Nutrition
All about vitamin B12. Biochemistry, diagnosis, clinical aspects, and supplementation.
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Dietista
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Vitamin B12 and its deficiency are one of the most complex aspects in terms of clinical management and diagnosis. In this topic we offer you a comprehensive study of B12 so that you can integrate it into your clinical practice.
1. VITAMIN B12, INTRODUCTION AND DIETARY SOURCES
2. BIOCHEMISTRY OF VITAMIN B12
3. METABOLISM OF VITAMIN B12
4. VITAMIN B12 DEFICIENCY
5. SYMPTOMS AND DIAGNOSIS OF VITAMIN B12 DEFICIENCY
6. VITAMIN B12, PREGNANCY AND LACTATION
7. VITAMIN B12 SUPPLEMENTATION
8. BIBLIOGRAPHY
1. VITAMIN B12, INTRODUCTION AND DIETARY SOURCES
1.1 VITAMIN B12, HISTORY, DISCOVERY, AND PRODUCTION
Vitamin B12 is a water-soluble vitamin belonging to the B vitamin family, essential for proper erythropoiesis, DNA synthesis, and maintenance of the nervous system, among other functions. In scientific literature, it also appears as cobalamin. Vitamin B12 is a cobalamin, formed by four pyrrole rings (tetrapyrrole structure) that form a corrin nucleus around a central cobalt atom. It is said to have a corrinoid structure and, as will be seen later, other corrinoid structures present in nature (such as those that serve as bacterial growth factors) can be counted in a serum B12 analysis, without these being active forms, with the limitations that this may entail.
This vitamin was a complete mystery during the 19th century. In the middle of that century, Dr. Addison observed a clinical condition that he named Addison's anemia, which other doctors later began to associate with gastric problems. In 1872, Bierner named it pernicious anemia. The first animal experiments conducted by Whipple in the 1920s on liver enzymes, liver disease, and hemoglobin showed that the intake of liver and liver extracts improved conventional anemia, which opened up a new avenue of research for pernicious anemia, still a great mystery. Minot became very interested in Whipple's studies and the possible application of a diet therapy involving large amounts of liver on a daily basis, which proved to be successful.
William B. Castle made an important discovery: the intrinsic factor, and spoke of the existence of an extrinsic factor that had to bind to it; it was later discovered that this extrinsic factor was actually vitamin B12. It was observed that patients with established pernicious anemia improved with liver intake, and concentrated extracts from animal livers began to be administered. These served for years as the most viable alternative for treating the disease, until it was discovered that it was vitamin B12 that reversed the symptoms. Work began on isolating it, which took place in the mid- to late 20th century.
Based on these facts and its presence in the liver, it is often associated with an animal origin. And this is not incorrect. Vitamin B12 is found in foods of animal origin (except honey), in varying amounts depending on the source (animal, and part of the animal; the liver being the most prominent place of accumulation, as we have already seen).
In fact, if we dig a little deeper, it has a primary bacterial origin (thanks to which it is now produced in laboratories). Animals must consume adequate amounts to ensure its presence, either through physiologically normal intake, i.e., by eating other animals and their viscera (in the case of carnivorous animals), or, depending on the type of animal, by eating directly from an environment/soil rich in precursor bacteria. There are some exceptions: ruminants can produce it in their second stomach through the microbiota present there (requiring a micronutritional dietary precursor, cobalt), or fish from their producing microbiota, through the intake of phytoplankton, or by eating other fish.
In animals that are completely removed from natural environments and used by the livestock industry, it is provided through supplementation: enriched feed or injections (the most common method due to the circumstances of stabling, production, and deprivation of natural food; but also used in animals with more freedom as a prophylaxis). The name cobalamin comes from the corrin-cobalt group it belongs to, and it is the cobalt crystals themselves that give it its distinctive red color. The microbial biosynthesis of vitamin B12 occurs through aerobic or anaerobic pathways. It occurs in bacteria and archaea. Industrial production is carried out through microbial fermentation. Some of the most common bacteria that produce B12 are:
The first bacterial strain used for its synthesis was Lactobacillus Lactis Doner, although it is now known that many other bacteria can synthesize it, such as Pseudomonas denitrificans and Propionibacterium shermanii, which are often used in laboratory synthesis for supplementation.
Vegans can only obtain this vitamin from supplements or fortified foods, and its intake is essential and vitally important at all stages of life. Possible marginal direct microbial contributions from soil, dirty food, manure/fecal matter, or certain rivers or contaminated water are nonsense, despite the fact that some circles have even proposed them as an “interesting” source for avoiding supplementation (we will discuss this further below).
Some herbivorous mammals produce their own bacteria and are able to reabsorb them; this has led to the belief that humans are also capable of doing so simply because they are mammals, and although there is synthesis in some areas, it is not reabsorbable as it is located far from the ileum. Furthermore, it has been seen that in many cases in these specific animals and under certain conditions, their endogenous production may not be sufficient and they are often supplemented as a matter of protocol to avoid problems and optimize levels.
There is also a popular belief that algae, mushrooms, and fermented foods contain abundant amounts of B12, but these are inactive analogues that can distort test results and hinder the metabolism of active B12. (Note: in some very specific cases and under certain conditions in some algae and mushrooms, there may be certain active fractions, but these are very small amounts that have not been shown to be useful or viable as strategies, and analogues may still be present).
On the other hand, ovo-lacto vegetarians often do not reach the recommended intake levels, and the precautionary principle of supplementation still applies, as the theoretical daily amounts of certain foods are not usually consumed (and even when they are, the final status may not be good for various reasons).
And it is not only the total amount that matters; timing and distribution are also very important, and there is specific chrononutrition (it is not the same to eat 6 eggs at once as it is to eat them in two or three separate meals a few hours apart: even if the theoretical amount of B12 is the same, the absorption will be different). In addition, there are digestive and genetic issues that are unique to each person (we do not all absorb, retain, and store nutrients in the same way). We can apply heuristic approximations and simple metrics at a general average level, but the final answer will be determined by each person's physiology.
Vitamin B12 is a highly complex and widely studied vitamin; today, it is the subject of ongoing research.
1.2. FUNCTIONS OF VITAMIN B12
1.3 PHYSIOLOGICAL AND NON-PHYSIOLOGICAL FORMS OF VITAMIN B12
We can divide the different forms in which vitamin B12 is found into two groups:
Physiological forms, which function as coenzymes for metabolic reactions:
Other forms: aquocobalamin, nitritocobalamin.
All forms are chemically related compounds with a similar molecular structure that function as vitamins. They are different forms in which the vitamin can be represented.
1.4. DIETARY SOURCES OF VITAMIN B12
Only animal products are a reliable source of B12. In plant products, only those that are fortified (i.e., that have been supplemented) are a source. For example, fortified products would include the misnamed “breakfast” cereals or some plant-based beverages and soy yogurts that have B12 added.
Vegetarians are often encouraged to consume fortified products to obtain B12. It should be noted that these are generally processed products and tend to be high in sugar, which should be taken into account if this route is to be used, as it does not seem very sensible to obtain B12 from processed products.
In addition, it is often cumbersome and inconvenient to have to count/calculate how many micrograms are in each serving we eat, take several doses a day to optimize absorption and release FI saturation, etc.
1.5. THE PROBLEM WITH VITAMIN B12 ANALOGUES
B12 analogues are corrinoid structures that contain cobalt but do not have the activity of the vitamin, as they have alterations in the corrinoid nucleus. They have little affinity for the intrinsic factor.
Problems with analogues:
Spirulina algae has not been shown to resolve B12-related problems. Many people are taking it thinking that it contains real B12, when in fact it is loaded with analogues. Ralph Carmel, one of the leading researchers on vitamin B12, published a study in 1988 with several subjects analyzed, suggesting a relationship between higher amounts of accumulated analogues and a greater risk of neurological symptoms, which could explain why some patients did not experience neurological symptoms (at least at the time) but did experience anemia.
Analogs are naturally present and circulating in varying amounts depending on the individual, which is completely normal. Some people have more analogs than others. Other common foods (both animal and plant) also provide small amounts of analogues that do not cause problems.
2. BIOCHEMISTRY OF VITAMIN B12
2.1. FUNCTIONS, METABOLIC REACTIONS, HOW A DEFICIENCY AFFECTS YOU, AND THE FOLATE TRAP
Vitamin B12 has many functions. Like many vitamins in the B complex, it also acts as a coenzyme. The most important ones are listed below, along with what happens in case of a deficiency:
It participates in two very important metabolic reactions:
Below, we will summarize and discuss the entire cycle:
MTHFR (Methyl Tetra Hydro Folate Reductase): is an enzyme involved in folate metabolism. It catalyzes the conversion of methylenetetrahydrofolate (or 5,10-M-THF) to methyltetrahydrofolate (M-THF). M-THF, remember, is a cofactor for breaking down homocysteine and ensuring that it is correctly converted to methionine. When we eat food, we obtain THF, which must be converted to M-THF in order to perform its correct functions and act as a cofactor for everything we are looking at. If MTHFR fails or is unable to perform its functions fully in this step, there will be a problem associated with folates. This is associated with genetic issues. If this is suspected, a mutation test can be requested (the most common are C677T and A1298C).
3. VITAMIN B12 METABOLISM
3.1. METABOLISM, TRANSPORT, AND STORAGE OF VITAMIN B12
Dietary B12 found in food is bound to binding proteins, from which it is released in the stomach by pepsin and the acidity of secreted hydrochloric acid.
Once B12 has been released from dietary proteins, it binds to salivary haptocorrina, a binding protein (also called protein R or cobalofilin) secreted in the salivary glands and binds in the stomach with cobalamin, which has a high affinity for this protein, forming a complex with it as it passes into the duodenum.
Once it reaches the duodenum, it is released from the R proteins by the action of proteases and pancreatic bicarbonate, which cause the elimination of the initially formed complex, leaving B12 free.
This vitamin B12 binds to the intrinsic factor, also known as Castle's intrinsic factor in honor of the scientist William Castle, whom we mentioned earlier, who conducted important research and made significant contributions in this field. The intrinsic factor (IF) is a glycoprotein secreted by the parietal cells of the gastric mucosa that binds to vitamin B12 once it has been released from the R proteins, making it resistant to gastric and pancreatic proteases and forming a B12+intrinsic factor complex known as the Castle complex. The intrinsic factor has a maximum binding capacity and becomes saturated at around 1.5-2 μg of ingested vitamin B12 (if we take more than that amount, less is absorbed, and less and less as the dose increases).
In the terminal ileum, the B12+intrinsic factor complex is absorbed through the recognition of specific receptors, which in turn limit absorption in physiological or dietary intakes. Here, cobalamin is released, and the intrinsic factor is degraded in the lysosomes (cell organelles with hydrolytic and proteolytic enzymes).
If none of the above has failed along the way, B12 has reached its first destination safe and sound; but it still has an important journey ahead of it via specific transporters (which we can illustrate as “cars”) to its final destination.
Free B12 binds to transport proteins (the available cars) present in plasma: haptocorrins, also called cobalofilins or transcobalamins, of which we find transcobalamin I, II, and III.
There is debate on the subject of I and III, and whether we should generally refer to transcobalamin I alone, or simply call it haptocorrina. These haptocorrins transport B12 but do not deliver the vitamin. They have a high affinity for inactive B12 analogues, although it is believed that this may also play a role in their elimination, as well as other functions that are still being studied and are largely unknown (including the transport of stored B12).
Transcobalamin II is the main “carrier” and is also sometimes referred to simply as transcobalamin (TC, or TC2 in some texts). It is the most important transporter, as it is responsible for the active transport of the vitamin and carries approximately 20% of it (the remaining 80% corresponds to haptocorrine, but this is inactive).
Many cells can secrete TC, which combines with free B12 in the cells of the ileum to form holotranscobalamin (holoTC), which enters the portal circulation and is responsible for delivering the vitamin to the cells, as it transports the functional fraction that can be absorbed by the tissues and is rapidly released into them by endocytosis (the process of incorporating molecules into cells) through their specific receptors.
In other words, transcobalamin-2 (transporter) loaded with B12 is holo-TC... Cobalamin is ultimately metabolized into methylcobalamin and deoxyadenosylcobalamin. It enters the plasma as methylcobalamin and accumulates as a reserve in the liver as deoxyadenosylcobalamin. Fifty percent (or more, depending on the source consulted and the individual) of vitamin B12 is stored in the liver, and approximately 1 μg is found per gram of liver tissue. Large amounts are also found in the kidneys. B12 is also present in the muscles. In most tissues, it does not tend to accumulate but is recycled through an active transport mechanism.
Reserves range from 1-6 mg in healthy adults (and can be significantly higher at the upper end of the range), with 2-3 mg being the most common average. The larger the reserves, the greater the normal daily losses, and vice versa: the smaller the pool (reservoir) of cobalamins, the less B12 will be eliminated, which could be the result of a metabolic adaptation to low reserves. In other words, the physiology of B12 reserves is as follows: if we have large reserves, the body knows that it has plenty and is not very interested in safeguarding them, so it loses more; and if we have low reserves, the body will try to save as much as possible (although it continues to lose the same amount, it tries to resist).
It is estimated that when the body pool is 300 μg or less, signs of deficiency will appear. However, it should not be ruled out that problems may already exist above this level.
A small portion of stored B12 is continuously secreted into the bile. Of that fraction, between 50% and 80% follows the steps already mentioned (detaching from R proteins and binding to IF) and is reabsorbed, while the rest is lost in the feces along with the rest of the corinoid analogues. This is called enterohepatic circulation, and it is for this reason that a deficiency due to dietary absence can take years to develop if there are sufficient reserves even in the absence of dietary intake, since it generally starts from a high pool and very small daily losses if the reabsorption mechanism is working at peak efficiency.
The amount of cobalamin stored and how the enterohepatic circuit and the buffering of general losses work as levels decrease varies greatly between individuals. Not everyone loses the same amount or at the same rate. Nor do they start from the same reserve levels.
The higher the initial pool and the more efficient the person is at recycling and conserving cobalamin, the longer it will take for the deficiency to develop. This explains why some cases may appear within a few months or several years. It also explains why some people say they have not had a deficiency in years, even without supplementation and on a full vegetarian diet. Be careful with this.
If there is dietary intake or supplementation and there are no problems or alterations in the transport-absorption-excretion pathway, the losses are compensated. If there is no IF or limited secretion, it is not reabsorbed in the enterohepatic circuit and is excreted, meaning that the deficiency will occur sooner (as the enterohepatic recycling circuit is failing), just as if the dietary intake is inadequate, there will come a point where enterohepatic circulation will not be sufficient.
The greatest loss is found in the feces. Among the excreted B12, we find the fraction secreted by bile that has not passed into the enterohepatic circulation, that which has not been absorbed from food, and that which has been synthesized in the colon by microorganisms (which cannot be absorbed since it is not found in the ileum and will never pass through it). The feces also show that a high amount (up to 98%) of the excreted B12 are cobalamin analogues, due to the conversion of cobalamin into analogues by microorganisms in the colon.
The other route of elimination is urinary, which is not usually significant except when blood binding capacity is exceeded or macrodoses are used through supplementation. Due to the existence of a reservoir that is efficiently used by the enterohepatic circuit, a deficiency due to dietary absence of B12 may take some time to appear if reserves are adequate at the time the vitamin supply ceases. But... how long does it take? This is somewhat indeterminate and will depend on each individual, previous reserves, how they are managed, and the efficiency of the enterohepatic circuit. It usually takes about 3-4 years, although there are individuals where it occurs much earlier or later.
3.2 ABSORPTION AND DIFFERENCES BETWEEN PHYSIOLOGICAL AND PHARMACOLOGICAL DOSES
The percentage of absorption decreases as the dose increases.
“The higher the dose, the less is absorbed.”
At low or moderate doses, also called physiological doses, which are those we would get through food (although we could also include B12 provided by fortified foods or supplementation in very small amounts), absorption depends on the intrinsic factor secreted and the intestinal receptors of the Castle complex, which regulate absorption. There is an absorption mechanism that under normal conditions saturates at approximately 1.5-2 μg per meal. If this amount is exceeded in a single dose, absorption becomes dependent on passive and diffuse mechanisms, which are much less efficient.
Simple rule: any single dose in a single meal that exceeds the saturation capacity of the IF will be very poorly absorbed. And if we don't produce IF, imagine what happens. It is estimated that the saturation capacity is fully recovered within 4-6 hours, allowing a new dose with the same absorption and saturation capacity as the previous one.
How much do we absorb? In summary, under ideal conditions and if intrinsic factor secretion is correct, approximately 50% is absorbed per meal. In its latest consensus, the EFSA recommends, as a precautionary measure, to consider an estimated average absorption of 40% due to the number of factors that can influence it.
For each 1 μg of B12 taken, approximately 40-50% would be absorbed, but remember that if the intake is higher, less is absorbed, and that there is also a saturation mechanism and a “recovery” period must elapse before it is fully absorbed again. For this reason, some authors prefer to be conservative in terms of not overestimating absorption and to consider that not all foods have the same absorption rate, since the richer the food is in B12, the less will be absorbed...
Apart from low doses, when opting for protocols with weekly macrodoses of supplementation or booster doses, we must provide a very high intake of B12 to ensure that we cover the absorption of a small but sufficient fraction, even at the expense of the vast majority of the B12 in the supplement not being utilized and being eliminated due to the lower absorption efficiency found with this route, as it is not dependent on the intrinsic factor. An example of this is macrodoses, also known as pharmacological doses, which can only be provided through supplements.
This is why, at the beginning of the 20th century, when it was discovered that eating liver improved patients with pernicious anemia, they had to eat huge amounts to achieve a “pharmacological effect.”
In these cases, we find an approximate absorption of, with luck, between 1-2% of the dose administered, but it is not uncommon for it to be even lower (0.5%) depending on the size of the dose, previous reserves, and other factors and individual conditions of each subject.
With these pharmacological doses or macrodoses, the resulting excess is excreted in the urine, as it has been unable to bind to the intrinsic factor or fully bind to transcobalamin because it has exceeded the binding capacity of the transport protein due to being present in very high doses (doses that will have been necessary, however, to ensure a specific absorption according to the objective and purpose).
Macrodoses of vitamin B12 are absorbed even in the absence of intrinsic factor and hydrochloric acid, as they are not dependent on these, making them a valid strategy for maintenance or recovery in processes or states where this protective protein is not being secreted, such as in gastrectomies, achlorhydria, etc.
How long do reserves last? From months to years. It depends on several factors:
3.3. HOMOCYSTEINE AND METHYLMALONIC ACID
As we have seen, in anemia due to B12 deficiency, both homocysteine and methylmalonic acid are elevated, while in B9 deficiency (also a cause of megaloblastic anemia), only homocysteine is found in plasma levels above normal.
Homocysteine
Homocysteine is a homologue of the amino acid cysteine that results from various metabolic processes and is derived from the normal metabolism of methionine. Cysteine is therefore dependent on methionine (an essential amino acid), as it is produced whenever there is sufficient methionine, and a methionine deficiency would in turn cause lower endogenous synthesis of cysteine.
The recycling of a large part of the resulting homocysteine back into methionine is essential, and when this does not occur correctly, homocysteine accumulates in the blood. Both B12 and B9 are involved in this process, as well as B6 (the latter in another pathway, responsible for transforming homocysteine into cysteine; remember the diagram with the arrows seen above). There is another pathway that carries out this process using the enzyme betaine. Therefore, to simplify the process, the metabolism of methionine results in homocysteine, and much of this must then be converted back into methionine. If something goes wrong in this process (for example, a lack of B12, B9, or a combination of both), homocysteine builds up in the blood.
Today, we know the importance of a marker such as serum homocysteine, whose high levels (hyperhomocysteinemia) are related to:
There is some debate as to whether it is homocysteine itself that causes these problems or the underlying factors that have led to elevated homocysteine levels. Whatever the case, what is clear is that there are strong correlations at the level of evidence (potentially causal relationship), and whether due to it directly or indirectly, its increase is a factor to be taken into account and should not be ignored.
