B12 is the last, but not the least, of the B vitamins. It is probably the best known B vitamin, and it is the most commonly supplemented B vitamin. Why? Because it is extremely important. Like folate, it plays a major role in all things methylation. As with folate, without B12, the system can’t operate at full capacity. It is essential for making DNA, for repairing DNA, for detoxification, for making red blood cells, for mental health, for histamine metabolism, for muscle growth, for choline metabolism, and for mitochondrial metabolism. When it comes to mitochondrial metabolism, it plays a unique role alongside B5—B5 needs B12 to do its job (and if there’s not enough B12, it’s as if there’s not enough B5).  Ya gotta have B12.

So what happens if you don’t have enough? Deficiency in B12 can lead to significant clinical findings, including megaloblastic anemia. This condition is a classic example of the interplay between B12 and folate. If there’s not enough B12, the enzyme methionine synthetase is impaired, and 5-MTHFR builds up in the cell, which leads to functional folate deficiency. This is often referred to as the methyl-folate trap, because folate gets trapped in the system and can’t do what it is supposed to do, causing the system to get backed up. This is similar to, but distinct from, the concept of pseudo-MTHFR deficiency that can be seen with excess folic acid. The result, though, is that DNA synthesis is impaired. Rapidly dividing cells, such as those in the bone marrow, can’t grow normally, which leads to enlarged, immature red and white blood cells with abnormal nuclei. The neutrophils are classically “hypersegmented”, with 5 or more lobes when you look at them under the microscope.                

Beyond anemia, B12 can cause a host of neurologic concerns. Some of these are cognitive in nature – it can cause memory loss (and even dementia), attention problems, changes in personality, and in severe causes, delirium and psychosis. Outside the brain, symptoms usually start at the feet and move upward. These include peripheral neuropathy, spasticity, loss of coordination, impaired gait, optic neuritis and visual disturbances, orthostatic hypotension (dizziness or faintness when standing quickly), and exercise intolerance. And while these symptoms can be reversible if they are caught early, if they go on long enough, they can become irreversible. That’s why it’s so important to think about B12 status in patients with unusual neurologic symptoms.

And B12 deficiency is quite common, though percentages vary depend on who you ask and the population you’re talking about. Subclinical deficiency may be present in about a quarter of the general population. And if you look at specific groups, the rates may be even higher. In vegans, for example, the rate of deficiency is probably above 50%, with rates of marginal status as high as 90%.

So where do you get B12? The only creatures on the planet capable of making B12 are certain bacteria. Anyone that isn’t a bacterium needs to get their B12 from somewhere else. Cows, for example, get B12 from the bacteria in their stomach – the bacteria synthesize B12, which is then stored in the cow’s tissues. Animals have developed strategies to get B12 either from their diet, or from relationships with bacteria. Plants, on the other hand don’t contain B12 because they don’t have the enzymes to create it, nor have they created the relationships with bacteria needed to get it. The major source of B12 for humans, then, is from animal-derived foods. The best sources are meat (especially organ meats)—and the best meat sources are from ruminants (that is, animals that have built-in symbiotic bacteria) – these include beef, lamb, and pork. The bioavailability of B12 from meat also tends to be very high.  Fish and shellfish are also very good sources of B12. Dairy products, including milk, cheese, and yogurt, are also good sources (though concentrations are lower than in meats). Eggs, despite being a good source for many vitamins, are not a great source for B12—they do contain some, but its bioavailability is low (only about 9% can be absorbed). Some fermented foods contain B12, because it is produced by the bacteria. Plants rarely contain it—one exception is nori (a type of seaweed). Some mushrooms have B12, but the amounts are lower than in animal-based foods, and the bioavailability is also lower. Many foods are fortified with B12. Commonly fortified foods include cereals, plant-based milk alternatives, nutritional yeast, and some meat substitutes.

Who is at risk for B12 deficiency? Since the best source of B12 by far is animal-derived foods, vegetarians and vegans are at particularly high risk for B12 deficiency and need to make a point to supplement or eat fortified foods. The elderly also tend to be at risk for deficiency. This is because of an age-related decline in the ability to absorb B12. B12 absorption is complex – it requires that the stomach, pancreas, and small intestine all function properly. In the elderly, one or more of these systems is often impaired. Elderly patients often have atrophic gastritis (which may affect up to 30% of individuals over age 60). Atrophic gastritis is chronic inflammation in the stomach; it can be autoimmune, though it is also often related to infections (especially helicobacter pylori, which is a major cause of ulcers). Reduced stomach acid production can also impair B12 absorption, and certain medications can affect it as well (especially proton pump inhibitors).

