Megaloblastic Anemia Flashcards
Normal blood cell counts
What is a good measure of bone marrow health?
Reticulocyte count: normally should be 0.2-2%
If it’s low, indicates possible bone marrow failure
What is anemia?
Decreased hemoglobin or hematocrit (packed rbc volume)
Can be caused by blood loss, decreased production, or increased destruction
Distinguish based on reticulocyte count
How metabolically active is the bone marrow? What is the implicatoin
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
What is megaloblastic anemia?
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
What are the hallmarks of megaloblastic anemia?
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
What are the two main causes of megaloblastic anemia?
B12 deficiency or folate deficiency
What is folic acid’s role in RBC turnover/preventing anemia?
Required for DNA synthesis; especially important in rapid cell turnover
Critical for one carbon transfers
Required for healthy RBC and to prevent anemia
How is folate absorbed from the GI tract?
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
What are the different forms of folic acid?
Transport form: comes from diet, body can convert it to any of the other forms
Thymidylate biosynthesis form
Purine biosynthesis form
What is the mechanism of action of methotrexate?
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
How can you get folate deficiency?
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
What are the manifestations of folate deficiency?
Megaloblastic anemia
Glossitis, stomatitis
GI malabsorption secondary to impaired GI epithelium (rare)
What is the function of Vitamin B12?
Required for demethylation of methyl-THF for folate metabolism
Conversion of methylmalonyl CoA to succinyl CoA in Krebs cycle
Methylation of myelin
What is the structure of Vitamin B12/cobalamin?
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
How is Vitamin B12 absorbed?
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
What can cause B12 deficiency?
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
What is pernicious anemia?
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
What’s the relationship between cobalamin deficiency and peripheral folate deficiency?
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
What are the manifestations of cobalamin deficiency?
Identical to folate deficiency bc it’s due to intracellular folate deficiency!!
Megaloblastic anemia
Stomatitis/glossitis
GI mucosa alterations
Can you correct B12 deficiency high dose of folic acid?
Why should you/not do this?
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
What is B12’s neurologic role?
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
What is the usual sequence of events in cobalaimin deficiency?
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
Properties of Folate/ cobalamin
What should you do if you suspect megaloblastic anemia to confirm/reject diagnosis?
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