Elevated homocysteine is not necessarily conclusive of a B12 or B9 deficiency and should be put into context. There are other factors that can cause hyperhomocysteinemia or put you at risk of developing it, the most common of which are:
Homocysteine is also known to be elevated in cases of osteoporosis. But if we take B12 and folic acid, thereby lowering homocysteine... does this reduce the risk of fracture? The answer is again no. Lowering homocysteine through vitamins does not reduce the existing risk of fracture. It does seem, at least according to a clinical trial by Clements et al, that if there are low levels of B12 present, supplementation could improve bone mineral density.
Low vitamin B12 has recently been linked to chronic migraine, and high homocysteine, with low cofactors and alterations in MTHFR (remember, the one that allowed the passage of THF to M-THF), has been linked to migraine with aura, due to incorrect methionine synthesis, which ultimately leads to an increase in homocysteine, causing an increase in reactive oxygen species (causing oxidative stress).
Methylmalonic acid
In the conversion of methylmalonyl CoA to succinyl CoA, where adenosylcobalamin plays a fundamental role as a cofactor, there is a defect in this reaction if there is not enough vitamin B12. This defect leads to a block in the conversion, resulting in the accumulation of methylmalonic acid (MMA), a product of the process responsible for the neurological effects that may begin to appear at a certain point. This is another important marker to look for in a blood test. In fact, it is considered the gold standard in blood tests as it is the most specific and valid marker.
Important: MMA levels may also be elevated in cases of kidney problems. Elevated methylmalonic acid is commonly seen in the elderly, either because B12 is poorly absorbed (which may be one of the reasons), or because there is not necessarily a B12 deficiency as such, but rather an alteration in kidney function; which is why it is important to check the glomerular filtration rate, as impaired kidney function or kidney disease increases MMA, which should be taken into account when screening with MMA.
4. VITAMIN B12 DEFICIENCY
4.1. SPANISH VEGETARIAN POPULATION: B12 AND METHYLMALONIC ACID
In 2018, the first study evaluating B12 + methylmalonic acid status in the Spanish vegetarian population was conducted.
The sample consisted of 103 people from Madrid, approximately 50% vegan and 50% ovo-lacto vegetarian. The sample was not particularly large, but it was well selected in terms of dietary habits (for example, participants could not consume meat or fish even occasionally, which is allowed in other studies, where anyone who does so is considered vegetarian).
More than 75% of people had low levels of methylmalonic acid (the best indicator of B12 deficiency), which would indicate that they were supplementing and out of danger (or that they had not been without supplementation long enough for levels to rise), but in 11 of the volunteers (5 OLV and 6 vegans) the levels were above the established cutoff point, of which 10 had plasma B12 levels “in range,” which would indicate a subclinical deficiency despite having apparently correct B12 in the analysis. Additionally, 2 more subjects had low plasma B12 levels.
The fact that the OLV group also had elevated levels of methylmalonic acid indicates, once again, that they are also at potential risk, and that many of them do not supplement and/or believe they meet their requirements from food.
Statistically, in the sample studied, 1 in 10 had subclinical deficiency.
The limitations of the study are that the sample size is not very large, the supplementation doses used are not known (although the frequency is), the length of time the participants had been following a vegetarian diet is not known, and there were many more supplement users (75%) than; the latter could indicate greater awareness of the need for supplementation. In fact, the study acknowledges that the vast majority of those recruited to participate were aware that they needed to take supplements.
Let's note one more thing, which is that it is possible that more than one person started at that time and improved their status because they were going to participate in a study and became aware at that time of supplementation so that they would not get a negative result. And the following: more than one of those who did not take supplements and had normal results, despite showing good status at this time, will have problems in the future.
4.2 “OFFICIAL” RECOMMENDED DAILY AMOUNTS AND SUPPLEMENTATION
These vary greatly depending on the source consulted. Let's look at two tables, one based on the Spanish population (FESNAD) and the other usually recommended for the US population but also used internationally (IOM).
In the EFSA review and position paper, they compile the statements of the main international organizations and ultimately take a position well above the rest.
CDR/IDR/RDA have always been a point of debate. Since a maxim in nutrition is that intake does not equal absorption and multiple factors influence absorption, not everyone will have the same absorption/yield of nutrients, and in the case of B12, the theoretical amounts were initially established to prevent megaloblastic anemia, but perhaps not to ensure that everyone has a good status, and not everyone has the same absorption or the same chrononutritional distribution.
And... we say it again... not everything is megaloblastic anemia as a symptom. The spectrum is very varied.
Furthermore... the final amount of B12 is not the same in everyone to compensate for losses. Studies have shown that some people may require significantly more vitamin B12 than others.
The EFSA has come down on the side of higher amounts. Why? As a precautionary measure after reviewing different studies and considering multiple factors at play, including variability in absorption, daily losses, and reduced absorption rates at high intakes.
In addition, they refer to these proposed values as a minimum; they suggest that this is the starting point. As already mentioned, depending on the size of the cobalamin pool, there are more or less losses, and these should be covered if approximately the same reserve values are to be maintained, taking into account the percentage of absorption:
Note: Some people may require more than 2000 mcg, between 2500-3000 mcg, to maintain adequate levels of B12 and low homocysteine. These are individual issues in clinical practice, but they should not be ignored (we should never rely on standardized tables).
For vegans/ovo-lacto vegetarians: The weekly protocol is usually considered more convenient and is cheaper than the daily protocol.
In addition, the weekly protocol is also useful in cases of malabsorption (whether chronic or occasional; although injectable forms are generally used in certain chronic cases).
Daily protocols are not effective in cases of malabsorption, nor is it effective to cover the dietary B12 requirement from animal products or fortified foods.
In people over 65, it has been observed that daily macrodoses work best. In the elderly, caution should be exercised with unnecessary folate supplements. There are not many studies on this subject, but what little we do have shows that those with subclinical deficiency did not recover until they took 500 μg per day, suggesting a possible maintenance dose (once again, speaking in general terms, without being able to generalize).
If we want to see a simple, minimalist maintenance protocol (for the adult population):
Daily dose through food: animal products (not suitable for vegetarians) or fortified products, or low-dose supplements.
With weekly supplementation, for people who do not consume dietary B12 (vegans), and ovo-lacto vegetarians or people who consume very little animal-based food.
It would also be useful for people with malabsorption. (Prior clinical assessment is required to decide the best protocol, dose, and route of administration in each case.)
Note 2: The daily protocol with supplements or the protocol with fortified products is not effective if there is malabsorption for any reason.
4.3 VITAMIN B12 IN OVO-LACTOVEGETARIANS
Ovo-lacto vegetarians should also take supplements as a precaution, as it is very likely that they do not consume adequate amounts every day. Let's look at some examples to cover the requirements according to the values of different positions in adults (according to values proposed by FESNAD, IOM, and EFSA).
Values obtained and calculated from the Spanish Food Composition Database (BEDCA) and the USDA database.
Remember: It would be ideal to spread this out over at least two meals a day. These are theoretical amounts; there are differences between individuals.
This is all very theoretical; there may be ovo-lacto vegetarians who need to consume more.
In any case, it would be prudent to take a supplement. If an OLV is not going to take supplements, they should consume relatively high amounts of dairy products and/or eggs, spread out over different meals throughout the day, and monitor their status correctly.
5. SYMPTOMS AND DIAGNOSIS OF VITAMIN B12 DEFICIENCY
5.1. VITAMIN B12 DEFICIENCY
Low and insufficient levels of vitamin B12 can lead to megaloblastic anemia (megaloblastic anemia should not be confused with pernicious anemia; not all megaloblastic anemia is pernicious) and produce neurological, psychiatric, cardiovascular, gastrointestinal, and dermatological symptoms.
Technically, the term pernicious anemia refers to a B12 deficiency due to malabsorption caused by atrophic gastritis, due to a lack of intrinsic factor or problems with its secretion due to atrophy of the gastric mucosa, autoimmune attack against the intrinsic factor, and/or autoimmune destruction of the secretory parietal cells (as in the case of atrophic gastritis, also of autoimmune origin, which causes achlorhydria and is secondary to some autoimmune diseases that can predispose to problems in the gastric mucosa).
As additional information, a very common condition: when atrophic gastritis and pernicious anemia are present, iron absorption problems may occur, including hidden iron deficiency anemia due to false test results caused by a dysfunction of serum iron metabolism, elevated ferritin, and elevated transferrin saturation index. It should be noted that, if this condition occurs, there will be a rapid decrease in these markers after treatment with B12, and this should be monitored; approximately half of patients with pernicious anemia and B12 deficiency, after replacement therapy with this vitamin, showed iron deficiency anemia in blood tests, which was previously hidden and masked.
Megaloblastic anemia can be caused by a deficiency of B12, B9, or both. Since B12 and B9 share interrelated functions, anemia and its mechanisms are the same regardless of the cause, with the difference that the onset of anemia is later in the case of a B12 deficiency.
Apart from the common characteristic of anemia (decrease in red blood cells), anemia due to B12 deficiency presents a process of macrocytosis (increase in the size of red blood cells or erythrocytes) that manifests itself in the abnormal growth of blood cells (the aforementioned megaloblasts), all of which is the result of a failure of their nucleus to mature and an increase in cytoplasmic mass and maturation. This is why megaloblastic anemia is referred to as macrocytic anemia. It should be noted that there may also be megaloblastic processes that do not cause anemia.
One of the characteristics, as we have seen, is an increase in the size of the erythrocytes, which would be reflected in a blood test when measuring the MCV (mean corpuscular volume). However, let us remember again: if there is a B12 deficiency but a high intake of folates through supplements or dietary sources, the MCV may not be altered, as the folate trap is neutralized when a more or less valid folate balance is restored, and this means that the alarms may not go off in a basic blood test. What would accumulate equally is homocysteine, a marker that does not appear in a standard blood test and must be requested specifically (although if folic acid is taken, it may cause it to be regulated somewhat downward). MMA (methylmalonic acid) is even more specific (considered the “gold standard” in testing for B12 deficiency).
This picture is common in some cases of vegans, as there is usually adequate and generally high folate intake from the diet itself, and this often prevents the folate trap from being triggered. Therefore, seeing a normal MCC and a correct erythrocyte count in a blood test does not rule out the risk of non-hematological symptoms typical of B12 deficiency without the presence of megaloblastic anemia (or it may present in a mild or very mild form). In addition, serum B12 analysis may give a value within the normal range, but there may be tissue deficiency.
Therefore, there are occasions when a B12 deficiency can occur without anemia, megaloblastosis, or initial symptoms if there is a high intake of folates, which further complicates early diagnosis and can worsen symptoms, as symptoms (many of which are serious) may appear suddenly at a later stage, having been masked by the deficiency until then. In fact, there are associations between fewer hematological symptoms and more severe neurological symptoms.
There are situations of symptoms and neurological damage that appear without previous anemia. The way to rule out masking is not only to look at B12 and anemia markers, but also to determine at least homocysteine levels and, more specifically, if possible, methylmalonic acid levels. The ovo-lacto-vegetarian population is also at high risk of deficiency, since although they consume animal products such as dairy products or eggs, they do not usually meet the minimum daily requirement, which is high and should ideally be spread over several meals. In addition, it is known that some thermal processes, such as pasteurization or UHT, to which much of the commercial milk is subjected, cause losses of up to 7% of vitamin B12, and boiling causes a 30% loss.
In addition, some of the vitamin B12 contained in food may be analogues, which complicates matters for this population group, and it is not useful to look exclusively at B12 in blood tests (nor to adhere to the minimum values of current laboratory ranges). It is true that both vegetarians and non-vegetarians can be deficient in B12, but in the non-vegetarian population, the deficiency is NOT dietary in origin, since the vitamin is consumed in animal-based foods. Rather, the deficiency is due to various causes of malabsorption or autoimmune origin, where antibodies against parietal cells and intrinsic factor are detected.
In other words, B12 deficiency in vegetarians would be due to dietary absence (or insufficient intake in the case of low consumption) and lack of supplementation. However, the causes of B12 deficiency in other population groups must be sought in other contexts, as they do consume this vitamin regularly through their diet, but something is wrong (they do not absorb it well, they do not have the necessary binding proteins, they have a pathology or infection that affects it, they do not produce enough hydrochloric acid, etc.).
Here is a summary of the causes of B12 deficiency not related to diet:
The classification of deficiencies includes established, subclinical, masked, asymptomatic, and functional deficiencies.
5.2 PROGRESSIVE STAGES OF A B12 DEFICIENCY
5.3 SYMPTOMS OF VITAMIN B12 DEFICIENCY
The following may occur:
It is important to remember that pregnant women who follow vegetarian diets (including some animal products such as milk and/or eggs) or strictly vegetarian diets (vegan) should take supplements and maintain adequate levels during pregnancy and breastfeeding, EVEN if they are asymptomatic. Of course, supplementation should not only be taken during pregnancy, but should be continued over time.
The symptoms of a deficiency in babies are very serious. They include brain atrophy, seizures, severe anemia, pancytopenia, damage to the myelin sheath, and residual post-treatment problems in cognitive and psychomotor development. In addition, measuring B12 in a blood test is not an accurate marker, as it can be overestimated, and laboratory range values have long been shown to be outdated.
There are many documented clinical cases, all of them varied, with a multitude of symptoms, combinations of several of them, and uncertain onset, and with relatively good responses to treatment, but sometimes with very serious consequences if action is delayed: pancytopenia, organ failure, partial or permanent vision loss that is not recovered, heart attacks, and death.
Anyone who loves clinical cases will surely enjoy reading them, because, although they are unfortunately sad (and we wish each of them the best outcome and a speedy recovery), the number and variety of symptoms, as well as the uncertainty of their onset and how they affect each person, is fascinating.
Ralph Carmel, one of the modern scientists who has studied B12 most thoroughly, comments in one of his studies:
NOTE: Deficiency IS NOT THE SAME AS symptoms (there may be temporary asymptomatic deficiency) and the onset of symptoms is variable and interindividual.
5.4. ANALYSIS AND RANGE VALUES
A test that only looks at serum B12 is incomplete.
HoloTC (TC+B12) could also be measured as another important marker, as it is responsible for delivering active B12 (a small fraction). Remember that 80% of vitamin B12 is transported by haptocorrine and corresponds to the non-active fraction. It is not common in medical tests but is used in studies on vitamin B12.
Laboratory range levels of the main markers involved (may vary depending on the laboratory):
Homocysteine: <10 µmol/liter. Some laboratories set the cutoff point at 12 and there is even talk of 15. As always, there is some variation, but we can get a general idea. Some proposals suggest giving men a little more leeway in the upper range, as men tend to have slightly higher homocysteine levels than women in general. There is a high correlation between B12 deficiency and hyperhomocysteinemia.
Methylmalonic acid (MMA), the best indicator of B12 deficiency:
General laboratory range values:
- MCV: 80-100 femtoliters.
- MCH: 27-31 pg/cell.
Other particularities that may be found at the analytical level: high lactate dehydrogenase (LDH) due to the destruction of red blood cells, possible increase in ferritin, bilirubin, hypersegmented neutrophils, and changes in red blood cell morphology. In severe cases, there may also be thrombocytopenia, severe leukopenia, or pancytopenia.
5.5 VERY HIGH VITAMIN B12
Abnormally high/very high levels of vitamin B12 should not be overlooked. They may be due to a functional deficiency (very high levels but where the vitamin does not work well), with over-uptake and/or over-release, for various reasons.
If high levels of cobalamin are found, certain underlying conditions should be ruled out.
If it is very high, it is usually caused by certain pathologies or functional problems related to defects in vitamin B12 uptake, leading to over-uptake and even over-release. However, excessive supplementation could also cause this in some cases.
Some causes that can lead to high B12 in a blood test and that should be ruled out:
And the section that many of you have been waiting for:
Andrès et al, in a paper that we always recommend to our students on excess cobalamin, state that at very high cobalamin levels, functional deficiencies should be ruled out, homocysteine and MMA should be checked, and the cause should be sought; if there is inflammatory disease, blood disorders, kidney problems, liver disease, neoplasms, and other situations that could cause this, as well as assessing another possibility: if there has been previous supplementation, excessive continuous doses, what doses, for how long, etc.
6. VITAMIN B12, PREGNANCY, AND BREASTFEEDING
6.1 VITAMIN B12 IN PREGNANCY AND BREASTFEEDING
Some organizations recommend only a small increase in dietary B12, while others recommend a little more, with discrepancies between them. A fetal accumulation of between 0.1-0.2 μg per day is required, which is why some organizations recommend increasing the mother's daily requirements by 0.2 μg (but then, who keeps track of this mathematically with their diet, and do we know exactly how much B12 each food contains when there are so many different figures in the tables and we don't know exactly how much each person absorbs?).
The EFSA adds at least +0.5 μg (since it considers 40% absorption) to its recommendation for adults of 4 μg or more. In lactating women, there is an estimated secretion of 0.4 μg/day through breast milk, although this varies depending on the population group studied.
It should be noted that children are much more susceptible to developing a deficiency of this vitamin much more quickly, since they do not start with the reserves of an adult, and their symptoms can be very severe and even remain after treatment. There may even be neurological damage to the fetus in deficient mothers.
Regarding vegetarian diets: all vegan or vegetarian mothers who do not take supplements, or any mother who does not consume sufficient amounts through her diet for any other reason or who has malabsorption problems, must take supplements (in cases of malabsorption, remember to always follow protocols with macrodoses).
Breastfeeding provides B12 to the child through milk, provided that the mother's levels are adequate.
For babies in the complementary feeding stage and children, you can choose either drops or oral tablets, provided that the latter are completely crushed to a powder, at least until the age of 3, to avoid choking.
Regarding B12, vegetarianism, and different situations, some authors have proposed different tables and protocols based on published data and studies. Let's look at some tables adapted from those published by Baroni:
6.2 VITAMIN B12 IN MOTHERS AND CHILDREN
This is a key point with extremely important and vital functions. In children, we have mentioned that the situation is even more complicated than in adults. They can suffer much earlier and more severe deficiencies from the outset, and the disaster that a B12 problem can cause for young children is well documented in the scientific literature through reported cases.
Some of these problems include neurological disorders, brain atrophy, demyelination, delayed cognitive development and growth, mental retardation, lack of emotional and communicative responses, lack of smiling and willingness to play, extreme fatigue, vomiting, tremors and convulsions, gait and motor coordination disorders, severe megaloblastic anemia, thrombocytopenia, pancytopenia, which can lead to coma, respiratory failure, and death. The following have also been described: hypotonia, muscle weakness, lack of response to stimuli, delayed speech development, lack of interaction with people, involuntary movements, hyperpigmentation, enlargement of the liver and spleen, and low bone mineral density. All of these have been documented in scientific literature.
The likelihood of residual symptoms remaining after treatment is much higher than in adults. It appears that between the fourth and tenth month is when the clinical picture is most likely to appear, but there are also cases reported earlier, as well as in older children.
7. VITAMIN B12 SUPPLEMENTATION
7.1 FORMS OF VITAMIN B12 IN SUPPLEMENTS: CYANOCobalamin, HYDROXOCobalamin, METHYLCobalamin
Regarding the different forms of B12, it is always advisable to supplement with cyanocobalamin, as it is the most studied form (and also inexpensive, since it is easily produced in the laboratory), as well as being very stable, resistant, and less photosensitive.
It has proven safety and the amount of cyanide it contains is low.
Cyanocobalamin has sometimes been proposed as the worst source because it must be converted to the two coenzymatic forms (methyl and adenosyl) before it can be used, but the reality is that the body can efficiently convert cyanocobalamin into methylcobalamin and adenosylcobalamin without any problems.
