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Dietary folate (B9) is converted to tetrahydrofolate (THF) for use in various reactions.
- Once in the form of THF, it can become THF-CH3 or N5N10-methylene-THF.
- After conversion to THF-CH3, vitamin B12 is a second cofactor that is used for methionine synthesis from homocysteine.
- After conversion to N5N10-methylene-THF, thymine can be made from uracil.
B9 is found in dark, green, leafy vegetables.
- If the USMLE asks you for the most likely nutrient deficiency in a vegan or strict vegetarian, but B12 is not listed, folate is the wrong answer. The correct answer is calcium, which is normally found in high amounts in fish and dairy.
- Folate deficiency is the most common vitamin deficiency in the United States.
- B12 is the only water-soluble vitamin that has a few years of stores before deficiency occurs. In contrast, folate stores deplete within ~6 months of low intake.
- If you get a USMLE vignette of an elderly woman on a tea and toast diet the past 6 months and her MCV is elevated, the answer is folate deficiency, not B12.
B9 or B12 deficiency causes megaloblastic anemia + hypersegemented neutrophils.
- Highest yield point to know for the USMLE regarding these vitamin deficiencies.
- Normal RBC MCV is 80-100 fL. Megaloblastic would be >100.
- Neutrophils normally have nuclei with 2-4 lobes. Hypersegmented ones have 5-7. If the USMLE is showing you one on an image it will be obvious.
Maternal deficiency of B9 in the first three pregnancy leads to neural tube defects.
- The neural tube forms at gestational weeks 3-4.
- Women planning for pregnancy should take 400 micrograms daily of folic acid. This should be continued throughout pregnancy as part of a standard pregnancy multivitamin, although it’s just the first 3-4 weeks where adequate folate is paramount.
- USMLE wants you to know that anti-epileptic meds (i.e., phenytoin, valproic acid, and carbamazepine) can cause folate deficiency by impairing gut absorption.
- Women with Hx of pregnancy with fetal neural tube defects or Hx of taking anti-epileptic medications require 4 mg of folate daily (10x standard dose).
Folate deficiency is the most common vitamin deficiency.
- B12 is the only water-soluble vitamin that has a few years of stores before deficiency occurs. In contrast, folate stores deplete within ~6 months of low intake.
Vitamin B12 (cyanocobalamin) is involved in two key reactions on the USMLE.
- Homocysteine → methionine, via methionine synthase, for use in protein synthesis. (Homocystinuria post here).
- Methylmalonyl-CoA → succinyl-CoA, via methylmalonyl-CoA mutase. (Gluconeognesis post here).
Blood levels of methylmalonyl-CoA and homocysteine
- Both are increased in B12 deficiency; only homocysteine is increased in B9 deficiency.
- This is because B12 is a cofactor for both homocysteine → methionine, and methylmalonyl-CoA → succinyl-CoA.
- In contrast, THF-CH3 (derived from B9) is only needed for homocysteine → methionine.
- Since homocysteine is elevated in both B9 and B12 deficiencies, increased serum methylmalonyl-CoA in the blood is a hallmark of B12 deficiency.
| Patient with ↑ MCV.
Serum methylmalonyl-CoA elevated? Yes, elevated → B12 deficiency Serum methylmalonyl-CoA elevated? No, not elevated → B9 deficiency (Homocysteine is ↑ in both) |
Causes of B12 deficiency are exceedingly HY on the Step.
- Pernicious anemia. Autoantibodies against gastric parietal cells (or intrinsic factor) lead to impaired B12 absorption. Intrinsic factor binds to B12 so that it can be absorbed in the terminal ileum.
- Veganism or strict vegetarianism. B12 is found largely in meat and fish.
- Surgery (i.e., gastric bypass, or terminal illectomy)
- Diphyllobothrium latum infection. It’s a cestode (tapeworm).
- Crohn disease
- Menetrier disease (atrophy of parietal cells + mucous neck cell hyperplasia + enlarged stomach rugae that resemble brain gyri)
- Most B12 deficiency is due to malabsorption, rather than ↓ intake, which is why it is usually corrected parenterally.
| If the USMLE tells you an, e.g., 22-year-old vegan with Hx of autoimmune disease, e.g., autoimmune thyroiditis, vitiligo, etc., has ↑ MCV + hypersegmented neutrophils, they want pernicious anemia as the most likely answer, not dietary deficiency.
Autoimmune diseases “go together,” meaning if you have one, you have increased risk for another. The HLA associations are not that strict. |
B12 deficiency is a reversible cause of cognitive decline
- Any patient, particularly elderly, who has possible dementia, he or she needs evaluation for depression (pseudodementia), hypothyroidism (check TSH levels), and B12 deficiency.
- And clearly if a patient is vegan or strict vegetarian, any cognitive dysfunction should be evaluated within the context of checking B12 levels.
Subacute combined degeneration
- The name given to the pattern of neurologic dysfunction seen in B12 deficiency. Occasionally questions will simply list this disease name as an answer, so know it.
- Decreased ability to convert methylmalonyl-CoA → succinyl-CoA leads to buildup of methylmalonyl-CoA, which is toxic to myelin.
- You must know the three tracts that are involved. It is a triad of demyelination of the lateral corticospinal tracts, spinocerebellar tracts and dorsal columns.
| I find an easy way to remember which three tracts are affected is to start by saying, “The spinothalamic tract is not involved.” |
Schilling test
- Tests for etiology of B12 deficiency
- First give patient B12 injection to make sure he or she is replete.
- Then give radiolabeled oral B12.
- If radiolabeled B12 is seen in urine, the cause of the deficiency is dietary.
- If not seen in urine, next give radiolabeled B12 orally with intrinsic factor.
- If seen in urine, cause is pernicious anemia.
- If not seen in urine, cause is intestinal (e.g., Celiac, Crohn, infective, etc.).
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