Macrocytic Anemias

Question 1

How does anemia present? How do we test for anemia? How are the anemias classified?

Answer 1

• anemia presents as hypoxia; weakness, fatigue, dyspnea, pale conjunctiva, headache, light-headedness (can present as angina/claudication in patients with CAD and atherosclerosis)
• tested for with Hb, hematocrit, and RBC count
• anemia is a Hb less than 13.5 g/dL in males (less than 12.5 in females)
• classified based on mean corpuscular volume (MCV): microcytic is less than 80, normocytic is between 80 and 100, macrocytic is greater than 100

Question 2

What is macrocytic anemia? What are the two major causes of macrocytic anemia and what results in the larger cell?

Answer 2

• macrocytic anemia is characterized by RBCs with an MCV greater than 100
• 2 most common causes are folate deficiency and vitamin B12 (cobalamin) deficiency
• these are both needed for the production of DNA precursor molecules; the lack of DNA precursors results in an incomplete maturation of the RBC (it’s essentially as if one LESS division occurs due to the lack of material vs. one EXTRA division in microcytic anemia)

Question 3

What’s the basic biochemistry involved with folate and vitamin B12 (cobalamin)? Where do tetrahydrofolate, methylation, homocysteine, and methionine fit in? (Additionally, what is methylmalonic acid?)

Answer 3

• folate enters the body as tetrahydrofolate and is quickly inactivated by methylation
• vitamin B12 (cobalamin) takes this methyl group from methyl-THF, allowing it to participate in the synthesis of DNA precursors
• homocysteine then takes the methyl group from methyl-cobalamin, becoming methionine in the process
• (additionally, methylmalonyl-CoA from odd-chain FAs gets converted into succinyl-CoA by methylmalonyl-CoA mutase, which uses vitamin B12 as a cofactor; without this reaction, methylmalonyl-CoA become methylmalonic acid)

Question 4

What is megaloblastic anemia? What do we see in this type of anemia?

Answer 4

• megaloblastic anemia is a subtype of macrocytic anemia
• this is an anemia in the setting of either folate or vitamin B12 (cobalamin) deficiency
• these micronutrients deficiencies affect all rapidly dividing cells (not just RBCs!), resulting in megaloblastic change in these cells
• we see megaloblastic anemia, hypersegmented neutrophils (greater than 5 lobes), and megaloblastic change in rapidly dividing cells (intestines, etc.)

Question 5

What are three less common causes of macrocytic anemia?

Answer 5

• alcoholism
• liver disease
• drugs (such as 5-fluorouracil)
• (note that these macrocytic anemias will NOT have hypersegmented neutrophils and megaloblastic change in other cells, which are only seen in megaloblastic anemia)

Question 6

What is the most common cause of macrocytic anemia? Where is this micronutrient found and where is it absorbed? How rapidly does the anemia develop? What are the major causes?

Answer 6

• MCC of macrocytic anemia is folate deficiency
• folate is obtained via fruits and veggies; absorbed in the jejunum
• the body has very minimal stores of folate (only 3-4 month supply), so the deficiency and the anemia develop rapidly (within months)
• poor diet/malnutrition, malabsorption, increased demand (pregnancy, cancer, hemolytic anemia), folate antagonists (methotrexate, phenytoin)

Question 7

What findings are associated with folate deficiency anemia?

Answer 7

• (remember this is a megaloblastic anemia)
• macrocytic RBCs, hypersegmented neutrophils, megaloblastic change in rapidly dividing cells
• glossitis
• decreased serum folate
• increased serum homocysteine (because it needs to take the methyl group from vitamin B12 in order to become methionine)
• normal methylmalonic acid (vitamin B12 is normal here, so methylmalonyl-CoA gets converted to succinyl-CoA as per normal)

Question 8

Where do we get vitamin B12 (cobalamin) from? Where is it absorbed? How rapidly does the related anemia develop?

Answer 8

• vitamin B12 (cobalamin) is obtained from animal products
• it is absorbed in the terminal ileum
• initially, vitB12 is rapidly bound to R-binder (secreted by the salivary glands); this complex is eventually cleaved by the pancreatic proteases, and vitB12 is then bound to intrinsic factor; this complex gets absorbed in the terminal ileum
• the body has very large vitamin B12 stores (6-9 year supply), so the anemia develops very slowly (over years)

Question 9

What are the major causes of vitamin B12 deficiency anemia?

Answer 9

• vitamin B12 (cobalamin) deficiency caused by:
• autoimmune destruction of gastric parietal cells, resulting in decreased levels of intrinsic factor (this is the MCC); this anemia is called PERNICIOUS ANEMIA
• pancreatic insufficiency, gastrectomy or PPIs (acid helps break B12 free from ingested food)
• damage to terminal ileum (via chrons, fish tape worm infection)
• diet (very rare; only seen in intense vegan diets)

Question 10

What findings are associated with vitamin B12 (cobalamin) deficiency anemia? What is a major complication of this disease?

Answer 10

• (remember this is a megaloblastic anemia)
• macrocytic RBCs, hypersegmented neutrophils, megaloblastic change in rapidly dividing cells
• glossitis
• decreased serum vitamin B12
• increased serum homocysteine (because it needs to take the methyl group from vitB12 in order to become methionine)
• increased methylmalonic acid (vitB12 needed to convert methylmalonyl-CoA into succinyl-CoA);*the acid builds up, especially in the myelin of the spinal cord, leading to subacute combined degeneration of the spinal cord (this damage is largely irreversible): peripheral neuropathy, dorsal column damage (vibration/proprioception), lateral corticospinal damage (spasticity), dementia