It is true that methyl- can have its uses, without a doubt, and it is not an incorrect form; it has also been said that once absorbed, it is better retained; but the doses to be used are not precisely known. However, when properly managed, anyone who wants to take the directly methylated form is an option.
Although methylcobalamin is the least common form when injected, recent studies are considering it as an option in some cases, such as in the early stages of amyotrophic lateral sclerosis, where a study by Ryosuke et al. worked with daily injections of 50 mg (which are extremely high doses).
Hydroxocobalamin is usually found in injectable form, although injectable cyanocobalamin is also more common, with Optovite (cyanocobalamin) being the most common drug in Spain for this use.
At low doses, from 1 μg to 25 μg, all forms are absorbed equally. At high doses, cyanocobalamin is better absorbed. Methylcobalamin in supplement form is converted very efficiently and without difficulty into adenosylcobalamin. It appears to be better retained once absorbed, but much higher doses are required. The necessary doses are currently unknown, and aspects of its metabolism are not fully understood. It is also a less stable form.
Among others, Leene A. Alane and Carlos Rojas-Fernández review studies with several groups of patients with B12 deficiency for different reasons (including dietary deficiency, atrophic gastritis, ileal resection, or medication use), where some received oral B12 and others received parenteral B12 (always at high pharmacological doses ranging from at least 500 μg to 2000 μg).
In one case, high-dose oral supplementation was found to be at least as effective as parenteral supplementation, and the authors venture to say —based on a study—that it is even superior when it comes to maintenance doses, since the levels of methylmalonic acid that remained slightly above the upper limit decreased more slowly in the group that received intramuscular injections. This would also represent a significant saving, since oral supplements based on cyanocobalamin are much cheaper than injectable preparations.
They comment that patients tend to prefer oral administration over injection for reasons of convenience and adherence. In the case of oral supplementation, there appears to be no difference between taking it sublingually or swallowing it. Among others, Amir Sharabi et al. compared the sublingual and oral (swallowed) routes with doses of 500 μg.
However, although there are studies on the effectiveness of high-dose oral supplementation when symptoms are present, in severe cases of neurological symptoms, B12 should be administered parenterally until the symptoms subside and normal levels are restored. In this case, maintenance oral supplementation may be continued if the patient wishes and finds it more convenient, always taking into account the personal needs of each individual and considering whether it may be an option for the clinical case in question.
In patients where levels are low, close to the lower limit, and where there are no symptoms, a loading dose can be given through oral supplementation. This dose may vary and will depend on many factors, but a minimum of 2-4 weeks with 2000 μg/day is usually recommended, followed by maintenance if levels have recovered well. It would also be useful for people who have not been taking supplements for some time or do not know their status, although it is always advisable in any case to have a check-up beforehand to assess the situation.
Ralph Carmel published a paper in 2008 entitled “How I Treat Cobalamin Deficiency,” in which he discusses his extensive clinical experience treating patients with vitamin B12 deficiency.
He comments that in maintenance doses, it does not matter whether injectable cobalamin is used monthly or taken orally daily (each with its own specific protocols and doses), and that it is patient adherence that matters. If we are looking to optimize absorption, it is better to take the oral supplement on an empty stomach or between meals than after a meal, as the fraction absorbed is greater.
In cases with established neurological symptoms, and in line with other experts, he recommends treatment with injections rather than oral medication. A 1000 μg injection can result in the retention of up to 150 μg in the vast majority of patients in very severe and advanced cases. The doctor will determine the protocol, dose, and frequency. He also recommends conducting a preliminary study before starting treatment in patients with anemia and symptoms.
Hydroxocobalamin has been found to be more effective than cyanocobalamin in treating symptomatic conditions when administered by injection, although Carmel recommends cycling between the two. She is also surprised by the number of vegetarians who refuse or are reluctant to take supplements.
Brief summary of some points from Carmel's paper (which we recommend reading in its entirety as it is very interesting):
A study by Bensky et al. that looked at oral versus intramuscular administration:
In oral/sublingual replacement therapy, it is administered daily, while intramuscular administration follows weekly and then monthly patterns (or daily/weekly/monthly depending on the protocol and case).
Passive diffusion, although a much less efficient route, is the appropriate route for people with malabsorption problems due to any cause (including atrophic gastritis, gastrectomy, various autoimmunities—against intrinsic factor, against parietal cells, malabsorption associated with other autoimmune diseases, etc..-, use of interfering drugs...).
In children with macrocytic anemia, a clinical trial by Tandon et al found that the parenteral protocol achieved better levels of B12 and hemoglobin than the oral protocol.
7.3 ADVERSE REACTIONS
Possible adverse reactions, considered rare and exceptional, include:
Acne is reported as a relatively common symptom when very high doses are administered at once. Cases of acne following protocols with high daily doses of B12 (5000-10000 mcg in a single dose) are not uncommon.
Regarding toxicity, oral cobalamin is considered very safe even at high doses, but according to Ralph Carmel himself, “toxicity is minimal, but not entirely non-existent,” and absurd and unjustified supplements should not be taken, especially not for long periods of time, as this does increase the risk of associated problems.
It is often said that B12 supplements do not cause problems, that there is no limit, that you can take as much as you want, that if you take too much it is eliminated in urine because it is water-soluble... This has even been heard from health professionals.
The fact that the IOM did not establish an upper level (UL) at the time, since, as the institute stated, “it cannot be determined due to a lack of data on adverse effects,” does not mean that there are none.
Even so—and we don't know why this is often omitted by those who support the 1998 IOM position, saying that “you can take as much B12 as you want”—they recommended that the source of this vitamin should only come from food to avoid high levels of intake (although logically this would not apply to vegetarians or in cases of vitamin malabsorption).
Some authors have already warned against “free supplementation.” In the words of Ralph Carmel: "People who really need B12 don't take it, and those who don't need it (e.g., athletes) usually take high doses (2000-5000 mcg/day). It is not known what such high daily doses sustained over time may cause. If an elderly person has low B12 levels, there is no problem with using 500-1000 mcg/day, but 5000 mcg is ridiculous."
It is true that problems are rare and tend to occur more with parenteral than oral administration, and more with forms of B12 other than cyanocobalamin, but this does not mean that indiscriminate supplementation should be allowed or that the doses to be used and the possible side effects should be ignored in recovery protocols. There is also a call for caution regarding proposals for mass fortification of products and foods with vitamin B12, as there may be more risks than benefits. On the other hand, folic acid supplementation in some products could aggravate problems associated with B12 in people with undetected deficiency, increasing the severity of neurological and psychiatric symptoms, which are uncertain in onset and in the vast majority of cases already in subclinical states.
7.4 RECOVERY PROTOCOLS
In replacement protocols, when there is low status, subclinical deficiency, asymptomatic deficiency, malabsorption that has led to deficiency without severe symptoms, established non-aggressive megaloblastic anemia, or mild symptoms, or when general repletion is sought, we have, orally:
As a boost via parenteral route, when there is severe pernicious anemia and neurological symptoms, or if only a maintenance dose is sought, it is generally done as follows:
This is a double-blind intervention involving vegetarian and vegan subjects with marginal (>220 pmol/L) or very low (>150 pmol/L) vitamin B12 levels but no symptoms.
Duration of 3 months. Both groups improved levels of B12, Hcy, MMA, and HoloTC.
Both methods are effective in improving B12 status.
It can therefore be concluded that for deficiencies that are beginning or suboptimal values in tests (and it would even be applicable to correct values but masked subclinical deficiencies), even a maintenance dose protocol could serve to avoid danger. However, it is always better to work with well-planned recovery protocols. But this leads us to see how starting supplementation in vegetarians at maintenance doses could save someone on the verge of deficiency from suffering from it, even if they have no symptoms and no blood tests. Taking B12 is crucial. Even if you are asymptomatic.
7.5 PERCENTAGES ABSORBED AND RETAINED IN DIFFERENT DOSES AND ROUTES
8. BIBLIOGRAPHY
A Garrido Pertierra. José María Teijon Rivera. Bioquímica metabólica. 2ºEd. Editorial Tebar.
A Kornic, Patricia & M J Harty, Margaret & Grant, Joshua. (2016). Influence of Treatment Parameters on Symptom Relief in Individuals with Vitamin B12 Deficiency. Annual Research & Review Biology. 11. 1-831711. 10.9734/ARRB/2016/31711.
Adams JF, Ross SK, Mervyn L, Boddy K and King P, 1971. Absorption of cyanocobalamin, coenzyme B12, methylcobalamin, and hydroxocobalamin at different dose levels. Scandinavian Journal of Gastroenterology, 6, 249–252.
Aguirre JA, Donato ML, Buscio M, Ceballos V, Armeno M, Aizpurúa L, Arpí L. [Serious neurological compromise due to vitamin B12 deficiency in infants of vegan and vegetarian mothers]. Arch Argent Pediatr. 2019 Aug 1;117(4):e420-e424.
Al Amin ASM, Gupta V. Vitamin B12 (Cobalamin). 2022 Jun 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.
Alenzuela B, Alfonso; Sanhueza C, Julio, Nieto K. Susana. Oxidos del Colesterol (oxisteroles): Factores que condicionan su formación, efectos biológicos y su presencia en los alimentoslRev. chil. nutr. 2002, vol.29, n.2, pp.116-124.
Allen RH, Stabler SP. Identification and quantitation of cobalamin and cobalamin analogues in human feces. Am J Clin Nutr. 2008 May;87(5):1324-35.
Andres E, Affenberger S, Vinzio S, Kurtz JE, Noel E, Kaltenbach G, Maloisel F, Schlienger JL and Blickle JF, 2005. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. American Journal of Medicine, 118, 1154–1159.
Andres E, Serraj K, Zhu J and Vermorken AJ, 2013. The pathophysiology of elevated vitamin B12 in clinical practice. QJM- Monthly Journal of the Association of Physicians, 106, 505–515.
Andrès E, Serraj K, Zhu J, Vermorken AJ. The pathophysiology of elevatedvitamin B12 in clinical practice. QJM. 2013 Jun;106(6):505-15. doi:10.1093/qjmed/hct051. Epub 2013 Feb 27. Review.
Ankar A, Kumar A. Vitamin B12 Deficiency. 2022 Jun 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.
Antoni AC. Megaloblastic anemias. En: Hematology basic principles and practice. 2nd ed. New York: Churchill Livingston,1995:552-86.
Antony AC. Prevalence of cobalamin (vitamin B-12) and folate deficiency in India--audi alteram partem. Am J Clin Nutr. 2001 Aug;74(2):157-9.
Anurag A. A Study on the Levels of Folic Acid, Vitamin B12 and Plasma Homocysteine in Patients with Chronic Kidney Disease. J Assoc Physicians India. 2022 Apr;70(4):11-12.
Aoyama T, Maezawa Y, Cho H, Saigusa Y, Tamura J, Tsuchida K, Komori K, Kano K, Segami K, Hara K, Senuki K, Suzuki Y, Yamakawa M, Tamagawa H, Oshima T, Yukawa N, Rino Y. Phase II Study of a Multi-center Randomized Controlled Trial to Evaluate Oral Vitamin B12 Treatment for Vitamin B12 Deficiency After Total Gastrectomy in Gastric Cancer Patients. Anticancer Res. 2022 Aug;42(8):3963-3970. doi: 10.21873/anticanres.15891.
Arendt JF, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS One. 2012;7(9):e45979.
Arendt JF, Pedersen L, Nexo E, Sørensen HT. Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study. J Natl Cancer Inst. 2013 Dec 4;105(23):1799-805.
Aslinia F, Mazza JJ, Yale SH. Megaloblastic anemia and other causes of macrocytosis. Clin Med Res. 2006 Sep;4(3):236-41. Review. Erratum in: Clin Med Res. 2006 Dec;4(4):342.
Barney AM, Danda S, Cherian AG, Aronraj J, Jayaprakash L, Abraham VJ, Christudass CS, Marcus TA. Association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with vitamin B12 deficiency and adverse perinatal outcomes among pregnant women of rural South India - a cross sectional longitudinal study. J Perinat Med. 2022 Jul 11. doi: 10.1515/jpm-2022-0119.
Batalha MA, Dos Reis Costa PN, Ferreira ALL, Freitas-Costa NC, Figueiredo ACC, Shahab-Ferdows S, Hampel D, Allen LH, Pérez-Escamilla R, Kac G. Maternal Mental Health in Late Pregnancy and Longitudinal Changes in Postpartum Serum Vitamin B-12, Homocysteine, and Milk B-12 Concentration Among Brazilian Women. Front Nutr. 2022 Jul 11;9:923569. doi: 10.3389/fnut.2022.923569.
Bell DSH. Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes. Diabetes Obes Metab. 2022 Aug;24(8):1423-1428. doi: 10.1111/dom.14734. Epub 2022 May 20.
Bensky MJ, Ayalon-Dangur I, Ayalon-Dangur R, Naamany E, Gafter-Gvili A, Koren G, Shiber S. Comparison of sublingual vs. intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency. Drug Deliv Transl Res. 2019 Jun;9(3):625-630. doi: 10.1007/s13346-018-00613-y.
Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968 Oct;184(4):247-58.
Blanco-Vaca F, Deulofeu R, Vilaseca MA, Chacón P, Dulin E. Determinación de homocisteína en plasma: metabolismo, metodología, interpretación de resultados y papel en la evaluación del riesgo cardiovascular. Química Clínica 2002;21:243-50.
Bobat H, Akyol M, Moradi P. Comment on: 'Patients with unexplained neurological symptoms and signs should be screened for vitamin B12 deficiency regardless of haemoglobin levels'. Eye (Lond). 2022 Jul 2. doi: 10.1038/s41433-022-02162-8.
Bondevik GT, Schneede J, Refsum H, Lie RT, Ulstein M, Kvåle G. Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalaminsupplementation be considered? Eur J Clin Nutr. 2001 Oct;55(10):856-64.
Brescoll J, Daveluy S. A review of vitamin B12 in dermatology. Am J Clin Dermatol. 2015 Feb;16(1):27-33. doi: 10.1007/s40257-014-0107-3. Review.
Carmel R, Gott PS, Waters CH, et al. The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities. Eur J Haematol. 1995;54:245–253.
Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea M, Azen C. Serum cobalamin, homocysteine and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities. Am J Clin Nutr. 1999;70:904–910.
Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology. 2003:62–81.
Carmel R, Karnaze DS, Weiner JM. Neurologic abnormalities in cobalamin deficiency are associated with higher cobalamin "analogue" values than are hematologic abnormalities. J Lab Clin Med. 1988 Jan;111(1):57-62.
Carmel R, Melnyk S, James SJ. Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Blood. 2003;101:3302–3308.
Carmel R, Sarrai M. Diagnosis and management of clinical and subclinical cobalamin deficiency: advances and controversies. Curr Hematol Rep. 2006;5:23–33.
Carmel R, Sinow RM, Karnaze DS. Atypical cobalamin deficiency: subtle biochemical evidence of deficiency is commonly demonstrable in patients without megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption. J Lab Clin Med. 1987;109:454–463.
Carmel R, Spencer CA. Clinical and subclinical thyroid disorders associated with pernicious anemia: observations on abnormal thyroid-stimulating hormone levels and on a possible association of blood group O with hyperthyroidism. Arch Intern Med. 1982;142:1465–1469.
Carmel R, Weiner JM, Johnson CS. Iron deficiency occurs frequently in patients with pernicious anemia. JAMA. 1987;257:1081–1083.
Carmel R. Cobalamin, the stomach, and aging. Am J Clin Nutr. 1997;66:750–759.
Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357–375.
Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357–375.
Carmel R. Efficacy and safety of fortification and supplementation with vitamin B12: biochemical and physiological effects. Food Nutr Bull. 2008 Jun;29(Suppl):S177-87. Review.
Carmel R. Efficacy and safety of fortification and supplementation with vitamin B12: biochemical and physiologic effects. Food Nutr Bull. 2008;29(suppl):S177–S187.
Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008 Sep 15;112(6):2214-21. doi: 10.1182/blood-2008-03-040253. Epub 2008 Jul 7.
Carmel R. Macrocytosis, mild anemia and delay in diagnosis of pernicious anemia. Arch Intern Med. 1979;139:47–50.
Carmel R. Malabsorption of food cobalamin. Baillieres Clin Haematol. 1995;8:639–655.
Carmel R. Nutritional vitamin B12 deficiency: possible contributory role of subtle vitamin B12 malabsorption. Ann Intern Med. 1978;88:647–649.
Carmel R. Pepsinogens and other serum markers in pernicious anemia. Am J Clin Pathol.
Carmel R. Pernicious anemia: the expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med. 1988;148:1712–1714.
Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med. 1996;156:1097–1100.
Çebi M, Metin B, Tarhan N. The association between vitamin B12 and plasma homocysteine levels with episodic memory and the volume of memory related brain structures in middle-aged individuals: a retrospective correlational study. Brain Struct Funct. 2022 Jul;227(6):2103-2109. doi: 10.1007/s00429-022-02499-6.
Cicero AF, Minervino A. Combined action of SAMe, Folate, and Vitamin B12 in the treatment of mood disorders: a review. Eur Rev Med Pharmacol Sci. 2022 Apr;26(7):2443-2459. doi: 10.26355/eurrev_202204_28479.
Clements M, Heffernan M, Ward M, Hoey L, Doherty LC, Hack Mendes R, Clarke MM, Hughes CF, Love I, Murphy S, McDermott E, Grehan J, McCann A, McAnena LB, Strain JJ, Brennan L, McNulty H. A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status. J Bone Miner Res. 2022 Sep 21. doi: 10.1002/jbmr.4709.
Cohen H, Weinstein WM, Carmel R. The heterogeneity of gastric histology and function in food cobalamin malabsorption: absence of atrophic gastritis and achlorhydria in some patients with severe malabsorption. Gut. 2000;47:638–645.
Conocimientos actuales sobre nutrición editado por Ekhard E. Ziegler,L.J. Filer (Jr), V. Herbert.
Cortés MF, Hirsch BS, de la Maza CMP. Importancia del ácido fólico en la medicina actual. Rev Méd Chile. Scielo Chile [en línea] Febrero de 2000 [fecha de acceso Junio de 2007]; 128 (2):
Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12 from algae appears not to be bioavailable. Am J Clin Nutr. 1991 Mar;53(3):695-7.
Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12 from algae appears not to be bioavailable. Am J Clin Nutr. 1991 Mar;53(3):695-7.
de Paz R, Hernández-Navarro F. [Management, prevention and control of megaloblastic anemia, secondary to folic acid deficiency]. Nutr Hosp. 2006 Jan-Feb;21(1):113-9.
Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, New Delhi, India. Perturbing Status of Vitamin B12 in Indian Infants and Their Mothers. M Mittal et al. Food Nutr Bull 38 (2), 209-215. 2017 Mar 07.
Depuis Z, Gatineau-Sailliant S, Ketelslegers O, Minon JM, Seghaye MC, Vasbien M, Dresse MF. Pancytopenia Due to Vitamin B12 and Folic Acid Deficiency-A Case Report. Pediatr Rep. 2022 Mar 3;14(1):106-114. doi: 10.3390/pediatric14010016.
Depuis Z, Gatineau-Sailliant S, Ketelslegers O, Minon JM, Seghaye MC, Vasbien M, Dresse MF. Pancytopenia Due to Vitamin B12 and Folic Acid Deficiency-A Case Report. Pediatr Rep. 2022 Mar 3;14(1):106-114. doi: 10.3390/pediatric14010016.
Dharmarajan TS, Norkus EP. Approaches to vitamin B12 deficiency. Early treatment may prevent devastating complications. Postgrad Med. 2001 Jul;110(1):99-105; quiz 106. Review.
Dobson R, Alvares D. The difficulties with vitamin B12. Pract Neurol. 2016 Aug;16(4):308-11.
Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008 May;66(5):250-5. doi: 10.1111/j.1753-4887.2008.00031.x. Review.
