Animal Nutrients, Part 4: Vitamin B12

You may have noticed that throughout my Animal/Plant Nutrients series, I don't really go into massive detail about all of the ways these nutrients behave in the human body. I tend to pick an interesting topic specific to each nutrient and weigh in on it. This time I'll be writing about vitamin B12 (B12), and I'll be weighing in on pernicious anemia (PA) specifically.

PA is a relatively common disease, and many of us likely know someone who has been afflicted with it. Both my father and my significant other have PA. My father is currently in his sixties, which is around the age PA tends to set in. My significant other is currently in her late twenties, having developed a rare form of the disease in childhood.

The disease is characterized by a weakened capacity to secrete intrinsic factor (IF) in the stomach [1]. IF binds vitamin B12 and facilitates uptake in the small intestine. As you can imagine, B12 absorption is heavily limited by IF secretion. In those who secrete no IF, only around 1-2% of B12 is absorbed [2]. This means that nutritional doses of B12 have virtually no impact on B12 status in those with the worst IF secretion. Without an appropriate intervention, deficiency is inevitable and the afflicted person will die.

Typically when someone is diagnosed with PA later in life it is assumed they retain at least some IF function and can make use of oral B12 supplements. As such, a simple 1000mcg B12 supplement may be prescribed. If the supplement isn't effective, or becomes less effective with age, the patient may be moved to intramuscular injection therapy (IIT). IIT involves regular appointments with a physician for a single injection of B12 directly into the patient's muscle tissue. This was the therapy that my significant other was placed on from the start when she was first diagnosed with PA as a teenager. For more than a decade she met with a physician once per month for IIT. Eventually it became less and less effective, which necessitated her self-injecting at home.

Over time she told me more about her history with the disease and how it was currently affecting her. Naturally I started researching it like crazy. I found many papers detailing the effectiveness of IIT, and I was left with the distinct impression that this was the only viable treatment method. Toward the end of my digging I used Twitter to ask Chris Masterjohn about the plausibility of using creatine to spare B12 in the methylation cycle. My idea was that she could perhaps extend the effectiveness of each injection. While he acknowledged that the mechanism was plausible, he also explained that it was probably pointless. He further explained that high dose oral supplementation was likely just as effective as IIT.

I fired up PubMed and immediately started looking for anything I could find relating to sublingual (SL) B12 supplementation as an alternative treatment for PA. Indeed, I found a number of papers detailing the effectiveness of SL B12 [3][4][5][6]. I remember immediately becoming irate. I can understand the unfortunate reality of regular self-injecting for type I diabetics, because there is no viable alternative for them. But I could not understand this. Why was the standard of care for PA so draconian when there were other demonstrably viable alternatives? It didn't make sense to me.

Shortly after my discovery, I suggested to my significant other that she start on 5000mcg of SL B12 per day. I advised her to continue with IIT if the SL B12 proved ineffective. Sure enough, however, from the moment she started SL B12 almost a year ago, she has not needed a single injection and presents with no symptoms of B12 deficiency. She reports that the SL B12 works better than IIT acutely, and is overall more effective on a month-to-month basis as well. Only time will tell whether or not the effect will wane, but I suspect it won't.

So, why does SL B12 work so well? The short answer is that B12 molecules are small enough to passively diffuse through tissues and into your circulation. So, when you hold 5000mcg of B12 under your tongue, it has to go somewhere. As previously mentioned, even without IF 1-2% of oral B12 is absorbed through passive diffusion in the gut. Which means that nutritional doses of B12 do virtually nothing for PA, but it also means that mega-doses can probably do a lot. For this reason, I highly suspect that if one finds IIT more effective than SL B12, it is merely because the SL dose was not high enough. I find it difficult to believe that dosing 20mg or more of SL B12 wouldn't overcome the issue.

Just last summer, approximately four months after my partner began SL B12, a trial was run wherein IIT was compared head-to-head against SL B12 [7]. Guess what. The effectiveness of SL B12 was equal, if not superior, to IIT. It overcomes the literal pain-in-the-ass of IIT, and probably has some other unique advantages as well. My only hope is that the standard of care adjusts in order to accommodate this effective, less invasive method of treating patients with PA. It seems as though I'm not alone with my hopes, either [8][9].

PS. If you like what you've read and want me to continue writing, consider supporting me on Patreon. Every little bit helps! Thank you for reading!

References:

[1] Bizzaro and Antico. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014 Apr. https://www.ncbi.nlm.nih.gov/pubmed/24424200

[2] Berlin H, et al. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968 Oct. https://www.ncbi.nlm.nih.gov/pubmed/5751528

[3] Bolaman Z, et al. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. Clin Ther. 2003 Dec. https://www.ncbi.nlm.nih.gov/pubmed/14749150

[4] Delpre G, et al. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet. 1999 Aug. https://www.ncbi.nlm.nih.gov/pubmed/10475189

[5] E Nyholm, et al. Oral vitamin B12 can change our practice. Postgrad Med J. 2003 Apr. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1742688/

[6] Andrès E, et al. Effects of oral crystalline cyanocobalamin 1000 μg/d in the treatment of pernicious anemia: An open-label, prospective study in Ten Patients. Curr Ther Res Clin Exp. 2005 Jan. https://www.ncbi.nlm.nih.gov/pubmed/24672108

