Drugs that inhibit purine or pyrimidine synthesis.

Question 42

What can cause non-megaloblastic macrocytic anemias (67)?

Answer 42

(1) Lipid deposition in RBC membrane
(2) Alcohol increases MCV
(3) Hemolytic anemia (release of reticulocytes)