D'Souza SW, Glazier JD. Homocysteine Metabolism in Pregnancy and Developmental Impacts. Front Cell Dev Biol. 2022 Jun 30;10:802285. doi: 10.3389/fcell.2022.802285.
Effects of smoking on metabolism and excretion of vitamin B12. J. C. Linnell, A. D. Smith, C. L. Smith, J. Wilson, and D. M. Matthews. Br Med J. 1968 Apr 27; 2(5599): 215–216.
EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2015. Scientific Opinion on Dietary Reference Values for cobalamin (vitamin B12). EFSA Journal 2015;13(7):4150, 64 pp.
Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005 May 23;165(10):1167-72.
Fang H, Kang J, Zhang D. Microbial production of vitamin B(12): a review and future perspectives. Microb Cell Fact. 2017 Jan 30;16(1):15.
Farooq MD, Tak FA, Ara F, Rashid S, Mir IA. Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes. J Xenobiot. 2022 May 31;12(2):122-130. doi: 10.3390/jox12020011.
Ferré N, Gómez F, Camps J, Simó JM, Murphy MM, Fernández-Baelart J, et al. Plasma homocysteine concentrations in patients with liver cirrhosis. Clin Chem 2002;48:183-5.
Forsyth JC, Mueller PD, Becker CE, Osterloh J, Benowitz NL, Rumack BH, Hall AH. Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol. 1993;31(2):277-94.
Folatos y prevención de enfermedad cardiovascular D.A. de Luis Román y R. Aller de La Fuente.
Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98:204 - 210.
Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.
Forsyth JC, Mueller PD, Becker CE, Osterloh J, Benowitz NL, Rumack BH, Hall AH. Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol. 1993;31(2):277-94.
Gallego-Narbón A, Zapatera B, Álvarez I, Vaquero MP. Methylmalonic Acid Levels and their Relation with Cobalamin Supplementation in Spanish Vegetarians. Plant Foods Hum Nutr. 2018 Sep;73(3):166-171. doi: 10.1007/s11130-018-0677-y.
Garcia Lopez M, Baron JA, Omsland TK, Søgaard AJ, Meyer HE. Homocysteine-Lowering Treatment and the Risk of Fracture: Secondary Analysis of a Randomized Controlled Trial and an Updated Meta-Analysis. JBMR Plus. 2018 Mar 24;2(5):295-303. doi: 10.1002/jbm4.10045. eCollection 2018 Sep.
Gerrard A, Dawson C. Homocystinuria diagnosis and management: it is not all classical. J Clin Pathol. 2022 Sep 19:jclinpath-2021-208029. doi: 10.1136/jcp-2021-208029.
Gilsing AM, Crowe FL, Lloyd-Wright Z, Sanders TA, Appleby PN, Allen NE, Key TJ. Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians and vegans: results from a cross-sectional analysis of the EPIC-Oxford cohort study. Eur J Clin Nutr. 2010 Sep;64(9):933-9.
Gomollón F, Gargallo CJ, Muñoz JF, Vicente R, Lue A, Mir A, García-Alvarado M,Gracia M, García-López S. Oral Cyanocobalamin is Effective in the Treatment of Vitamin B12 Deficiency in Crohn's Disease. Nutrients. 2017 Mar 20;9(3). pii: E308. doi: 10.3390/nu9030308.
Grover IS, Bharti R, Kapahi R, Sodhi MK, Kapahi R. Correlations between serum vitamin B12 and folate levels among mother-infant dyads in Punjab state, North-West India. J Paediatr Child Health. 2022 Sep 13. doi: 10.1111/jpc.16207.
Guéant JL, Guéant-Rodriguez RM, Alpers DH. Vitamin B12 absorption and malabsorption. Vitam Horm. 2022;119:241-274. doi: 10.1016/bs.vh.2022.01.016.
Guéant JL, Guéant-Rodriguez RM, Alpers DH. Vitamin B12 absorption and malabsorption. Vitam Horm. 2022;119:241-274. doi: 10.1016/bs.vh.2022.01.016.
Guyton y Hall. Tratado de Fisiología Médica. Elsevier.
Halsted JA, Carroll J, Rubert S. Serum and tissue concentration of vitamin B12 in certain pathologic states. N Engl J Med. 1959;260:575-80.
Hanger HC, Sainsbury R, Gilchrist NL, Beard ME, Duncan JM. A community study of vitamin B12 and folate levels in the elderly. J Am Geriatr Soc. 1991;39:1155–1159.
Herbert V, Castle WB. Intrinsec factor. N Engl J Med 1964;270:118-26.
Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S. Review.
Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.
Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015 - 2022.
Howard JM, Azen C, Jacobsen DW, Green R, Carmel R. Dietary intake of cobalamin in elderly people who have abnormal serum cobalamin, methylmalonic acid and homocysteine levels. Eur J Clin Nutr. 1998;52:582–587.
Huang HH, Cohen AA, Gaudreau P, Auray-Blais C, Allard D, Boutin M, Reid I, Turcot V, Presse N. Vitamin B-12 Intake from Dairy But Not Meat is Associated with Decreased Risk of Low Vitamin B-12 Status and Deficiency in Older Adults from Quebec, Canada. J Nutr. 2022 Jun 23:nxac143. doi: 10.1093/jn/nxac143.
Huđek Turković A, Matovinović M, Žuna K, Škara L, Kazazić S, Bačun-Družina V, Durgo K. Association of Vitamins D, B9 and B12 with Obesity-Related Diseases and Oral Microbiota Composition in Obese Women in Croatia. Food Technol Biotechnol. 2022 Jun;60(2):135-144. doi: 10.17113/ftb.60.02.22.7478.
Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria) Orphanet Journal of Rare Diseases2006 Ralph Gräsbeck. Ingestas Dietéticas de Referencia para Población Española. FESNAD, 2010. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US); 1998.
Interrelación entre vitamina B12 y ácido fólico. Dr. Bernardo Condado Arenas. Ishtulin AF, Korotkova NV, Matveeva IV, Minaev IV, Polyakova PM. Vitamin B12 kak diagnosticheskiĭ marker snizheniia reproduktivnoĭ funktsii u muzhchin [Vitamin B12 is a diagnostic marker of decreased men reproductive function]. Biomed Khim. 2022 Jun;68(3):228-231. Russian. doi: 10.18097/PBMC20226803228.
Jack Norris. veganhealth.org
Jaeger B, Corpeleijn W, Dijsselhof M, Goorden S, Haverkamp J, Langeveld M, Waterham H, Westerbeek E, Bosch AM. Mind the B2: Life-Threatening Neonatal Complications of a Strict Vegan Diet during Pregnancy. Neonatology. 2022 Sep 19:1-4. doi: 10.1159/000526334.
Kacharava T, Giorgadze E, Janjgava S, Lomtadze N, Iamze T. Correlation between Vitamin B12 Deficiency and Autoimmune Thyroid Diseases. Endocr Metab Immune Disord Drug Targets. 2022 Jun 27. doi: 10.2174/1871530322666220627145635.
Kalkan Ç, Karakaya F, Tüzün A, Gençtürk ZB, Soykan I. Factors related to low serum vitamin B12 levels in elderly patients with non-atrophic gastritis in contrast to patients with normal vitamin B12 levels. Geriatr Gerontol Int. 2016 Jun;16(6):686-92.
Karnaze DS, Carmel R. Neurologic and evoked potential abnormalities in subtle cobalamin deficiency states, including deficiency without anemia and with normal absorption of free cobalamin. Arch Neurol. 1990 Sep;47(9):1008-12.
Khattab R, Albannawi M, Alhajjmohammed D, Alkubaish Z, Althani R, Altheeb L, Ayoub H, Mutwalli H, Altuwajiry H, Al-Sheikh R, Purayidathil T, Abuzaid O. Metformin-Induced Vitamin B12 Deficiency among Type 2 Diabetes Mellitus' Patients: A Systematic Review. Curr Diabetes Rev. 2022 Apr 18. doi: 10.2174/1573399818666220418080959.
Kim HI, Hyung WJ, Song KJ, Choi SH, Kim CB, Noh SH. Oral vitamin B12 replacement: an effective treatment for vitamin B12 deficiency after total gastrectomy in gastric cancer patients. Ann Surg Oncol. 2011 Dec;18(13):3711-7.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR C77CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288:2023-31.
Kolhouse JF, Kondo H, Allen NC, Podell E, Allen RH. Cobalamin analogues are present in human plasma and can mask cobalamin deficiency because current radioisotope dilution assays are not specific for true cobalamin. N Engl J Med. 1978 Oct 12;299(15):785-92.
Kostick N, Chen E, Eckert T, Sirotkin I, Baldinger E, Frontera A. Clinical Presentation of Subacute Combined Degeneration in a Patient With Chronic B12 Deficiency. Fed Pract. 2022 Mar;39(3):142-146. doi: 10.12788/fp.0228. Epub 2022 Mar 14.
Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N. Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant. 1997 Aug;12(8):1622-8.
Koyyalamudi SR, Jeong SC, Cho KY, Pang G. Vitamin B12 is the active corrinoid produced in cultivated white button mushrooms (Agaricus bisporus). J Agric Food Chem. 2009 Jul 22;57(14):6327-33.
Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998 Aug 15;92(4):1191-8.
L.Kathleen Mahan y Janice L. Raymond. Krause Dietoterapia. Lamers Y. Vitamin B-12 Requirements in Older Adults-Increasing Evidence Substantiates the Need To Re-Evaluate Recommended Amounts and Dietary Sources. J Nutr. 2022 Sep 22:nxac179. doi: 10.1093/jn/nxac179.
Lane LA, Rojas-Fernandez C. Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy. Ann Pharmacother. 2002 Jul-Aug;36(7-8):1268-72. Review.
Lanzkowski P. Anemias megaloblásticas y otras anemias nutricionales. En: Hematología pediátrica. 3a ed. La Habana, 1983:195-237. (Edición Revolucionaria).
Lawhorne L, Ringdahl D. Cyanocobalamin injections for patients without documented deficiency: reasons for administration and patient responses to proposed discontinuation. JAMA. 1989;261:1920–1923.
Lawrence AC, Bevington JM, Young M. Storage of blood and the mean corpuscular volume. J Clin Pathol. 1975 May;28(5):345-9.
Lee YK, Kim HS, Kang HJ. Holotranscobalamin as an indicator of vitamin B12 deficiency in gastrectomized patients. Ann Clin Lab Sci. 2009 Fall;39(4):361-6.
Lerman TT, Cohen E, Sochat T, Goldberg E, Goldberg I, Krause I. Proton pump inhibitor use and its effect on vitamin B12 and homocysteine levels among men and women: A large cross-sectional study. Am J Med Sci. 2022 Jul 24:S0002-9629(22)00313-5. doi: 10.1016/j.amjms.2022.07.006.
Lesbia Meertens R, Liseti Solano R. Vitamina B12, ácido fólico y función mental en adultos mayores. Invest. Clin. Scielo Chile. [en línea] Marzo de 2005 [fecha de acceso 4 de Octubre de 2017]; 46 (1).
Lic. Mariela Forrellat Barrios, Lic. Irma Gómis Hernández y Dra. Hortensia Gautier du Défaix Gómez, Vitamina B12, metabolismo y aspectos clínicos de su deficiencia. Rev Cubana Hematol Inmunol Hemoter 1999;15(3):159-74.
Linnell JC, Matthews DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.
Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50.
Martens JH, Barg H, Warren MJ, Jahn D. Microbial production of vitamin B12. Appl Microbiol Biotechnol. 2002;58:275–285.
Martínez Sánchez P. Anemias por alteración de la síntesis de ADN. Anemias megaloblásticas. Medicine. Doyma. [en línea] Septiembre de 2001.
Martín-Rivada Á, Cambra Conejero A, Martín-Hernández E, Moráis López A, Bélanger-Quintana A, Cañedo Villarroya E, Quijada-Fraile P, Bellusci M, Chumillas Calzada S, Bergua Martínez A, Stanescu S, Martínez-Pardo Casanova M, Ruíz-Sala P, Ugarte M, Pérez González B, Pedrón-Giner C. Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns. J Pediatr Endocrinol Metab. 2022 Sep 19. doi: 10.1515/jpem-2022-0340.
Mascarenhas R, Gouda H, Ruetz M, Banerjee R. Human B12-dependent enzymes: Methionine synthase and Methylmalonyl-CoA mutase. Methods Enzymol. 2022;668:309-326. doi: 10.1016/bs.mie.2021.12.012. Epub 2022 Jan 30.
McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006 Jun 29;354(26):2764-72.
Merchant RE, Phillips TW, Udani J. Nutritional Supplementation with Chlorella pyrenoidosa Lowers Serum Methylmalonic Acid in Vegans and Vegetarians with a Suspected Vitamin B₁₂ Deficiency. J Med Food. 2015 Dec;18(12):1357-62.
Mizrahi EH, Jacobsen DW, Friedland RP. Plasma homocysteine: a new risk factor for Alzheimer's disease? Isr Med Assoc J. 2002;4:187 - 190.
Moghadasian MH, McManus BM, Frohlich JJ. Homocyst(e)ine and coronary artery disease. Arch Intern Med. 1997;157:2299 - 2308.
Mok KC, Hallberg ZF, Taga ME. Purification and detection of vitamin B12 analogs. Methods Enzymol. 2022;668:61-85. doi: 10.1016/bs.mie.2021.11.023. Epub 2021 Dec 30.
Morado, M., & Paz, R. de. (2011). Anemia megaloblástica y gastritis atrófica. Revista Española de Enfermedades Digestivas, 103(6), 332.
Morales-Gutierrez J, Díaz-Cortés S, Montoya-Giraldo MA, Zuluaga AF. Toxicity induced by multiple high doses of vitamin B(12) during pernicious anemia treatment: a case report. Clin Toxicol (Phila). 2019 Apr 24:1-3. doi: 10.1080/15563650.2019.1606432.
Mounsey A, Brendle DC, Flowers K. Oral vs. Intramuscular Vitamin B12 for Treating Vitamin B12 Deficiency. Am Fam Physician. 2022 Jun;105(6):663-664.
N RS, Sharma R, Madhulata, Sharma R. Pancytopenia: Etiology and it's Variables. J Assoc Physicians India. 2022 Apr;70(4):11-12.
Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr. 2011 Jul;94(1):359S-365S. doi: 10.3945/ajcn.111.013458. Epub 2011 May 18. Review.
Niiyama S, Mukai H. Reversible cutaneous hyperpigmentation and nails with white hair due to vitamin B12 deficiency. Eur J Dermatol.2007 Nov-Dec;17(6):551-2. Epub 2007 Oct 19.
Nyholm E., Turpin P., Swain D., Cunningham B., Daly S., Nightingale P., Fegan C. Oral vitamin B12 can change our practice. Postgrad. Med. J. 2003;79:218–220. doi: 10.1136/pmj.79.930.218.
Oki R,et al. Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators. Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2022 Jun 1;79(6):575-583. doi: 10.1001/jamaneurol.2022.0901.
O'Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010 Mar;2(3):299-316. doi: 10.3390/nu2030299. Epub 2010 Mar 5. Review.
Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr. 2014 May;68(5):541-8. doi: 10.1038/ejcn.2014.46. Epub 2014 Mar 26. Review.
Pecikoza U, Tomić M, Nastić K, Micov A, Stepanović-Petrović R. Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy. Biomed Pharmacother. 2022 Sep;153:113441. doi: 10.1016/j.biopha.2022.113441.
Pfnür IAH. Vitamin B12 Deficiency as the Cause. Dtsch Arztebl Int. 2022 Mar 25;119(12):216. doi: 10.3238/arztebl.m2022.0053.
Praveen G, Sivaprasad M, Reddy GB. Telomere length and vitamin B12. Vitam Horm. 2022;119:299-324. doi: 10.1016/bs.vh.2022.01.014.
Praveen G, Sivaprasad M, Reddy GB. Telomere length and vitamin B12. Vitam Horm. 2022;119:299-324. doi: 10.1016/bs.vh.2022.01.014.
R Muhammad, MD, P Fernhoff, MD, Dept of Pediatrics, Emory Univ, Atlanta, Georgia. S Rasmussen, MD, Div of Birth Defects and Developmental Disabilities; B Bowman, PhD, Div of Diabetes Translation; K Scanlon, PhD, L Grummer-Strawn, PhD, L Kettel Khan, PhD, Div of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion; M Jefferds, PhD, EIS Officer, CDC.
Rasmussen K, Moelby L, Jensen MK. Studies on methylmalonic acid in humans. II. Relationship between concentrations in serum and urinary excretion, and the correlation between serum cobalamin and accumulation of methylmalonic acid. Clin Chem. 1989 Dec;35(12):2277-80.
Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41.
Reischl-Hajiabadi AT, Garbade SF, Feyh P, Weiss KH, Mütze U, Kölker S, Hoffmann GF, Gramer G. Maternal Vitamin B12 Deficiency Detected by Newborn Screening-Evaluation of Causes and Characteristics. Nutrients. 2022 Sep 13;14(18):3767. doi: 10.3390/nu14183767.
Rhode BM, Tamim H, Gilfix BM, Sampalis JS, Nohr C, MacLean LD. Treatment of vitamin B12 deficiency after gastric surgery for severe obesity. Obes Surg. 1995;5:154–158.
Rizzo G, Laganà AS, Rapisarda AM, La Ferrera GM, Buscema M, Rossetti P, Nigro A, Muscia V, Valenti G, Sapia F, Sarpietro G, Zigarelli M, Vitale SG. Vitamin B12 among Vegetarians: Status, Assessment and Supplementation. Nutrients. 2016 Nov 29;8(12).
Rodriguez NM, Shackelford K. Pernicious Anemia. 2022 Jul 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan
Rodriguez-Carnero G, Lorenzo PM, Canton-Blanco A, Mendizabal L, Arregi M, Zulueta M, Simon L, Macia-Cortiñas M, Casanueva FF, Crujeiras AB. Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Pregnant Women of a Homogeneous Spanish Population: The Need for Revisiting the Current Vitamin Supplementation Strategies. Nutrients. 2022 Jun 29;14(13):2702. doi: 10.3390/nu14132702.
Sadagopan N. Severe Hemolytic Anemia due to Vitamin B12 Deficiency in Six Months. Hematol Rep. 2022 Jun 22;14(3):210-212. doi: 10.3390/hematolrep14030028.
Samson ME, Yeung LF, Rose CE, Qi YP, Taylor CA, Crider KS. Vitamin B-12 malabsorption and renal function are critical considerations in studies of folate and vitamin B-12 interactions in cognitive performance: NHANES 2011-2014. Am J Clin Nutr. 2022 Jul 6;116(1):74-85. doi: 10.1093/ajcn/nqac065.
Sarode R, Garewal G, Marwaha N, Marwaha RK, Varma S, Ghosh K, Mohanty D, Das KC. Pancytopenia in nutritional megaloblastic anaemia. A study from north-west India. Trop Geogr Med. 1989 Oct;41(4):331-6.
Sechi LA, De Carli S, Catena C, Zingaro L, Bartoli E. Benign familial macrocytosis. Clin Lab Haematol. 1996 Mar;18(1):41-3.
Shankar PR. VigiAccess: promoting public access to VigiBase.Indian J Pharmacol. 2016;48:606–607. y vigiaccess.org/
Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003 Dec;56(6):635-8.
Shen Y, Huang L, Zou Y, Su D, He M, Fang Y, Zhao D, Wang W, Zhang R. Intake of Vitamin B12 and Folate and Biomarkers of Nutrient Status of Women within Two Years Postpartum. Nutrients. 2022 Sep 19;14(18):3869. doi: 10.3390/nu14183869. P
Shivkar RR, Gawade GC, Padwal MK, Diwan AG, Mahajan SA, Kadam CY. Association of MTHFR C677T (rs1801133) and A1298C (rs1801131) Polymorphisms with Serum Homocysteine, Folate and Vitamin B12 in Patients with Young Coronary Artery Disease. Indian J Clin Biochem. 2022 Apr;37(2):224-231. doi: 10.1007/s12291-021-00982-1.