[7] Bensky MJ, et al. Comparison of sublingual vs. intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency. Drug Deliv Transl Res. 2019 Jun. https://www.ncbi.nlm.nih.gov/pubmed/30632091

[8] Josep Vidal-Alaball, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005 Jul. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112015/

[9] Catherine Qiu Hua Chan, et al. Oral Vitamin B12 Replacement for the Treatment of Pernicious Anemia. Front Med (Lausanne). 2016 Aug. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993789/

Measuring Nutrient Density: Calories vs Weight

The Nutrient Density Cheat Sheet considers the nutritional yield of foods per standard serving size. Serving size is a food measurement based on the weight of a given food, and is meant to reflect the food portion sizes that people typically eat. Recently the Nutrient Density Cheat Sheet was criticized by a somewhat fanatical vegan. She claimed that by considering nutrition per serving, I was unfairly biasing all of my scores toward animal foods. She doubled down and further claimed that if my scores were recalculated using calories instead of weight, leafy green vegetables would certainly be revealed as the most nutrient dense foods on the list.

We went back and forth about the correct methodology for some time. It took quite a while for her to coherently distill her objections down into something I could actually work with. Essentially, she asserts that water and fibre confound the weight and volume measurements in unacceptable ways, and that calories are a more accurate way to measure nutrient density. She suggested that I completely remove weight as a variable, and do my calculations strictly with nutrients per calorie. So, I decided to humour her and I did precisely what she asked me to do.

I spent a couple hours going back and recalculating all of the nutrient data by calories instead of serving weight. The results are still adjusted for bioavailability, nutrient absorption capacity, and metabolic conversion inefficiencies (my methods for each adjustment are detailed in an earlier blog post here). There are absolutely no weight measurements considered in the nutrition per calorie scoring calculations. Here are the results:

Animal foods seem to still come out on top. However, in order to insulate myself against criticisms regarding my nutrient yield adjustments, I also produced two other unadjusted scores. They use the same methodology— one is nutrient density per serving, and the other is nutrient density per calorie. Neither is adjusted for nutrient bioavailability, nutrient absorption capacity, or metabolic conversion inefficiencies. It's literally just each nutrient divided by its respective DRI and divided by calories. Results are summed across all nutrients per food, and the results across all foods are sorted and ranked. Here are those results:

As you can see some leafy green vegetables do get a boost, but ultimately animal foods are still dominating the top of the list. But, why is this? Leafy greens are low calorie and animal foods are higher calorie. So, it seems intuitive that leafy greens would be some of the lowest calorie foods, so why does measuring nutrient density per calorie actually produce these counter-intuitive results? It's because dividing nutrition by calories just gives you a silly little ratio. That's it. The results don't actually have to favour low calorie foods at all. The results just favour foods that have a similar ratio of nutrition to calories, which can include both high and low calorie foods.

Highly nutritious, high calorie foods (like Atlantic salmon) get similar scores as poorly nutritious, low calorie foods (like spinach). Think about it. If you divide 1000 by 100, you get 10. If you divide 10 by 1, you get 10. It's just a ratio. It tells you nothing about realistic portion sizes or caloric density. Which is why dividing nutrition by calories is a foolish and uninformative way of quantifying nutrient density. For example, black coffee can be found in both the adjusted and unadjusted scores when calculating nutrition per calorie. Which could leave one with the false impression that black coffee is a great source of nutrients, or is at least comparable to oysters or mussels. However, one would have to consume approximately 1.7 litres in order to exceed the RDA of a single essential nutrient found in coffee (riboflavin in this case). Whereas eating just 10g of either mussels or oysters yields more than the RDA of vitamin B12. 10g is barely the size of the tip of your finger. Whereas 1.7 litres is an insane amount of coffee to drink to get the RDA of riboflavin.

One of this vegan's primary arguments in support of nutrition per calorie measurements was that humans have a limited calorie budget (approximately 2000 kcal/day), so assessing nutrition per calorie is best. While it's true we all eat within a similar calorie budget, it's not true that measuring nutrition per calorie actually gives you much meaningful insight into the calorie yield of a food. It's just a ratio. The foods on the top of the list need not be low calorie foods at all.

Ultimately, my position is that calories are a subjective value-judgement. Calories are something you assess completely independently of nutrient density, and you increase or decrease calories according to your goals. On this basis alone, I suggest that factoring calories into the nutrient density score necessarily injects subjective bias into the results. Nutrition divided by calories has a number of unacceptable drawbacks. 

Firstly, considering nutrition per calorie assumes that calories are always a disadvantage. Secondly, it punishes foods for having essential nutrition. Both essential amino acids and essential fatty acids contain calories, so they actually lower the nutrient density score. Which clearly doesn't make any sense. Lastly, it just doesn't actually give you any meaningful information about calories. So, why even bother? Nutrition per serving also has significant interpretive challenges, but they are far less severe, and far less limiting, than measuring nutrition per calorie. Serving size simply gives you a better approximation of how humans interact with food, and that's what matters.

PS. If you like what you've read and want me to continue writing, consider supporting me on Patreon. Every little bit helps! Thank you for reading!