Megaloblastic Anemia

Question 1

Normal blood cell counts

Answer 1

Question 2

What is a good measure of bone marrow health?

Answer 2

Reticulocyte count: normally should be 0.2-2%

If it’s low, indicates possible bone marrow failure

Question 3

What is anemia?

Answer 3

Decreased hemoglobin or hematocrit (packed rbc volume)

Can be caused by blood loss, decreased production, or increased destruction

Distinguish based on reticulocyte count

Question 4

How metabolically active is the bone marrow? What is the implicatoin

Answer 4

Highly metabolically active bc lots of cell turnover: white cells 12-24 hour life span, platelets 7 days, RBC 120 days

Any slowing of DNA production –> marrow failure

Question 5

What is megaloblastic anemia?

Answer 5

Anemia with big red blood cells

Usually, Hb production is normal but there’s a defect in nuclear replication & division that affects RBC as well as the other element of the blood

Due to deficiency in folate or B12

Can be accompanied by other cytopenias

Slow developing anemia, usually well compensated, response to therapy is usually rapid & dramatic

Treatment is essential to avoid other complications

Question 6

What are the hallmarks of megaloblastic anemia?

Answer 6

Oval macrocytes: MCV>100
- large rbc is pretty much required for this illness!!!!

Hypersegmented neutrophils: >5% 5 lobed neutrophil or 1% 6 lobed neutrophil

Pancytopenia: low levels of all the blood counts, esp if anemia is severe

Reticulocytopenia: low reticulocyte count

Elevated LDH: end product of glycolysis, which happens a lot on RBC bc they only do anaerobic metabolism; so in this dz, the RBC get chopped up bc they’re abnormal so lots of LDH is released

Serum Fe normal or elevated

Serum B12 or folate low

Marrow –> classic megaloblastic changes: giant pronormoblast, basophilic cytoplasm

Question 7

What are the two main causes of megaloblastic anemia?

Answer 7

B12 deficiency or folate deficiency

Question 8

What is folic acid’s role in RBC turnover/preventing anemia?

Answer 8

Required for DNA synthesis; especially important in rapid cell turnover

Critical for one carbon transfers

Required for healthy RBC and to prevent anemia

Question 9

How is folate absorbed from the GI tract?

Answer 9

Both active and passive absorption occurs

You absorb an inactive form, gets activated by an enzyme that requires B12 to catalyze the step to a form that can be taken up inside the cell

Question 10

What are the different forms of folic acid?

Answer 10

Transport form: comes from diet, body can convert it to any of the other forms

Thymidylate biosynthesis form

Purine biosynthesis form

Question 11

What is the mechanism of action of methotrexate?

Answer 11

Blocks the enzyme that converts a form of folate backwards to a its active form, that can be recycled

This is a chemtherapeutic agent that stops cell synthesis

Question 12

How can you get folate deficiency?

Answer 12

Folate poor diet: alcoholism

Increased folate requirement i.e. rapid cell turnover- pregnancy, severe hemolytic anemia, severe psoriasis

Drug therapy: chemo i.e. methotrexate

Malabsorption: tropical sprue, Celiac dz

Question 13

What are the manifestations of folate deficiency?

Answer 13

Megaloblastic anemia

Glossitis, stomatitis

GI malabsorption secondary to impaired GI epithelium (rare)

Question 14

What is the function of Vitamin B12?

Answer 14

Required for demethylation of methyl-THF for folate metabolism

Conversion of methylmalonyl CoA to succinyl CoA in Krebs cycle

Methylation of myelin

Question 15

What is the structure of Vitamin B12/cobalamin?

Answer 15

Similar to a heme but has different bonds and has cobalt as the metal

Differs in beta groups

• Cyano form= inactive but most stable, often given as supplement
• Methyl = necessary for folate metabolism
• Adenosyle = necessary for mutase activity

Question 16

How is Vitamin B12 absorbed?

Answer 16

Must be protected by another protein:

• *Intrinsic Factor**: made by parietal cells of stomach
• binds & escorts Cobalamin through intestine, where therae are alkaline pH’s

Once it gets across the cell membrane, Cobalamin splits from IF & binds a second transport protein Transcobalamin II

TCII caries B12 to the red cell precursors, then spilts apart nad Cobalamin can participate in the reactions that it catalyzes

Question 17

What can cause B12 deficiency?

Answer 17

Gastric failure: gastrectomy or pernicious anemia

Ileal failure: regional enteritis i.e. Chron’s, ileal resection, tropical sprue

Competing organisms: bacterial overgrowth bc bacteria love to eat B12, D. latum

Question 18

What is pernicious anemia?

Answer 18

Autoimmune destruction of parietal cells so you can’t make stomach acid

Antibodies against parietal cells, intrinsic factor

Achlorhydria (low production of GI acid) is universal

Increased incidence of gastric cancer

More common in American blacks & northern Europeans

Associated with other immune dz i.e. Hashimoto’s thyroiditis

Question 19

What’s the relationship between cobalamin deficiency and peripheral folate deficiency?

Answer 19

B12 catalyzes the reaction from methlyated to unmethylated versions of folic acid

The unmethylated form can have groups attached to it so it can do its job (i.e. DNA synthesis)

Lack of B12 leads to folate deficiency because of this relationship!! The folate you have isn’t available to do its job bc B12 cant catalyze the reaction to the active form

Question 20

What are the manifestations of cobalamin deficiency?

Answer 20

Identical to folate deficiency bc it’s due to intracellular folate deficiency!!

Megaloblastic anemia

Stomatitis/glossitis

GI mucosa alterations

Question 21

Can you correct B12 deficiency high dose of folic acid?

Why should you/not do this?

Answer 21

YES and this will correct all the manifestations of B12 deficiency.

You NEVER want to do this: not a good treatment, bc it doesn’t address the neurological implications of B12 deficiency

Question 22

What is B12’s neurologic role?

Answer 22

Catalyzes methylation of myelin both in brain and spinal cord

B12 deficient patients can develop peripheral and central neuvous system issues

Brain: dementia, psychological distrubances

Spinal cord: demyelinating dz, loss of posterior & lateral columns (symptom= loss of proprioception, falling)

Neurologic dz is stabilized with treatment but not usually reversed

Treatment with folate does nothing for neurologic disease!! Because the reactions that B12 catalyze in the nervous system do not depend on folic acid at all

Question 23

What is the usual sequence of events in cobalaimin deficiency?

Answer 23

Serum homocysteine & methylmalonic acid rise

Serum cobalamin falls

MCV rises, neutrophil hypersegmentation

MCV rises above normal

Anemia

Symptoms, including neurologic symtoms

Note that sometimes a patient will present with neurologic complaints only, so even though this is the typical order, it can be in a different order

Question 24

Properties of Folate/ cobalamin

Answer 24

Question 25

What should you do if you suspect megaloblastic anemia to confirm/reject diagnosis?

Answer 25

Draw levels at first suspicion of problem before any therapy

Then begin treatment with both B12 and folate

Once levels are back, you can stop the normal vitamin

Transfusions are to be avoided unless hemodynamic compromise is present or patient is having angina

After treatment, pt will feel better within 24 hours & reticulocyte count will go up within 3-5 days