Shorb, M. S. (1947). Unidentified Essential Growth Factors for Lactobacillus-Lactis Found in Refined Liver Extracts and in Certain Natural Materials. Journal of Bacteriology 53, 669-669.
Shorb, M. S. (1948). Activity of Vitamin-B12 for the Growth of Lactobacillus-Lactis. Science 107, 397-398.
Silverstein WK, Cheung MC, Lin Y. Vitamin B12 deficiency. CMAJ. 2022 Jun 20;194(24):E843. doi: 10.1503/cmaj.220306.
Silverstein WK, Cheung MC, Lin Y. Vitamin B12 deficiency. CMAJ. 2022 Jun 20;194(24):E843. doi: 10.1503/cmaj.220306.
Simeone G, Bergamini M, Verga MC, Cuomo B, D'Antonio G, Iacono ID, Mauro DD, Mauro FD, Mauro GD, Leonardi L, Miniello VL, Palma F, Scotese I, Tezza G, Vania A, Caroli M. Do Vegetarian Diets Provide Adequate Nutrient Intake during Complementary Feeding? A Systematic Review. Nutrients. 2022 Aug 31;14(17):3591. doi: 10.3390/nu14173591.
Singh J, Dinkar A, Gupta P, Atam V. Vitamin B12 deficiency in northern India tertiary care: Prevalence, risk factors and clinical characteristics. J Family Med Prim Care. 2022 Jun;11(6):2381-2388. doi: 10.4103/jfmpc.jfmpc_650_21.
Stabler SP, Allen RH. Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr. 2004;24:299-326. Review.
Susan E. Mulroney. Adam K. Myers. Netter Fundamentos de Fisiología. 2da edición. Elsevier.
Susanti D, Ruslan FS, Shukor MI, Nor NM, Aminudin NI, Taher M, Khotib J. Optimisation of Vitamin B12 Extraction from Green Edible Seaweed (Ulva lactuca) by Applying the Central Composite Design. Molecules. 2022 Jul 12;27(14):4459. doi: 10.3390/molecules27144459.
Talari HR, Molaqanbari MR, Mokfi M, Taghizadeh M, Bahmani F, Tabatabaei SMH, Sharifi N. The effects of vitamin B12 supplementation on metabolic profile of patients with non-alcoholic fatty liver disease: a randomized controlled trial. Sci Rep. 2022 Aug 18;12(1):14047. doi: 10.1038/s41598-022-18195-8.
Tandon R, Thacker J, Pandya U, Patel M, Tandon K. Parenteral vs Oral Vitamin B12 in Children With Nutritional Macrocytic Anemia: A Randomized Controlled Trial. Indian Pediatr. 2022 Sep 15;59(9):683-687.
Taneja S, Chowdhury R, Kvestad I, Bhandari N, Strand TA. Vitamin B12 and/or folic acid supplementation on linear growth; a 6 years follow-up study of a randomised controlled trial in early childhood in North India. Br J Nutr. 2022 Jul 25:1-22. doi: 10.1017/S0007114522002343.
Ting RZ, Szeto CC, Chan MH, Ma KK and Chow KM. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Archives of internal medicine. 2006 Oct 9; 166 (18) :1975-9.
Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, Wilson PW, Selhub J. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr. 2000 Feb;71(2):514-22.
Ueno A, Hamano T, Enomoto S, Shirafuji N, Nagata M, Kimura H, Ikawa M, Yamamura O, Yamanaka D, Ito T, Kimura Y, Kuriyama M, Nakamoto Y. Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment. Nutrients. 2022 Apr 2;14(7):1494. doi: 10.3390/nu14071494.
Ueno A, Hamano T, Enomoto S, Shirafuji N, Nagata M, Kimura H, Ikawa M, Yamamura O, Yamanaka D, Ito T, Kimura Y, Kuriyama M, Nakamoto Y. Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment. Nutrients. 2022 Apr 2;14(7):1494. doi: 10.3390/nu14071494.
Üstün Özek S. A study on the correlation between pain frequency and severity and vitamin B12 levels in episodic and chronic migraine. Arq Neuropsiquiatr. 2022 Jun;80(6):586-592. doi: 10.1590/0004-282X-ANP-2021-0192.
Vademecum. Prospecto Optovite. vademecum.es
van Loon SL, Wilbik AM, Kaymak U, van den Heuvel ER, Scharnhorst V, Boer AK. Improved testing for vitamin B(12) deficiency: correcting MMA for eGFR reduces the number of patients classified as vitamin B(12) deficient. Ann Clin Biochem. 2018.
Vidal-Alaball J, Butler CC, Cannings-John R, Goringe A, Hood K, McCaddon A,McDowell I, Papaioannou A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004655. Review.
Vitamin Supplementation as Possible Prophylactic Treatment against Migraine with Aura and Menstrual Migraine Munvar Miya Shaik and Siew Hua Gan. Biomed Res Int. 2015; 2015: 469529.
Wang C, Zhang Y, Shu J, Gu C, Yu Y, Liu W. Association Between Methylmalonic Acid and Cognition: A Systematic Review and Meta-Analysis. Front Pediatr. 2022 Jun 29;10:901956. doi: 10.3389/fped.2022.901956.
Wang C, Zhang Y, Shu J, Gu C, Yu Y, Liu W. Association Between Methylmalonic Acid and Cognition: A Systematic Review and Meta-Analysis. Front Pediatr. 2022 Jun 29;10:901956. doi: 10.3389/fped.2022.901956.
Watanabe F, Schwarz J, Takenaka S, Miyamoto E, Ohishi N, Nelle E, Hochstrasser R, Yabuta Y. Characterization of vitamin B₁₂compounds in the wild edible mushrooms black trumpet (Craterellus cornucopioides) and golden chanterelle (Cantharellus cibarius).
Watanabe F, Takenaka S, Kittaka-Katsura H, Ebara S, Miyamoto E. Characterization and bioavailability of vitamin B12-compounds from edible algae. J Nutr Sci Vitaminol (Tokyo). 2002 Oct;48(5):325-31. Review.
Wei J, Wei Y, Huang M, Wang P, Jia S. Is metformin a possible treatment for diabetic neuropathy? J Diabetes. 2022 Sep 18. doi: 10.1111/1753-0407.13310
White ND. Vitamin B12 and Plant-Predominant Diets. Am J Lifestyle Med. 2022 May 4;16(3):295-297. doi: 10.1177/15598276221076102.
Wong S, Ahmad N, Rossetti AL. Vomiting as a Presenting Symptom of Infantile Vitamin B12 Deficiency. Cureus. 2022 May 19;14(5):e25134. doi: 10.7759/cureus.25134.
Wu HHL, Wang AY. Vitamin B12 and chronic kidney disease. Vitam Horm. 2022;119:325-353. doi: 10.1016/bs.vh.2022.01.011.
Wu HHL, Wang AY. Vitamin B12 and chronic kidney disease. Vitam Horm. 2022;119:325-353. doi: 10.1016/bs.vh.2022.01.011.
Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Steouwer CD. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003 Nov;254(5):455-63.
Xu B, Zhang L, Chen Q, Wang Y, Peng Y, Tang H. Case Report: A Case of Late-Onset Combined Methylmalonic Acidemia and Hyperhomocysteinemia Induced by a Vegetarian Diet. Front Pediatr. 2022 Jul 12;10:896177. doi: 10.3389/fped.2022.896177.
Yan S, Liu H, Yu Y, Han N, Du W. Changes of Serum Homocysteine and Vitamin B12, but Not Folate Are Correlated With Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis of Case-Control Studies. Front Psychiatry. 2022 May 9;13:754165. doi: 10.3389/fpsyt.2022.754165.
Yu YM, So SKC, Khallouq BB. The effect of metformin on vitamin B12 levels in pediatric patients. Ann Pediatr Endocrinol Metab. 2022 May 16. doi: 10.6065/apem.2142210.105.
Yuan X, Han X, Zhou W, Long W, Wang H, Yu B, Zhang B. Association of folate and vitamin B12 imbalance with adverse pregnancy outcomes among 11,549 pregnant women: An observational cohort study. Front Nutr. 2022 Jul 25;9:947118. doi: 10.3389/fnut.2022.947118.
Zhang B, Dong H, Xu Y, Xu D, Sun H, Han L. Associations of dietary folate, vitamin B6 and B12 intake with cardiovascular outcomes in 115664 participants: a large UK population-based cohort. Eur J Clin Nutr. 2022 Sep 13. doi: 10.1038/s41430-022-01206-2.
Zibold J, von Livonius B, Kolarova H, Rudolph G, Priglinger CS, Klopstock T, Catarino CB. Vitamin B12 in Leber hereditary optic neuropathy mutation carriers: a prospective cohort study. Orphanet J Rare Dis. 2022 Aug 9;17(1):310. doi: 10.1186/s13023-022-02453-z.
Zou R, Dai Y, Wang D, Zhang X. Association between MTHFR polymorphism and seizure control in epileptic patients with hyperhomocysteinaemia. Epileptic Disord. 2022 Oct 1;24(5):1-9. English. doi: 10.1684/epd.2022.1470.
1. VITAMIN B12, INTRODUCTION AND DIETARY SOURCES
- 1.1 VITAMIN B12, HISTORY, DISCOVERY, AND PRODUCTION
- 1.2. FUNCTIONS OF VITAMIN B12
- 1.3 PHYSIOLOGICAL AND NON-PHYSIOLOGICAL FORMS OF VITAMIN B12
- 1.4. DIETARY SOURCES OF VITAMIN B12
- 1.5. THE PROBLEM OF VITAMIN B12 ANALOGUES
2. BIOCHEMISTRY OF VITAMIN B12
3. METABOLISM OF VITAMIN B12
- 3.1. METABOLISM, TRANSPORT, AND STORAGE OF VITAMIN B12
- 3.2 ABSORPTION AND DIFFERENCES BETWEEN PHYSIOLOGICAL AND PHARMACOLOGICAL DOSES
- 3.3. HOMOCYSTEINE AND METHYLMALONIC ACID
4. VITAMIN B12 DEFICIENCY
- 4.1. SPANISH VEGETARIAN POPULATION: B12 AND METHYLMALONIC ACID
- 4.2 "OFFICIAL" RECOMMENDED DAILY AMOUNTS AND SUPPLEMENTATION
- 4.3 VITAMIN B12 IN OVO-LACTOVEGETARIANS
5. SYMPTOMS AND DIAGNOSIS OF VITAMIN B12 DEFICIENCY
- 5.1. VITAMIN B12 DEFICIENCY
- 5.2 PROGRESSIVE STAGES OF B12 DEFICIENCY
- 5.3 SYMPTOMS OF VITAMIN B12 DEFICIENCY
- 5.4. ANALYTICAL AND RANGE VALUES
- 5.5 VERY HIGH VITAMIN B12
6. VITAMIN B12, PREGNANCY AND LACTATION
7. VITAMIN B12 SUPPLEMENTATION
- 7.1 FORMS OF VITAMIN B12 IN SUPPLEMENTS: CYANO, HYDROXY, METHYL
- 7.2. ORAL VS PARENTERAL SUPPLEMENTATION
- 7.3 ADVERSE REACTIONS
- 7.4 PROTOCOLS FOR RECOVERY
- 7.5 PERCENTAGES ABSORBED AND RETAINED IN DIFFERENT DOSES AND ROUTES
8. BIBLIOGRAPHY
1. VITAMIN B12, INTRODUCTION AND DIETARY SOURCES
1.1 VITAMIN B12, HISTORY, DISCOVERY, AND PRODUCTION
Vitamin B12 is a water-soluble vitamin belonging to the B vitamin family, essential for proper erythropoiesis, DNA synthesis, and maintenance of the nervous system, among other functions. In scientific literature, it also appears as cobalamin. Vitamin B12 is a cobalamin, formed by four pyrrole rings (tetrapyrrole structure) that form a corrin nucleus around a central cobalt atom. It is said to have a corrinoid structure and, as will be seen later, other corrinoid structures present in nature (such as those that serve as bacterial growth factors) can be counted in a serum B12 analysis, without these being active forms, with the limitations that this may entail.
This vitamin was a complete mystery during the 19th century. In the middle of that century, Dr. Addison observed a clinical condition that he named Addison's anemia, which other doctors later began to associate with gastric problems. In 1872, Bierner named it pernicious anemia. The first animal experiments conducted by Whipple in the 1920s on liver enzymes, liver disease, and hemoglobin showed that the intake of liver and liver extracts improved conventional anemia, which opened up a new avenue of research for pernicious anemia, still a great mystery. Minot became very interested in Whipple's studies and the possible application of a diet therapy involving large amounts of liver on a daily basis, which proved to be successful.
William B. Castle made an important discovery: the intrinsic factor, and spoke of the existence of an extrinsic factor that had to bind to it; it was later discovered that this extrinsic factor was actually vitamin B12. It was observed that patients with established pernicious anemia improved with liver intake, and concentrated extracts from animal livers began to be administered. These served for years as the most viable alternative for treating the disease, until it was discovered that it was vitamin B12 that reversed the symptoms. Work began on isolating it, which took place in the mid- to late 20th century.
| SUMMARY OF KEY POINTS IN THE DISCOVERY OF VITAMIN B12 UNTIL ITS LABORATORY SYNTHESIS |
| Dr. Addison began researching a strange disease that ended up being very serious and deadly: Addison's anemia.
Bierner in 1872: named it pernicious anemia, and suspected an association with gastric problems. George Whipple experiments with animals: improvement of anemia with liver intake. This opens up a line of research for PA, which Minot takes advantage of in his experiments to observe that the liver can be used to treat PA. William Bosworth Castle: Intrinsic Factor and Extrinsic Factor. George Minot, William Murphy, and George Whipple: Extrinsic factor or “anti-AP factor” as a treatment (at that time) for pernicious anemia: Nobel Prize (1934). Mary Shaw Shorb and Karl August Folkers: Extrinsic factor = vitamin B12. Dorothy Hodking: determines chemical structure: Nobel Prize (1964). Old treatment: High intake of liver (approx. half a kilogram per day) and liver juice. Work was done on a more powerful and effective injectable liver extract in the late 1920s. Later: Isolated synthesis in the laboratory from microorganisms. |
Based on these facts and its presence in the liver, it is often associated with an animal origin. And this is not incorrect. Vitamin B12 is found in foods of animal origin (except honey), in varying amounts depending on the source (animal, and part of the animal; the liver being the most prominent place of accumulation, as we have already seen).
In fact, if we dig a little deeper, it has a primary bacterial origin (thanks to which it is now produced in laboratories). Animals must consume adequate amounts to ensure its presence, either through physiologically normal intake, i.e., by eating other animals and their viscera (in the case of carnivorous animals), or, depending on the type of animal, by eating directly from an environment/soil rich in precursor bacteria. There are some exceptions: ruminants can produce it in their second stomach through the microbiota present there (requiring a micronutritional dietary precursor, cobalt), or fish from their producing microbiota, through the intake of phytoplankton, or by eating other fish.
In animals that are completely removed from natural environments and used by the livestock industry, it is provided through supplementation: enriched feed or injections (the most common method due to the circumstances of stabling, production, and deprivation of natural food; but also used in animals with more freedom as a prophylaxis). The name cobalamin comes from the corrin-cobalt group it belongs to, and it is the cobalt crystals themselves that give it its distinctive red color. The microbial biosynthesis of vitamin B12 occurs through aerobic or anaerobic pathways. It occurs in bacteria and archaea. Industrial production is carried out through microbial fermentation. Some of the most common bacteria that produce B12 are:
- Aerobic: Pseudomonas dentrificans, Rhodobacter capusulatus, Rhodobacter sphaeroides, Sinorhizobium meliloti.
- Anaerobic: Bacillus megaterium, Propionibacterium shermanii, Salmonella typhimurium.
The first bacterial strain used for its synthesis was Lactobacillus Lactis Doner, although it is now known that many other bacteria can synthesize it, such as Pseudomonas denitrificans and Propionibacterium shermanii, which are often used in laboratory synthesis for supplementation.
Vegans can only obtain this vitamin from supplements or fortified foods, and its intake is essential and vitally important at all stages of life. Possible marginal direct microbial contributions from soil, dirty food, manure/fecal matter, or certain rivers or contaminated water are nonsense, despite the fact that some circles have even proposed them as an “interesting” source for avoiding supplementation (we will discuss this further below).
Some herbivorous mammals produce their own bacteria and are able to reabsorb them; this has led to the belief that humans are also capable of doing so simply because they are mammals, and although there is synthesis in some areas, it is not reabsorbable as it is located far from the ileum. Furthermore, it has been seen that in many cases in these specific animals and under certain conditions, their endogenous production may not be sufficient and they are often supplemented as a matter of protocol to avoid problems and optimize levels.
There is also a popular belief that algae, mushrooms, and fermented foods contain abundant amounts of B12, but these are inactive analogues that can distort test results and hinder the metabolism of active B12. (Note: in some very specific cases and under certain conditions in some algae and mushrooms, there may be certain active fractions, but these are very small amounts that have not been shown to be useful or viable as strategies, and analogues may still be present).
On the other hand, ovo-lacto vegetarians often do not reach the recommended intake levels, and the precautionary principle of supplementation still applies, as the theoretical daily amounts of certain foods are not usually consumed (and even when they are, the final status may not be good for various reasons).
And it is not only the total amount that matters; timing and distribution are also very important, and there is specific chrononutrition (it is not the same to eat 6 eggs at once as it is to eat them in two or three separate meals a few hours apart: even if the theoretical amount of B12 is the same, the absorption will be different). In addition, there are digestive and genetic issues that are unique to each person (we do not all absorb, retain, and store nutrients in the same way). We can apply heuristic approximations and simple metrics at a general average level, but the final answer will be determined by each person's physiology.
Vitamin B12 is a highly complex and widely studied vitamin; today, it is the subject of ongoing research.
1.2. FUNCTIONS OF VITAMIN B12
- Synthesis and maturation of red blood cells: a deficiency can lead to anemia due to ineffective hematopoiesis.
- DNA synthesis during cell division: this is a process that requires speed to ensure proper DNA replication; in the event of a deficiency of B12, B9, or both, cells are unable to successfully duplicate DNA and there is a delay in cell division, which leads to an alteration of this process, stalling in the growth phase and being unable to move on to the mitosis phase. The cell grows because it cannot divide properly, giving rise to megaloblasts, which are present in peripheral blood and bone marrow. Megaloblasts are giant blood cells that are abnormally large, hence the prefix megalo. Blasts, the other part of the word, are cells found in the bone marrow in an immature state, not fully developed and still without function. Under normal conditions, once they mature, they transform into red or white blood cells. If B12 is lacking but there is sufficient dietary intake of vitamin B9, megaloblastosis may not occur (since we are avoiding the folate trap), which makes diagnosis difficult.
- Maintenance of the nervous system / myelin: Myelin is a protective substance that surrounds the axons of some neurons, forming sheaths that enable the transmission of nerve impulses between the brain and the spinal cord. B12 participates in the preservation of the myelin sheath. A deficiency of this vitamin causes a maturation disorder of myeloid precursors and will weaken and alter myelin due to increased levels of methylmalonic acid.
- Synthesis of neuronal lipids and production of neurotransmitters: the increase in methylmalonic acid described in the previous point means that myelin cannot be stabilized correctly, as abnormal fatty acids are formed as a result of succinyl-CoA deficiency.
- Synthesis of methionine, proteins, and amino acids.
- Methylation in the methionine cycle of phospholipids, proteins, myelin, catecholamines, creatine, carnitine, DNA, and RNA.
1.3 PHYSIOLOGICAL AND NON-PHYSIOLOGICAL FORMS OF VITAMIN B12
We can divide the different forms in which vitamin B12 is found into two groups:
Physiological forms, which function as coenzymes for metabolic reactions:
- 5-Deoxyadenosylcobalamin. This is the form of B12 that is stored in the liver. Predominant in all tissues. Also present in cell mitochondria.
