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Riboflavin (vitamin B2)
Not a commonly tested vitamin on Step1, but mentioning it here for the sake of comprehensiveness prior to talking about niacin.
It’s a cofactor for any reaction involving FAD/FADH2 or FMN. This means B2 is a cofactor for oxidation/reduction reactions.
Remember that FADH2 is produced via succinate dehydrogenase in the conversion of succinate → fumarate in the TCA cycle.
| Most students won’t be able to identify the succinate → fumarate step of the TCA cycle as the one that relates to vitamin B2. |
If you get a question assessing B2 deficiency (ariboflavinosis), the one thing you want to be on the lookout for is corneal vascularization combined with angular cheilosis. The latter is a common finding in B vitamin deficiencies in general, but the corneal vascularization is what they like for ariboflavinosis.
Now for the real stuff.
Vitamin B3 (niacin)
| Do not walk into the Step1 testing center without knowing everything from this entry on niacin. |
It is used in reactions involving NADH/NAD+or NADPH/NADP+. B6 and B2 are needed for its synthesis.
If used as a lipid-improving agent, it does two things:
1) It increases HDL.
2) It decreases hepatic export of VLDL (↓ TGAs)
It used to be that point #1 was emphasized in isolation, but the USMLE is now asking for point #2.
Side-effects of niacin
Although niacin increases HDL and decreases TGAs, we do not use it clinically because of its side-effects, in combination with lack of evidence for its clinical benefit, notably in patients already receiving statins for cardiovascular disease (New England Journal of Medicine article here).
Niacin (not even excess; just supplemental niacin in general, taken within the therapeutic range) can cause:
1) Flushing of the face and body
- Treated with aspirin
- This therefore means the flushing is due to PROSTAGLANDINS, not histamine.
- Think about it. Aspirin is the Tx, and inhibition of COX leads to ↓ prostaglandin synthesis.
- The USMLE loves asking this question. Histamine is the #1 wrong answer.
2) Hyperglycemia due to insulin resistance
- Pushes patients who are pre-diabetic into type-II diabetes
- Worsens type-II diabetes
- If the USMLE asks you how the dose of a T2DM patient’s hypoglycemic med needs to be tweaked if taking niacin, the answer is the dose must be increased.
3) Gout due to hyperuricemia
- USMLE will tell you a guy has a history of podagra (swollen big toe from gout) and then ask you which drug is contraindicated in this patient. Answer is simply niacin.
| Niacin deficiency is called pellagra. Do not confuse that with podagra, which is gout of the big toe. |
Niacin deficiency
As discussed here, the most commonly tested causes of niacin deficiency are:
- Hartnup disease (↓ tryptophan reabsorption in the kidney → ↓ niacin synthesis because tryptophan is the precursor).
- Carcinoid syndrome (tryptophan is the precursor of both niacin and serotonin. ↑ serotonin synthesis → depletion of tryptophan → ↓ niacin synthesis).
Pyridoxine (vitamin B6) deficiency secondary to izoniazid (INH) use for TB can also, in theory, cause B3 deficiency (B6 is a cofactor for the synthesis of niacin from tryptophan; INH for tuberculosis → ↓ B6). It’s essentially a scenario where niacin deficiency doesn’t actually happen this way in real life, but the USMLE can ask this in a “what could theoretically happen” type of question.
| Deficiency of niacin causes pellagra. This presents as the “3Ds,” = dementia, dermatitis, diarrhea. |
It should be noted that one of the biggest risk factors for delirium is underlying dementia. That is, an elderly patient with decreased mental reserve is much more likely to experience delirium than a young, healthy patient. This means:
Rather than dementia, a pellagra vignette can present as an elderly, hospitalized patient with delirium instead. Then when you’re like, “wait wtf?” If you realize that patients with underlying dementia are more easily able to get delirium, it makes sense.
| 73-year-old male in hospital has visual hallucinations, hyperpigmentation of his forearms, and increased bowel motions. Which vitamin is deficient?
B3. |
Some resources will discuss the dermatitis in pellaga as classically presenting with Casal necklace (hyperpigmentation of sun-exposed neck), but bear in mind the forearms can easily be just as sun-exposed.
A general point about niacin
If a patient has low HDL, the best initial Tx is recommending lifestyle change.
However, the most effective way to increase HDL is niacin. That is, niacin exceeds lifestyle changes in efficacy of increasing HDL levels.
| Patient has low HDL. Next best step in management to increase it?
Answer = lifestyle modification – i.e., smoking cessation, exercise, healthy diet, 1-2 alcoholic drinks per day (yes, superior to zero; the UpToDate article is here). |
| Patient has low HDL. Most effective way to increase it?
Answer = niacin. We don’t actually prescribe niacin in real life because of its side-effects + it hasn’t been proven to improve outcomes, but niacin is still most effective in increasing HDL. |
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