Another group at high risk for deficiency is anyone with malabsorption issues. This would include anyone with inflammatory bowel disease (like Crohn’s or Ulcerative Colitis) or celiac disease, but it also includes people with dysbiosis. SIBO, for example, can cause B12 deficiency. Pregnant and breastfeeding women are also at risk of deficiency because of higher utilization – deficiency rates in this group may be close to 2/3.

One of the classic causes of B12 deficiency is pernicious anemia. This is an autoimmune condition in which the body produces autoantibodies against certain cells in the stomach (parietal cells) as well as a molecule called intrinsic factor that these stomach cells make to support B12 absorption. The condition is somewhat rare in the general population (it occurs in about 0.1%), but it increases in the elderly, where it may be present in as many as 5% of patients over 60.  Pernicious anemia is diagnosed by measuring antibodies to parietal cells and intrinsic factor.

Beyond these more common causes of deficiency, there are also rare genetic problems with B12 metabolism. One such condition is Imerslund-Grosbeck syndrome, which is an inherited B12 malabsorption condition. Another condition is hereditary intrinsic factor deficiency (also known as congential pernicious anemia), in which individuals lack intrinsic factor. There are also several mutations that can affect B12 transport.

How much B12 do you need? B12 is interesting because, unlike some of the other B vitamins, the body can hold a surplus – in fact, this amount can exceed 2,500 micrograms. That being said, you can only absorb a day’s worth at one time. The recommended daily allowance (RDA) for adults is 2.4 micrograms per day. The amount is higher during pregnancy and breast-feeding and is lower for children. But with high B12 intake over the long term, you can build up quite a surplus – enough to last almost 3 years.  So how do you reach the RDA? 8 grams of liver would be enough for a day’s supply, as would 8 grams of clams or oysters. A teaspoon of fortified nutritional yeast would get you there, as would less than a serving of beef, crab, mackerel, or salmon.

If you can’t get enough from your diet, though, supplementation is an important strategy. B12 supplements exist in several forms, and can be given orally, intramuscularly, and intravenously. The major forms of B12 are cyanocobalamin, hydroxocobalamin, adenosylcobalamin, and methylcobalamin. Cyanocobalamin is by far the most common form found in supplements in the US. It is stable and inexpensive. It is not naturally found in foods. Methylcobalamin is one of the bioactive form of B12 – a form that is directly used by the body. This one is generally well tolerated (though some people with methylation problems may be more sensitive to it). Adenosylcobalamin is another bioactive form of B12 used by the mitochondria for energy production (specifically, metabolism of fatty acids and amino acids). Hydroxocobalamin is well-absorbed and tends to remain in the body longer that cyanocobalamin, so it is particularly useful for treatment of long-term deficiency. This is also the form that is given for cyanide toxicity (at very high doses – often 5 grams, which is 200,000 times the RDA)—it binds with cyanide to for cyanocobalamin, which is then excreted. Hydroxocobalamin is used more frequently in Europe. All these forms work; I tend to prefer hydroxocobalamin, adenosylcobalamin, and methylcobalamin (though I avoid methylcobalamin in individuals who tend to be more sensitive to medications and supplements).

How do you know if you have enough B12? The best way is through testing. One strategy is to do comprehensive micronutrient testing. With routine bloodwork, you can check both serum B12 and methylmalonic acid, or MMA. If serum B12 levels are low, this is consistent with insufficiency. If they are normal or high, however, this doesn’t mean your B12 status is ok – it doesn’t tell you anything about intracellular B12 concentration. This is where MMA comes in. MMA is a functional marker that is highly specific to B12 status and independent of methylation. If you just check one lab for B12, check MMA. A HIGH MMA (greater than 280 nmol/L) is diagnostic of deficiency.

In summary, B12 is a critical B vitamin involved in DNA synthesis and repair, detoxification, histamine metabolism, mitochondrial function, methylation, and many other processes in the body. Deficiency can lead to anemia, neurologic problems. B12 deficiency is relatively common, and certain groups are at significant risk. These include vegetarians, vegans, the elderly, and anyone with gut issues. B12 is found almost exclusively in animal foods, though is straightforward to supplement.

Are you getting enough B12?

 

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