- Methylcobalamin: the form in which B12 is found in plasma. A small amount also appears at the cellular level.
- Cyanocobalamin: the most common form of supplementation (oral, sublingual, and injectable). It is converted into a physiological form once metabolized.
- Hydroxocobalamin: Commonly found in injections.
Other forms: aquocobalamin, nitritocobalamin.
All forms are chemically related compounds with a similar molecular structure that function as vitamins. They are different forms in which the vitamin can be represented.
1.4. DIETARY SOURCES OF VITAMIN B12
Only animal products are a reliable source of B12. In plant products, only those that are fortified (i.e., that have been supplemented) are a source. For example, fortified products would include the misnamed “breakfast” cereals or some plant-based beverages and soy yogurts that have B12 added.
Vegetarians are often encouraged to consume fortified products to obtain B12. It should be noted that these are generally processed products and tend to be high in sugar, which should be taken into account if this route is to be used, as it does not seem very sensible to obtain B12 from processed products.
In addition, it is often cumbersome and inconvenient to have to count/calculate how many micrograms are in each serving we eat, take several doses a day to optimize absorption and release FI saturation, etc.
1.5. THE PROBLEM WITH VITAMIN B12 ANALOGUES
B12 analogues are corrinoid structures that contain cobalt but do not have the activity of the vitamin, as they have alterations in the corrinoid nucleus. They have little affinity for the intrinsic factor.
Problems with analogues:
- They do not act as active B12.
- They cannot be metabolized into active forms.
- They compete for the absorption of active B12, among other things because the corrinoid structures are used by intestinal bacteria for their growth.
- They can distort serum B12 measurements.
Spirulina algae has not been shown to resolve B12-related problems. Many people are taking it thinking that it contains real B12, when in fact it is loaded with analogues. Ralph Carmel, one of the leading researchers on vitamin B12, published a study in 1988 with several subjects analyzed, suggesting a relationship between higher amounts of accumulated analogues and a greater risk of neurological symptoms, which could explain why some patients did not experience neurological symptoms (at least at the time) but did experience anemia.
Analogs are naturally present and circulating in varying amounts depending on the individual, which is completely normal. Some people have more analogs than others. Other common foods (both animal and plant) also provide small amounts of analogues that do not cause problems.
2. BIOCHEMISTRY OF VITAMIN B12
2.1. FUNCTIONS, METABOLIC REACTIONS, HOW A DEFICIENCY AFFECTS YOU, AND THE FOLATE TRAP
Vitamin B12 has many functions. Like many vitamins in the B complex, it also acts as a coenzyme. The most important ones are listed below, along with what happens in case of a deficiency:
It participates in two very important metabolic reactions:
- Conversion of methylmalonyl-CoA to succinyl-CoA in the cell mitochondria by methylmalonyl-CoA mutase and adenosylcobalamin as a cofactor. Methylmalonyl-CoA mutase is a B12-dependent enzyme.
Methylmalonyl-CoA is formed by the breakdown of certain amino acids and fatty acids.
Succinyl-CoA is one of the intermediates in the Krebs cycle and is involved in energy production.
If there is insufficient B12, methylmalonyl CoA accumulates; this is why elevated methylmalonic acid appears in vitamin B12 deficiency. Methylmalonic acid is a by-product of propionic acid metabolism through the enzyme methylmalonyl CoA mutase.
The conversion of methylmalonyl CoA to succinyl-CoA involves adenosylcobalamin as a cofactor, and a deficiency of this enzyme leads to an accumulation of methylmalonic acid.
- Conversion of homocysteine to methionine occurs in the cell cytoplasm by the enzyme methionine synthase, which requires methylcobalamin as a cofactor, resulting in an accumulation of homocysteine in plasma if there is no B12. Methionine is an essential amino acid that forms part of proteins, but it also has different biological functions: it is a precursor of adenosylmethionine, which participates in the synthesis of proteins, creatine, and neurotransmitters.
Basic circuit summary (only the part from Homocysteine to Methionine; we’ll explore an extended pathway later):
The conversion of homocysteine to methionine occurs in the cytoplasm of the cell and involves methylcobalamin and methyl-THF as cofactors. There is a synergy between vitamin B12 and B9 metabolism in DNA synthesis.
If this process fails, homocysteine accumulates and the folate trap occurs, causing folate levels to drop.
(This trap can sometimes be bypassed by consuming high amounts of folate or by taking folic acid supplements directly, but these do NOT prevent B12 levels from remaining low, which can lead to future consequences).
This conversion also involves folates, with methyl-tetrahydrofolate as a cofactor (Methyl-THF, the most bioavailable form of folate).
However, if there is a B12 deficiency, methyl-THF will accumulate (“get trapped”) and will not reach its final destination (THF), causing what is known as the “folate trap.” This will also affect proper DNA synthesis and lead to megaloblastic anemia (not to be confused with iron deficiency anemia).
Warning: Supplementing with folate, even in some cases of high dietary folate intake, “prevents” or “masks” this folate trap process, but it does not remedy B12 deficiency or homocysteine accumulation (although it is possible that the latter may appear somewhat lower in the analysis than if you were not taking a diet high in folate, as folate is a cofactor that lowers homocysteine; even so, homocysteine in the analysis is a very good indicator of problems with B12).
“Folate trap rescue,” or “folate non-trapping,” or “not falling into the folate trap” (we are using different terms to try to convey the concept) does not always occur in the situations described, but it is very common. Folic acid supplementation is known to prevent the folate trap; dietary intake will depend on various factors, but it is more common than is believed.
If the folate trap is avoided, we may not have signs of B12 deficiency anemia. Although this seems attractive, it is not positive, because even in the early stages (which can be prolonged), there may be no hematological symptoms and standard conventional tests may come back normal without megaloblastic anemia, but we will have very serious problems later on, as we will not be free from other types of symptoms that appear later and are uncertain. Furthermore, we know that the longer anemia goes untreated, the more neuropsychiatric problems and severity will arise (in an uncertain time frame, shorter or longer). In addition, we may experience vague and unclear symptoms in the early stages, such as general fatigue, muscle aches, waking up tired... which can be attributed to many other things.
Remember: the absence of megaloblastic anemia does not mean that there cannot be problems with B12. Problems can arise over time. Once a severe deficiency develops, anemia may or may not be present, or it may appear later. Therefore, checking for megaloblastic anemia in a blood test is not conclusive evidence of a B12 deficiency, as we have seen many times, it does not occur, or it occurs later but not in the early stages.
Really, if we stop to think about it... it would be ideal if a problem with B12 always warned us with megaloblastic anemia. It would give symptoms at an early stage, it is easily detected in blood tests... but this is not always the case.
Let's look at the description of the folate trap given in the document “Interrelation of Vitamin B12 and Folic Acid, by Dr. Bernardo Condado Arenas” on this particular clinical picture we are explaining:
In the absence of vitamin B12, folate cannot be recycled. And in the absence of folate, no part of the cycle can be carried out. Thus, a deficiency of either stops the cycle. Vitamin B12 deficiency in DNA synthesis reduction is explained by the “folate trapping theory as methyl-tetrahydrofolate.”(...) methionine synthase cannot be activated and folate remains as methyl-FH4, which also causes a functional folate deficiency, thus explaining megaloblastic anemia." SOURCE: Interrelation of Vitamin B12 and Folic Acid. Dr. Bernardo Condado Arenas.
As we have already mentioned, the folate trap can be avoided (through folic acid supplementation, or sometimes through diets high in folate). By avoiding the folate trap, we will have fewer or no signs of anemia, but more complications and potential for other symptoms. And in fact, if there is B12 anemia, taking folic acid will cure it. So we avoid the folate trap! But be careful, because this has serious consequences... If there is a B12 deficiency with anemia, folic acid should not be taken, even if it initially alleviates the symptoms of anemia.
Folic acid is often prescribed for megaloblastic anemia, and this may be incorrect. It is true that it can be caused by problems or deficiencies with folates. But these can be secondary to problems with B12, and in that case, giving folic acid or methylfolate would be a mistake.
Explanations for this:
- “If you take folic acid instead of cyanocobalamin, the folic acid will resolve the anemia but not the neurological disorders.” Source: Vademecum. OPTOVITE (injectable B12) package insert
- “The administration of folic acid to patients with cobalamin deficiency induces hematological improvement but worsens the neurological picture.” Source: de Paz R, Hernández-Navarro F. [Management, prevention, and control of megaloblastic anemia secondary to folic acid deficiency]. Nutr Hosp. 2006
- Since plants are deficient in vitamin B12, a totally vegetarian diet will cause cobalamin deficiency, but due to the high intake of folates, the signs will tend to be more neurological than hematological. Source: Ralph Gräsbeck, 2006.
And, even if we don't take supplements, if we eat a diet rich in folate (fruits, vegetables, legumes, nuts...), it is possible to avoid the folate trap (this does not always happen, but it is common).
In this case, we do not experience anemia (or we may have very mild or temporary symptoms in some cases), but this does not mean that B12 levels are still low, and we will not avoid clinical symptoms later on (with uncertain onset, in the short term or in the medium/long term). We may be asymptomatic or have mild and diffuse symptoms for a long time, or they may present severely. The onset is uncertain and the range of symptoms is very wide.
In fact, individuals with high folate levels and low vitamin B12 levels often show cognitive impairment (folate trap, no hematological signs—or only mild ones—but neuropsychological signs). - “If you take folic acid instead of cyanocobalamin, the folic acid will resolve the anemia but not the neurological disorders.” Source: Vademecum. OPTOVITE (injectable B12) package insert
Below, we will summarize and discuss the entire cycle:
- We ingest protein from our diet and obtain methionine (MET), an essential amino acid (we cannot produce it, and it must be obtained through food).
- MET must be converted into homocysteine (HCY). This is done by MAT (methionine adenosyl transferase), using ATP and MET, to produce SAM (S-adenosylmethionine). SAM is then converted into SAH (S-adenosylhomocysteine), and finally we obtain homocysteine.
- Much of the homocysteine must be recycled back into methionine, and this is where B12 (in the form of methylcobalamin), METHYL-THF, and methionine synthase (which allows us to convert to methionine) come into play.
- We don't want serious problems Everything needs to work properly, and we need enough B12 to activate methionine synthase. The other cofactor is METHYL-THF, which must be converted to THF (tetrahydrofolate) for proper DNA synthesis.
- Let's imagine that we have insufficient B12: homocysteine will accumulate abnormally, methionine synthase will not work properly, and we may also experience the folate trap phenomenon (methyl-THF will not convert properly to THF!). and we will have problems with cell division and DNA synthesis, resulting in megaloblastic processes with anemia; BUT remember that this folate trapping can be remedied in some situations (remember: by supplementing with folic acid, and in many cases also with a diet rich in folate). This prevents the symptoms of anemia or makes them mild. And we may be asymptomatic while all this is happening, but this will not prevent B12 from remaining low, methionine synthase from malfunctioning, and homocysteine from accumulating. And we also know that the more we save the anemia, the more severe the future neurological problems will be.
- Cysteine is also obtained from homocysteine (in fact, “homo-cysteine” comes from “homologous to cysteine”). This is done first by obtaining cystathionine (an intermediate of cysteine) through CBS (cystathionine beta synthase), which uses the pyridoxal factor of vitamin B6 as a cofactor, forming cystathionine, from homocysteine and serine (an amino acid involved in purine synthesis and a precursor of glycine). Alpha-ketobutyrate (also known as alpha-ketobutyric acid) is also produced here, which is considered a product of homocysteine degradation when cystathionine is “broken down.” Alpha-ketobutyrate participates in the production of succinyl-CoA.
- Finally, this intermediate called cystathionine ends up being converted into cysteine. This is why cysteine is an amino acid that goes hand in hand with methionine.
- And through cysteine we obtain taurine and glutathione.
- Glutathione is a powerful antioxidant with a cell protection function.
- Let's look at how this whole cycle involves DNA synthesis, protein synthesis, phospholipids, myelin, catecholamines, carnitine, creatine... The implications of something going wrong here can be dire and dangerous. We can have serious problems at the energetic, neurological, psychiatric, and cardiovascular levels...
MTHFR (Methyl Tetra Hydro Folate Reductase): is an enzyme involved in folate metabolism. It catalyzes the conversion of methylenetetrahydrofolate (or 5,10-M-THF) to methyltetrahydrofolate (M-THF). M-THF, remember, is a cofactor for breaking down homocysteine and ensuring that it is correctly converted to methionine. When we eat food, we obtain THF, which must be converted to M-THF in order to perform its correct functions and act as a cofactor for everything we are looking at. If MTHFR fails or is unable to perform its functions fully in this step, there will be a problem associated with folates. This is associated with genetic issues. If this is suspected, a mutation test can be requested (the most common are C677T and A1298C).
3. VITAMIN B12 METABOLISM
3.1. METABOLISM, TRANSPORT, AND STORAGE OF VITAMIN B12
Dietary B12 found in food is bound to binding proteins, from which it is released in the stomach by pepsin and the acidity of secreted hydrochloric acid.
Once B12 has been released from dietary proteins, it binds to salivary haptocorrina, a binding protein (also called protein R or cobalofilin) secreted in the salivary glands and binds in the stomach with cobalamin, which has a high affinity for this protein, forming a complex with it as it passes into the duodenum.
Once it reaches the duodenum, it is released from the R proteins by the action of proteases and pancreatic bicarbonate, which cause the elimination of the initially formed complex, leaving B12 free.
This vitamin B12 binds to the intrinsic factor, also known as Castle's intrinsic factor in honor of the scientist William Castle, whom we mentioned earlier, who conducted important research and made significant contributions in this field. The intrinsic factor (IF) is a glycoprotein secreted by the parietal cells of the gastric mucosa that binds to vitamin B12 once it has been released from the R proteins, making it resistant to gastric and pancreatic proteases and forming a B12+intrinsic factor complex known as the Castle complex. The intrinsic factor has a maximum binding capacity and becomes saturated at around 1.5-2 μg of ingested vitamin B12 (if we take more than that amount, less is absorbed, and less and less as the dose increases).
In the terminal ileum, the B12+intrinsic factor complex is absorbed through the recognition of specific receptors, which in turn limit absorption in physiological or dietary intakes. Here, cobalamin is released, and the intrinsic factor is degraded in the lysosomes (cell organelles with hydrolytic and proteolytic enzymes).
If none of the above has failed along the way, B12 has reached its first destination safe and sound; but it still has an important journey ahead of it via specific transporters (which we can illustrate as “cars”) to its final destination.
Free B12 binds to transport proteins (the available cars) present in plasma: haptocorrins, also called cobalofilins or transcobalamins, of which we find transcobalamin I, II, and III.
There is debate on the subject of I and III, and whether we should generally refer to transcobalamin I alone, or simply call it haptocorrina. These haptocorrins transport B12 but do not deliver the vitamin. They have a high affinity for inactive B12 analogues, although it is believed that this may also play a role in their elimination, as well as other functions that are still being studied and are largely unknown (including the transport of stored B12).
Transcobalamin II is the main “carrier” and is also sometimes referred to simply as transcobalamin (TC, or TC2 in some texts). It is the most important transporter, as it is responsible for the active transport of the vitamin and carries approximately 20% of it (the remaining 80% corresponds to haptocorrine, but this is inactive).
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Vitamin B12 and its binding proteins in human plasma. Only the fraction bound to HoloTC is delivered to the cells and is therefore active. Chart based on a sample with a total B12 of 300 pmol/L and a transcobalamin level of 1000 pmol/L. Total Transcobalamin (TC) = 1000 pmol/L Of which: HoloTC = 100 pmol/L ApoTC = 900 pmol/L Total Haptocorrin (HC) = 450 pmol/L Of which: B12HC = 200 pmol/L AnaHC = 200 pmol/L ApoHC = 50 pmol/L |
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Total B12 = 300 pmol/L B12HC: B12 bound to haptocorrin ApoTC: Apotranscobalamin AnaHC: B12 analogs bound to haptocorrin ApoHC: Apohaptocorrin Source: Adapted from Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility, 2011 |
Many cells can secrete TC, which combines with free B12 in the cells of the ileum to form holotranscobalamin (holoTC), which enters the portal circulation and is responsible for delivering the vitamin to the cells, as it transports the functional fraction that can be absorbed by the tissues and is rapidly released into them by endocytosis (the process of incorporating molecules into cells) through their specific receptors.
In other words, transcobalamin-2 (transporter) loaded with B12 is holo-TC... Cobalamin is ultimately metabolized into methylcobalamin and deoxyadenosylcobalamin. It enters the plasma as methylcobalamin and accumulates as a reserve in the liver as deoxyadenosylcobalamin. Fifty percent (or more, depending on the source consulted and the individual) of vitamin B12 is stored in the liver, and approximately 1 μg is found per gram of liver tissue. Large amounts are also found in the kidneys. B12 is also present in the muscles. In most tissues, it does not tend to accumulate but is recycled through an active transport mechanism.
Reserves range from 1-6 mg in healthy adults (and can be significantly higher at the upper end of the range), with 2-3 mg being the most common average. The larger the reserves, the greater the normal daily losses, and vice versa: the smaller the pool (reservoir) of cobalamins, the less B12 will be eliminated, which could be the result of a metabolic adaptation to low reserves. In other words, the physiology of B12 reserves is as follows: if we have large reserves, the body knows that it has plenty and is not very interested in safeguarding them, so it loses more; and if we have low reserves, the body will try to save as much as possible (although it continues to lose the same amount, it tries to resist).
It is estimated that when the body pool is 300 μg or less, signs of deficiency will appear. However, it should not be ruled out that problems may already exist above this level.
A small portion of stored B12 is continuously secreted into the bile. Of that fraction, between 50% and 80% follows the steps already mentioned (detaching from R proteins and binding to IF) and is reabsorbed, while the rest is lost in the feces along with the rest of the corinoid analogues. This is called enterohepatic circulation, and it is for this reason that a deficiency due to dietary absence can take years to develop if there are sufficient reserves even in the absence of dietary intake, since it generally starts from a high pool and very small daily losses if the reabsorption mechanism is working at peak efficiency.
The amount of cobalamin stored and how the enterohepatic circuit and the buffering of general losses work as levels decrease varies greatly between individuals. Not everyone loses the same amount or at the same rate. Nor do they start from the same reserve levels.
The higher the initial pool and the more efficient the person is at recycling and conserving cobalamin, the longer it will take for the deficiency to develop. This explains why some cases may appear within a few months or several years. It also explains why some people say they have not had a deficiency in years, even without supplementation and on a full vegetarian diet. Be careful with this.
If there is dietary intake or supplementation and there are no problems or alterations in the transport-absorption-excretion pathway, the losses are compensated. If there is no IF or limited secretion, it is not reabsorbed in the enterohepatic circuit and is excreted, meaning that the deficiency will occur sooner (as the enterohepatic recycling circuit is failing), just as if the dietary intake is inadequate, there will come a point where enterohepatic circulation will not be sufficient.
The greatest loss is found in the feces. Among the excreted B12, we find the fraction secreted by bile that has not passed into the enterohepatic circulation, that which has not been absorbed from food, and that which has been synthesized in the colon by microorganisms (which cannot be absorbed since it is not found in the ileum and will never pass through it). The feces also show that a high amount (up to 98%) of the excreted B12 are cobalamin analogues, due to the conversion of cobalamin into analogues by microorganisms in the colon.
The other route of elimination is urinary, which is not usually significant except when blood binding capacity is exceeded or macrodoses are used through supplementation. Due to the existence of a reservoir that is efficiently used by the enterohepatic circuit, a deficiency due to dietary absence of B12 may take some time to appear if reserves are adequate at the time the vitamin supply ceases. But... how long does it take? This is somewhat indeterminate and will depend on each individual, previous reserves, how they are managed, and the efficiency of the enterohepatic circuit. It usually takes about 3-4 years, although there are individuals where it occurs much earlier or later.
3.2 ABSORPTION AND DIFFERENCES BETWEEN PHYSIOLOGICAL AND PHARMACOLOGICAL DOSES
The percentage of absorption decreases as the dose increases.
“The higher the dose, the less is absorbed.”
At low or moderate doses, also called physiological doses, which are those we would get through food (although we could also include B12 provided by fortified foods or supplementation in very small amounts), absorption depends on the intrinsic factor secreted and the intestinal receptors of the Castle complex, which regulate absorption. There is an absorption mechanism that under normal conditions saturates at approximately 1.5-2 μg per meal. If this amount is exceeded in a single dose, absorption becomes dependent on passive and diffuse mechanisms, which are much less efficient.
Simple rule: any single dose in a single meal that exceeds the saturation capacity of the IF will be very poorly absorbed. And if we don't produce IF, imagine what happens. It is estimated that the saturation capacity is fully recovered within 4-6 hours, allowing a new dose with the same absorption and saturation capacity as the previous one.
How much do we absorb? In summary, under ideal conditions and if intrinsic factor secretion is correct, approximately 50% is absorbed per meal. In its latest consensus, the EFSA recommends, as a precautionary measure, to consider an estimated average absorption of 40% due to the number of factors that can influence it.
For each 1 μg of B12 taken, approximately 40-50% would be absorbed, but remember that if the intake is higher, less is absorbed, and that there is also a saturation mechanism and a “recovery” period must elapse before it is fully absorbed again. For this reason, some authors prefer to be conservative in terms of not overestimating absorption and to consider that not all foods have the same absorption rate, since the richer the food is in B12, the less will be absorbed...
Apart from low doses, when opting for protocols with weekly macrodoses of supplementation or booster doses, we must provide a very high intake of B12 to ensure that we cover the absorption of a small but sufficient fraction, even at the expense of the vast majority of the B12 in the supplement not being utilized and being eliminated due to the lower absorption efficiency found with this route, as it is not dependent on the intrinsic factor. An example of this is macrodoses, also known as pharmacological doses, which can only be provided through supplements.
This is why, at the beginning of the 20th century, when it was discovered that eating liver improved patients with pernicious anemia, they had to eat huge amounts to achieve a “pharmacological effect.”
In these cases, we find an approximate absorption of, with luck, between 1-2% of the dose administered, but it is not uncommon for it to be even lower (0.5%) depending on the size of the dose, previous reserves, and other factors and individual conditions of each subject.
With these pharmacological doses or macrodoses, the resulting excess is excreted in the urine, as it has been unable to bind to the intrinsic factor or fully bind to transcobalamin because it has exceeded the binding capacity of the transport protein due to being present in very high doses (doses that will have been necessary, however, to ensure a specific absorption according to the objective and purpose).
Macrodoses of vitamin B12 are absorbed even in the absence of intrinsic factor and hydrochloric acid, as they are not dependent on these, making them a valid strategy for maintenance or recovery in processes or states where this protective protein is not being secreted, such as in gastrectomies, achlorhydria, etc.
| Type of Dose | Where It's Found | Intrinsic Factor Dependent | % Absorption | Absorption Mechanism Saturation |
|---|---|---|---|---|
| Physiological dose | Animal-based foods. This group may also include fortified foods and low-dose supplementation* | Yes | 40–50% |
Normal mechanism (IF): 1.5–2.0 µg, above that it switches to passive mechanism. Recovers saturation capacity every 4–6 hours. |
| Pharmacological doses | High-dose supplements | No | 0.5–2% |
Passive mechanism: inefficient. That’s why very high doses are used. The rule of thumb: “the more you take, the less you absorb.” |
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Data are estimated through oral supplementation (not parenteral). *Low-dose supplementation: even using low doses (e.g., 5 µg, or the typical 2.4 µg in many multivitamins), the saturation capacity is exceeded. Therefore, part of the dose will be absorbed passively. |
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How long do reserves last? From months to years. It depends on several factors:
- Initial reserves.
- Amount of FI secreted.
- Individual efficiency of the enterohepatic circuit.
- Ability to maintain a high cobalamin pool for longer.
- Tolerance and management of low reserves.
- Presence or absence of gastric or malabsorption problems.
- Concomitant medication (metformin, omeprazole, etc. interfere).
- Possible metabolic adaptations and phenotypes with good management.
- Marginal intake in developing countries (fecal and contaminated water, poor hygiene, etc.).
3.3. HOMOCYSTEINE AND METHYLMALONIC ACID
As we have seen, in anemia due to B12 deficiency, both homocysteine and methylmalonic acid are elevated, while in B9 deficiency (also a cause of megaloblastic anemia), only homocysteine is found in plasma levels above normal.
Homocysteine
Homocysteine is a homologue of the amino acid cysteine that results from various metabolic processes and is derived from the normal metabolism of methionine. Cysteine is therefore dependent on methionine (an essential amino acid), as it is produced whenever there is sufficient methionine, and a methionine deficiency would in turn cause lower endogenous synthesis of cysteine.
The recycling of a large part of the resulting homocysteine back into methionine is essential, and when this does not occur correctly, homocysteine accumulates in the blood. Both B12 and B9 are involved in this process, as well as B6 (the latter in another pathway, responsible for transforming homocysteine into cysteine; remember the diagram with the arrows seen above). There is another pathway that carries out this process using the enzyme betaine. Therefore, to simplify the process, the metabolism of methionine results in homocysteine, and much of this must then be converted back into methionine. If something goes wrong in this process (for example, a lack of B12, B9, or a combination of both), homocysteine builds up in the blood.
Today, we know the importance of a marker such as serum homocysteine, whose high levels (hyperhomocysteinemia) are related to:
- Cardiovascular risk and atherosclerosis.
- Cerebrovascular diseases.
- Neuronal cell damage and neurological diseases: Alzheimer's, Parkinson's, dementia.
- Peripheral artery disease (hardening of the arteries and decreased blood flow).
- Carotid stenosis (narrowing of the carotid arteries, which are the main vessels that supply blood to the brain).
- Complications in pregnancy (neural tube defects, recurrent miscarriages, preeclampsia, intrauterine growth retardation).
- Increased risk of osteoporosis.
There is some debate as to whether it is homocysteine itself that causes these problems or the underlying factors that have led to elevated homocysteine levels. Whatever the case, what is clear is that there are strong correlations at the level of evidence (potentially causal relationship), and whether due to it directly or indirectly, its increase is a factor to be taken into account and should not be ignored.
Elevated homocysteine is not necessarily conclusive of a B12 or B9 deficiency and should be put into context. There are other factors that can cause hyperhomocysteinemia or put you at risk of developing it, the most common of which are:
- Vitamin B6 or pyridoxine deficiency: this vitamin is also involved in the metabolism of methionine and in the synthesis and degradation of homocysteine. Its deficiency is rare. It is found in legumes, fruits, nuts, cereals, offal, meat, and fish.
- Metabolic problems.
- Hypothyroidism.
- Sedentary lifestyle.
- Impaired or altered kidney function, as the kidneys play a vital role in homocysteine catabolism.
- Severe liver disease, especially alcoholic and cirrhotic, as these conditions are often associated with folate deficiency and reduced levels of the enzymes responsible for homocysteine metabolism.
- Medications, in many cases due to their ability to alter the concentrations of vitamins involved in homocysteine metabolism. Examples: antiepileptics, methotrexate, theophylline, nitrous oxide.
- High-dose methionine supplementation.
- Alzheimer's disease.
- Chronic inflammatory diseases.
- Neoplasms (benign or malignant).
- AIDS.
- Transplanted organs.
- Oxidative stress (cellular imbalance due to an increase in free radicals and a decrease in antioxidants, which can cause tissue damage).
- Genetic defects.
- Presence of oxysterols in the blood (cholesterol oxides).
- Drug use (including alcohol and tobacco).
- Genetic factors, certain medications, or the aforementioned B9 and B6 deficiencies (very rare in vegetarians unless there is a malabsorption syndrome).
- It is usually higher in males, during menopause, and in old age.
Homocysteine is also known to be elevated in cases of osteoporosis. But if we take B12 and folic acid, thereby lowering homocysteine... does this reduce the risk of fracture? The answer is again no. Lowering homocysteine through vitamins does not reduce the existing risk of fracture. It does seem, at least according to a clinical trial by Clements et al, that if there are low levels of B12 present, supplementation could improve bone mineral density.
Low vitamin B12 has recently been linked to chronic migraine, and high homocysteine, with low cofactors and alterations in MTHFR (remember, the one that allowed the passage of THF to M-THF), has been linked to migraine with aura, due to incorrect methionine synthesis, which ultimately leads to an increase in homocysteine, causing an increase in reactive oxygen species (causing oxidative stress).
Methylmalonic acid
In the conversion of methylmalonyl CoA to succinyl CoA, where adenosylcobalamin plays a fundamental role as a cofactor, there is a defect in this reaction if there is not enough vitamin B12. This defect leads to a block in the conversion, resulting in the accumulation of methylmalonic acid (MMA), a product of the process responsible for the neurological effects that may begin to appear at a certain point. This is another important marker to look for in a blood test. In fact, it is considered the gold standard in blood tests as it is the most specific and valid marker.
Important: MMA levels may also be elevated in cases of kidney problems. Elevated methylmalonic acid is commonly seen in the elderly, either because B12 is poorly absorbed (which may be one of the reasons), or because there is not necessarily a B12 deficiency as such, but rather an alteration in kidney function; which is why it is important to check the glomerular filtration rate, as impaired kidney function or kidney disease increases MMA, which should be taken into account when screening with MMA.
4. VITAMIN B12 DEFICIENCY
4.1. SPANISH VEGETARIAN POPULATION: B12 AND METHYLMALONIC ACID
In 2018, the first study evaluating B12 + methylmalonic acid status in the Spanish vegetarian population was conducted.
The sample consisted of 103 people from Madrid, approximately 50% vegan and 50% ovo-lacto vegetarian. The sample was not particularly large, but it was well selected in terms of dietary habits (for example, participants could not consume meat or fish even occasionally, which is allowed in other studies, where anyone who does so is considered vegetarian).
More than 75% of people had low levels of methylmalonic acid (the best indicator of B12 deficiency), which would indicate that they were supplementing and out of danger (or that they had not been without supplementation long enough for levels to rise), but in 11 of the volunteers (5 OLV and 6 vegans) the levels were above the established cutoff point, of which 10 had plasma B12 levels “in range,” which would indicate a subclinical deficiency despite having apparently correct B12 in the analysis. Additionally, 2 more subjects had low plasma B12 levels.
The fact that the OLV group also had elevated levels of methylmalonic acid indicates, once again, that they are also at potential risk, and that many of them do not supplement and/or believe they meet their requirements from food.
Statistically, in the sample studied, 1 in 10 had subclinical deficiency.
The limitations of the study are that the sample size is not very large, the supplementation doses used are not known (although the frequency is), the length of time the participants had been following a vegetarian diet is not known, and there were many more supplement users (75%) than; the latter could indicate greater awareness of the need for supplementation. In fact, the study acknowledges that the vast majority of those recruited to participate were aware that they needed to take supplements.
Let's note one more thing, which is that it is possible that more than one person started at that time and improved their status because they were going to participate in a study and became aware at that time of supplementation so that they would not get a negative result. And the following: more than one of those who did not take supplements and had normal results, despite showing good status at this time, will have problems in the future.
4.2 “OFFICIAL” RECOMMENDED DAILY AMOUNTS AND SUPPLEMENTATION
These vary greatly depending on the source consulted. Let's look at two tables, one based on the Spanish population (FESNAD) and the other usually recommended for the US population but also used internationally (IOM).
| Age | IDR (µg) |
| 0-6 months | 0.4 |
| 7-12 months | 0.5 |
| 1-3 years | 0.7 |
| 4-5 years | 1.1 |
| 6-9 years | 1.2 |
| 10-13 years | 1.8 |
| 14 years and older | 2.0 |
| Pregnancy | 2.2 |
| Breastfeeding > Breastfeeding | 2.6 |
| Adapted from: Dietary Reference Intakes for the Spanish Population. FESNAD, 2010. | |
| Age | IDR (µg) |
| 0-6 months | 0.4 |
| 7-12 months | 0.5 |
| 1-3 years | 0.9 |
| 4-8 years | 1.2 |
| 9-13 years | 1.8 |
| 14 years and older | 2.4 |
| Pregnancy | 2.6 |
| Breastfeeding | 2.8 |
| Adapted from Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (Institute of Medicine, IOM 1998).
NOTE: This is the most classic and most cited position. | |
In the EFSA review and position paper, they compile the statements of the main international organizations and ultimately take a position well above the rest.
| Age | IDR (µg) |
| 0-6 months | Breastfeeding |
| 7-11 months | 1.5 |
| 1-3 years | 1.5 |
| 4-6 years | 1.5 |
| 11-14 years | 3.5 |
| 7-10 years | 2.5 |
| 15 years and older | 4 |
| Pregnancy | 4.5 |
| Breastfeeding | 5 |
| Adapted from Scientific Opinion on Dietary Reference Values for Cobalamin (Vitamin B12) EFSA Panel on Dietetic Products, Nutrition and Allergies. EFSA Journal 2015. | |
CDR/IDR/RDA have always been a point of debate. Since a maxim in nutrition is that intake does not equal absorption and multiple factors influence absorption, not everyone will have the same absorption/yield of nutrients, and in the case of B12, the theoretical amounts were initially established to prevent megaloblastic anemia, but perhaps not to ensure that everyone has a good status, and not everyone has the same absorption or the same chrononutritional distribution.
And... we say it again... not everything is megaloblastic anemia as a symptom. The spectrum is very varied.
Furthermore... the final amount of B12 is not the same in everyone to compensate for losses. Studies have shown that some people may require significantly more vitamin B12 than others.
The EFSA has come down on the side of higher amounts. Why? As a precautionary measure after reviewing different studies and considering multiple factors at play, including variability in absorption, daily losses, and reduced absorption rates at high intakes.
In addition, they refer to these proposed values as a minimum; they suggest that this is the starting point. As already mentioned, depending on the size of the cobalamin pool, there are more or less losses, and these should be covered if approximately the same reserve values are to be maintained, taking into account the percentage of absorption:
Note: Some people may require more than 2000 mcg, between 2500-3000 mcg, to maintain adequate levels of B12 and low homocysteine. These are individual issues in clinical practice, but they should not be ignored (we should never rely on standardized tables).
For vegans/ovo-lacto vegetarians: The weekly protocol is usually considered more convenient and is cheaper than the daily protocol.
In addition, the weekly protocol is also useful in cases of malabsorption (whether chronic or occasional; although injectable forms are generally used in certain chronic cases).
Daily protocols are not effective in cases of malabsorption, nor is it effective to cover the dietary B12 requirement from animal products or fortified foods.
In people over 65, it has been observed that daily macrodoses work best. In the elderly, caution should be exercised with unnecessary folate supplements. There are not many studies on this subject, but what little we do have shows that those with subclinical deficiency did not recover until they took 500 μg per day, suggesting a possible maintenance dose (once again, speaking in general terms, without being able to generalize).
If we want to see a simple, minimalist maintenance protocol (for the adult population):
Daily dose through food: animal products (not suitable for vegetarians) or fortified products, or low-dose supplements.
- Between 2 and 4 mcg (FESNAD value - EFSA value).
- Recent positions point more towards 4-5 mcg.
- Ideally spread over at least two doses with 4-6 hours between doses.
- If taken in a single dose, a higher amount will be needed (since when the FI saturation capacity is exceeded, absorption is very poor; and the more we take, the less we absorb).
- This protocol is not suitable for people who do not absorb the vitamin well for any reason.
With weekly supplementation, for people who do not consume dietary B12 (vegans), and ovo-lacto vegetarians or people who consume very little animal-based food.
It would also be useful for people with malabsorption. (Prior clinical assessment is required to decide the best protocol, dose, and route of administration in each case.)
- 2000 mcg/week.
- Important: Some people may require 2500-3000 mcg/week.
- Between 25-100 mcg/day (in a single dose). Recent studies suggest up to 200-250 mcg per day (in a single dose).
- If more doses are taken, the dose should be reduced for each dose. However, this is not usually done in practice.
- This protocol is not suitable for people who do not absorb the vitamin well for any reason (macro doses should be used).
Note 2: The daily protocol with supplements or the protocol with fortified products is not effective if there is malabsorption for any reason.
4.3 VITAMIN B12 IN OVO-LACTOVEGETARIANS
Ovo-lacto vegetarians should also take supplements as a precaution, as it is very likely that they do not consume adequate amounts every day. Let's look at some examples to cover the requirements according to the values of different positions in adults (according to values proposed by FESNAD, IOM, and EFSA).
| Food | µg B12 per 100g (1st value BEDCA - 2nd value USDA) |
Approx. amount needed to reach RDI of 2.0 µg (FESNAD 2010) | Approx. amount needed to reach classic RDA of 2.4 µg (IOM 1998) | Approx. amount needed to reach EFSA value of 4 µg (2015, considered more realistic) |
|---|---|---|---|---|
| Whole milk | 0.3–0.4 | 3 and a half glasses of 200 ml | 4 glasses of 200 ml | 6 and a half glasses of 200 ml |
| Plain yogurt | 0.3–0.4 | 5–6 yogurts of 125 g | 6–7 yogurts of 125 g | 10–11 yogurts of 125 g |
| Boiled egg | 1.1–1.2 | 3–4 eggs | 4 eggs | 6–7 eggs |
| Fresh cheese / Burgos type | 0.6–0.9 | 225–325 g | 275–400 g | 450–650 g |
| Manchego / aged cheese | 1.5–1.7 | 120–130 g | 150–160 g | 240–250 g |
Remember: It would be ideal to spread this out over at least two meals a day. These are theoretical amounts; there are differences between individuals.
This is all very theoretical; there may be ovo-lacto vegetarians who need to consume more.
In any case, it would be prudent to take a supplement. If an OLV is not going to take supplements, they should consume relatively high amounts of dairy products and/or eggs, spread out over different meals throughout the day, and monitor their status correctly.
5. SYMPTOMS AND DIAGNOSIS OF VITAMIN B12 DEFICIENCY
5.1. VITAMIN B12 DEFICIENCY
Low and insufficient levels of vitamin B12 can lead to megaloblastic anemia (megaloblastic anemia should not be confused with pernicious anemia; not all megaloblastic anemia is pernicious) and produce neurological, psychiatric, cardiovascular, gastrointestinal, and dermatological symptoms.
Technically, the term pernicious anemia refers to a B12 deficiency due to malabsorption caused by atrophic gastritis, due to a lack of intrinsic factor or problems with its secretion due to atrophy of the gastric mucosa, autoimmune attack against the intrinsic factor, and/or autoimmune destruction of the secretory parietal cells (as in the case of atrophic gastritis, also of autoimmune origin, which causes achlorhydria and is secondary to some autoimmune diseases that can predispose to problems in the gastric mucosa).
As additional information, a very common condition: when atrophic gastritis and pernicious anemia are present, iron absorption problems may occur, including hidden iron deficiency anemia due to false test results caused by a dysfunction of serum iron metabolism, elevated ferritin, and elevated transferrin saturation index. It should be noted that, if this condition occurs, there will be a rapid decrease in these markers after treatment with B12, and this should be monitored; approximately half of patients with pernicious anemia and B12 deficiency, after replacement therapy with this vitamin, showed iron deficiency anemia in blood tests, which was previously hidden and masked.
Megaloblastic anemia can be caused by a deficiency of B12, B9, or both. Since B12 and B9 share interrelated functions, anemia and its mechanisms are the same regardless of the cause, with the difference that the onset of anemia is later in the case of a B12 deficiency.
Apart from the common characteristic of anemia (decrease in red blood cells), anemia due to B12 deficiency presents a process of macrocytosis (increase in the size of red blood cells or erythrocytes) that manifests itself in the abnormal growth of blood cells (the aforementioned megaloblasts), all of which is the result of a failure of their nucleus to mature and an increase in cytoplasmic mass and maturation. This is why megaloblastic anemia is referred to as macrocytic anemia. It should be noted that there may also be megaloblastic processes that do not cause anemia.
One of the characteristics, as we have seen, is an increase in the size of the erythrocytes, which would be reflected in a blood test when measuring the MCV (mean corpuscular volume). However, let us remember again: if there is a B12 deficiency but a high intake of folates through supplements or dietary sources, the MCV may not be altered, as the folate trap is neutralized when a more or less valid folate balance is restored, and this means that the alarms may not go off in a basic blood test. What would accumulate equally is homocysteine, a marker that does not appear in a standard blood test and must be requested specifically (although if folic acid is taken, it may cause it to be regulated somewhat downward). MMA (methylmalonic acid) is even more specific (considered the “gold standard” in testing for B12 deficiency).
This picture is common in some cases of vegans, as there is usually adequate and generally high folate intake from the diet itself, and this often prevents the folate trap from being triggered. Therefore, seeing a normal MCC and a correct erythrocyte count in a blood test does not rule out the risk of non-hematological symptoms typical of B12 deficiency without the presence of megaloblastic anemia (or it may present in a mild or very mild form). In addition, serum B12 analysis may give a value within the normal range, but there may be tissue deficiency.
Therefore, there are occasions when a B12 deficiency can occur without anemia, megaloblastosis, or initial symptoms if there is a high intake of folates, which further complicates early diagnosis and can worsen symptoms, as symptoms (many of which are serious) may appear suddenly at a later stage, having been masked by the deficiency until then. In fact, there are associations between fewer hematological symptoms and more severe neurological symptoms.
There are situations of symptoms and neurological damage that appear without previous anemia. The way to rule out masking is not only to look at B12 and anemia markers, but also to determine at least homocysteine levels and, more specifically, if possible, methylmalonic acid levels. The ovo-lacto-vegetarian population is also at high risk of deficiency, since although they consume animal products such as dairy products or eggs, they do not usually meet the minimum daily requirement, which is high and should ideally be spread over several meals. In addition, it is known that some thermal processes, such as pasteurization or UHT, to which much of the commercial milk is subjected, cause losses of up to 7% of vitamin B12, and boiling causes a 30% loss.
In addition, some of the vitamin B12 contained in food may be analogues, which complicates matters for this population group, and it is not useful to look exclusively at B12 in blood tests (nor to adhere to the minimum values of current laboratory ranges). It is true that both vegetarians and non-vegetarians can be deficient in B12, but in the non-vegetarian population, the deficiency is NOT dietary in origin, since the vitamin is consumed in animal-based foods. Rather, the deficiency is due to various causes of malabsorption or autoimmune origin, where antibodies against parietal cells and intrinsic factor are detected.
In other words, B12 deficiency in vegetarians would be due to dietary absence (or insufficient intake in the case of low consumption) and lack of supplementation. However, the causes of B12 deficiency in other population groups must be sought in other contexts, as they do consume this vitamin regularly through their diet, but something is wrong (they do not absorb it well, they do not have the necessary binding proteins, they have a pathology or infection that affects it, they do not produce enough hydrochloric acid, etc.).
Here is a summary of the causes of B12 deficiency not related to diet:
- Atrophic gastritis, where the atrophy of the gastric mucosa walls fails to produce intrinsic factor, causing pernicious anemia.
- Low production or absence of intrinsic factor.
- Presence of antibodies against intrinsic factor.
- Autoimmune diseases that are often associated with pernicious anemia or various digestive issues that would affect its absorption: type 1 diabetes mellitus, vitiligo, Addison's disease, Hashimoto's hypothyroidism, hyperthyroidism (Graves' disease), hypoparathyroidism, systemic lupus erythematosus, etc.). In fact, pernicious anemia/atrophic gastritis sometimes presents as a secondary autoimmune condition in primary autoimmune diseases.
- Celiac disease.
- Crohn's disease, which can cause damage to the gastric mucosa.
- Gastric resection.
- Resection of the ileum.
- Other problems in the ileum.
- Pancreatic insufficiency.
- Hypochlorhydria, achlorhydria (low or no production of hydrochloric acid).
- Achilia (lack of pepsin in gastric juice and hydrochloric acid).
- Drugs and ileal malabsorption associated with drug use.
- Alcoholism.
- Parasites.
- Bacterial overgrowth in the small intestine (SIBO).
- Certain infections (such as Giardia or Helicobacter Pylori, which can compromise absorption in the ileum through competition).
- Zollinger-Ellison syndrome.
- Defects in the lumen.
- Drugs, including: omeprazole and other proton pump inhibitors, metformin, cholestyramine, azathioprine, neomycin, colchicine, chemotherapeutics, and oral contraceptives.
- Infantile pernicious anemia due to a genetic-hereditary defect.
- Specific congenital deficits in the metabolism of cobalamins and/or their transporters.
- Problems with B12 transporters or with vitamin-associated binding proteins.
- Advanced age is associated with increased risk. People over 65 have a 15% prevalence of deficiency due to malabsorption caused by gastric atrophy. It is suspected that in many cases this could be due to Helicobacter Pylori infection. Screening for MMA, especially in the elderly, should always be done in conjunction with glomerular filtration to rule out any kidney problems.
The classification of deficiencies includes established, subclinical, masked, asymptomatic, and functional deficiencies.
5.2 PROGRESSIVE STAGES OF A B12 DEFICIENCY
| Stage | Marker | Phase name | Interpretation |
|---|---|---|---|
| I | HTCII | Serum depletion | Blood and cellular reserves with low HTCII content |
| II | HC | Cellular depletion | Low concentration of HC and red blood cells |
| III | HCY/MMA | Biochemical deficiency | Functional imbalance with elevated Hcy and MMA |
| IV | MCV/Hb | Clinical deficiency | Clinical signs, high MCV and MCH, low Hb |
|
Adapted from: Rizzo G, Laganà AS, Rapisarda AM, La Ferrera GM, Buscema M, Rossetti P, Nigro A, Muscia V, Valenti G, Sapia F,
Saripietro G, Zigarelli M, Vitale SG. Vitamin B12 among Vegetarians: Status, Assessment and Supplementation. Nutrients.
2016 Nov 29;8(12) And from: Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S. |
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Note: Let us remember that phase IV may not occur in megaloblastic anemia if the folate trap is bypassed. Nomenclature: HTCII: Holotranscobalamin II (HoloTC) HC: Haptocorrins HCY: Homocysteine MMA: Methylmalonic acid MCV: Mean Corpuscular Volume MCH: Mean Corpuscular Hemoglobin Hb: Hemoglobin |
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5.3 SYMPTOMS OF VITAMIN B12 DEFICIENCY
The following may occur:
- Anemia with megaloblastosis (remember, this does not always occur, nor does it always occur early on).
- Fatigue, extreme fatigue, waking up very tired.
- Anxiety.
- Insomnia.
- Blurred vision.
- Various pains (common in the neck, shoulders, and face).
- Anorexia.
- Glossitis.
- Paresthesia.
- Ataxia.
- Neurological dysfunction: neuropathy, myelopathy, neuropsychiatric abnormalities.
- Poor concentration, cognitive dysfunction, short-term memory loss, mental lapses, mental fogginess.
- Mental symptoms such as personality changes, irritability, memory impairment, mental dullness, depression, dementia, psychosis with hallucinations and paranoia, loss of judgment, aggressive behavior, meaningless conversations, obsessive-compulsive disorder.
- Subacute combined degeneration.
- Lhermitte's phenomenon: electric shock sensation running down the spine and limbs. Often associated with subacute combined degeneration.
- Demyelinating lesions.
- Tachycardia, arrhythmias, atherosclerosis, collapse.
- Intestinal problems, vomiting, abdominal pain, diarrhea, urinary incontinence.
- Loss of sexual appetite.
- Erectile dysfunction. Poor sperm quality.
- Hyperpigmentation of skin and nails, changes in hair and nails, premature graying, and other dermatological symptoms. Rare cases after injectable treatment: rosacea, acne.
- In children, neuromuscular symptoms, brain atrophy (there are also cases in adults), cognitive development problems.
- Megaloblastic insanity (paranoid schizophrenia).
- Damage to the optic nerve.
- Hyposmia, anosmia.
- A wide variety of neurological and psychiatric symptoms.
- Changes in hair and nails.
- Premature graying.
- Hyperpigmentation.
- Glossitis.
- Vitiligo.
- Dermatological problems may also occur during post-treatment recovery therapy: acne, rosacea... (very rare, not common).
It is important to remember that pregnant women who follow vegetarian diets (including some animal products such as milk and/or eggs) or strictly vegetarian diets (vegan) should take supplements and maintain adequate levels during pregnancy and breastfeeding, EVEN if they are asymptomatic. Of course, supplementation should not only be taken during pregnancy, but should be continued over time.
The symptoms of a deficiency in babies are very serious. They include brain atrophy, seizures, severe anemia, pancytopenia, damage to the myelin sheath, and residual post-treatment problems in cognitive and psychomotor development. In addition, measuring B12 in a blood test is not an accurate marker, as it can be overestimated, and laboratory range values have long been shown to be outdated.
There are many documented clinical cases, all of them varied, with a multitude of symptoms, combinations of several of them, and uncertain onset, and with relatively good responses to treatment, but sometimes with very serious consequences if action is delayed: pancytopenia, organ failure, partial or permanent vision loss that is not recovered, heart attacks, and death.
Anyone who loves clinical cases will surely enjoy reading them, because, although they are unfortunately sad (and we wish each of them the best outcome and a speedy recovery), the number and variety of symptoms, as well as the uncertainty of their onset and how they affect each person, is fascinating.
Ralph Carmel, one of the modern scientists who has studied B12 most thoroughly, comments in one of his studies:
- “Most of the newly recognized deficiency is subclinical in nature, with an uncertain impact on health.”
- “The prevalence has increased with the inclusion of people with ‘normal’ B12 levels, some of whom are deficient.”
- “Folic acid fortification of some products/foods has raised concerns about the potential adverse neurological consequences of folate in people with undetected B12 deficiency.”
| Percentage of occurrence of early and common symptoms |
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PERCENTAGES ROUNDED AND ADAPTED FROM: A Kornic, Patricia & M J Harty, Margaret & Grant, Joshua. (2016). Influence of Treatment Parameters on Symptom Relief in Individuals with Vitamin B12 Deficiency. Annual Research & Review Biology. 11. 1-831711. 10.9734/ARRB/2016/31711. |
NOTE: Deficiency IS NOT THE SAME AS symptoms (there may be temporary asymptomatic deficiency) and the onset of symptoms is variable and interindividual.
5.4. ANALYSIS AND RANGE VALUES
A test that only looks at serum B12 is incomplete.
- It does not distinguish between analogues of active B12.
- Some people, even with low actual levels, may score higher than others due to the presence of more circulating analogues (either exogenous or because they genetically have more).
- Sometimes laboratories apply criteria such as “no need to check B12 levels” simply because the MCV and hemoglobin are normal and there are no abnormalities in the blood count, and they consider that since there is no established megaloblastic anemia, B12 will be normal. And we know that this is a significant error.
- B12 may appear normal, but the transport mechanism may not be saturated and therefore, in the absence of dietary intake, transcobalamin may not be delivering the vitamin to the tissues (tissue deficiency), but blood values will continue to appear normal.
- It is not just the analytical level that matters, but the physiological functionality status of each person. There will be people who are asymptomatic with 270pg/mL, or who do not yet have a deficiency as such, and other people who already show certain symptoms.
HoloTC (TC+B12) could also be measured as another important marker, as it is responsible for delivering active B12 (a small fraction). Remember that 80% of vitamin B12 is transported by haptocorrine and corresponds to the non-active fraction. It is not common in medical tests but is used in studies on vitamin B12.
Laboratory range levels of the main markers involved (may vary depending on the laboratory):
- B12: 211-700 pg/ml, variable value between laboratories (other laboratories place the lower limit between 187pg/mL). Sometimes the upper limit is set slightly higher.
These lower values are already considered problematic, and even values above them often cause problems, or we may remain asymptomatic but with a subclinical deficiency or problems that we do not associate with low B12 status, or on the verge of real problems, all of which, as we already know, are highly unlikely to lead to anemia as such... so... - Be very cautious with B12 laboratory ranges, they are considered outdated and not very useful.
The most current evidence suggests that the minimum value should be higher; some authors consider that below 300 pg/mL it would already be considered moderate, subclinical deficiency, and it has even been considered marginal levels. Ideally, levels should be at least 400 pg/mL or higher with normal homocysteine, or at least 300 pg/mL (pushing the margin down quite a bit). - Surprisingly, it is not uncommon for a patient to be told that their B12 is fine because it is 195, because the lower range is 187. Or to be told that it is not too bad if it is 170 and the lower range is 211. "We have seen this repeatedly in clinical practice. Furthermore, it is sometimes incorrect to prescribe a supplement of 2.4 mcg. This is totally insufficient.
- There are suggestions that reference values in laboratories should be reviewed, taking into account all the accumulated evidence on B12.
- The conversion equivalent is that 1 pmol/L is equivalent to 1.35 pg/mL.
- Therefore, to convert from pmol/mL to pg/mL, multiply by 1.35.
- The website unitslab.com offers a conversion calculator for common laboratory values, including B12 and many other markers.
Homocysteine: <10 µmol/liter. Some laboratories set the cutoff point at 12 and there is even talk of 15. As always, there is some variation, but we can get a general idea. Some proposals suggest giving men a little more leeway in the upper range, as men tend to have slightly higher homocysteine levels than women in general. There is a high correlation between B12 deficiency and hyperhomocysteinemia.
Methylmalonic acid (MMA), the best indicator of B12 deficiency:
- In blood: 0.07 to 0.27 micromoles/L (some laboratories consider up to 0.50 micromoles/L to be “normal,” but 0.30 micromoles/L and above is usually considered critical).
- In urine: below <3.6 micromoles/mol creatinine. Normal range between 0.5-3.6.
General laboratory range values:
- MCV: 80-100 femtoliters.
- MCH: 27-31 pg/cell.
Other particularities that may be found at the analytical level: high lactate dehydrogenase (LDH) due to the destruction of red blood cells, possible increase in ferritin, bilirubin, hypersegmented neutrophils, and changes in red blood cell morphology. In severe cases, there may also be thrombocytopenia, severe leukopenia, or pancytopenia.
5.5 VERY HIGH VITAMIN B12
Abnormally high/very high levels of vitamin B12 should not be overlooked. They may be due to a functional deficiency (very high levels but where the vitamin does not work well), with over-uptake and/or over-release, for various reasons.
If high levels of cobalamin are found, certain underlying conditions should be ruled out.
If it is very high, it is usually caused by certain pathologies or functional problems related to defects in vitamin B12 uptake, leading to over-uptake and even over-release. However, excessive supplementation could also cause this in some cases.
Some causes that can lead to high B12 in a blood test and that should be ruled out:
- Liver disease in general, including acute hepatitis and cirrhosis. Elevated haptocorrin levels and decreased TC levels are observed as there is less hepatic synthesis of this transporter.
- Presence of antibodies attacking TC2, or a dysfunctional TC2.
- Very high concentrations of haptocorrins.
- Hematological neoplasms.
- Tumors.
- Renal, autoimmune, hepatic, and bronchopulmonary diseases, alcoholism, infections.
- Benign possibilities: possible very high reserves and circulating analogues in plasma that are normal in that specific subject (other pathological situations must be assessed and ruled out).
And the section that many of you have been waiting for:
- The indiscriminate use of supplements can indeed lead to high levels of cobalamins. Consuming supplements in known doses does not usually increase B12 to very high levels. It can improve status or achieve significant increases or even exceed the upper limits, but without this being pathological. In general, only injectable or high and sustained oral doses can achieve high circulating levels, or in exceptional cases where there is a tendency to over-uptake, or where there are pre-existing liver problems, etc. Autoimmunity that attacks TC2 with very high or prolonged doses via injectables (usually in hydroxy form) is also possible.
Andrès et al, in a paper that we always recommend to our students on excess cobalamin, state that at very high cobalamin levels, functional deficiencies should be ruled out, homocysteine and MMA should be checked, and the cause should be sought; if there is inflammatory disease, blood disorders, kidney problems, liver disease, neoplasms, and other situations that could cause this, as well as assessing another possibility: if there has been previous supplementation, excessive continuous doses, what doses, for how long, etc.
6. VITAMIN B12, PREGNANCY, AND BREASTFEEDING
6.1 VITAMIN B12 IN PREGNANCY AND BREASTFEEDING
Some organizations recommend only a small increase in dietary B12, while others recommend a little more, with discrepancies between them. A fetal accumulation of between 0.1-0.2 μg per day is required, which is why some organizations recommend increasing the mother's daily requirements by 0.2 μg (but then, who keeps track of this mathematically with their diet, and do we know exactly how much B12 each food contains when there are so many different figures in the tables and we don't know exactly how much each person absorbs?).
The EFSA adds at least +0.5 μg (since it considers 40% absorption) to its recommendation for adults of 4 μg or more. In lactating women, there is an estimated secretion of 0.4 μg/day through breast milk, although this varies depending on the population group studied.
It should be noted that children are much more susceptible to developing a deficiency of this vitamin much more quickly, since they do not start with the reserves of an adult, and their symptoms can be very severe and even remain after treatment. There may even be neurological damage to the fetus in deficient mothers.
Regarding vegetarian diets: all vegan or vegetarian mothers who do not take supplements, or any mother who does not consume sufficient amounts through her diet for any other reason or who has malabsorption problems, must take supplements (in cases of malabsorption, remember to always follow protocols with macrodoses).
Breastfeeding provides B12 to the child through milk, provided that the mother's levels are adequate.
For babies in the complementary feeding stage and children, you can choose either drops or oral tablets, provided that the latter are completely crushed to a powder, at least until the age of 3, to avoid choking.
Regarding B12, vegetarianism, and different situations, some authors have proposed different tables and protocols based on published data and studies. Let's look at some tables adapted from those published by Baroni:
| B12 MAINTENANCE FOR DIFFERENT AGES | ||||
|---|---|---|---|---|
| Single Daily Dose | Multiple Daily Dose | Weekly Dose | ||
| Pregnant and breastfeeding women | 50 µg** | 2 µg × 3 | 1,000 µg × 2 times | |
| Children 6 months – 3 years | 5 µg | 1 µg × 2 | 250 µg × 2 times* | |
| Children 4 to 10 years | 25 µg | 2 µg × 2 | 500 µg × 2 times* | |
| Over 10 years old | 50 µg | 2 µg × 3 | 1,000 µg × 2 times | |
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Adapted from: Baroni L, Goggi S, Battaglino R, et al. Vegan Nutrition for Mothers and Children: Practical Tools for Healthcare Providers. Nutrients. 2018;11(1):5. Published 2018 Dec 20. doi:10.3390/nu11010005 Expanded with data from: Recommendations of the Spanish Pediatric Association's Committee on Nutrition and Breastfeeding on vegetarian diets. Susana Redecilla Ferreiro, Ana Moráis López, José Manuel Moreno Villares, on behalf of the Nutrition and Breastfeeding Committee of the AEP. |
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* The values marked with an asterisk for Weekly Dose have been supplemented with values provided by the Spanish Association of Pediatrics, which proposes a similar table. Baroni does not propose these values in his text. ** In the double asterisk value of 50μg for the Single Daily Dose for Pregnant and Breastfeeding Mothers, Baroni tells us that taking it in two doses (25+25) can increase the bioavailability of B12. |
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| B12 RECOVERY PROTOCOL ALGORITHM BASED ON BLOOD TEST RESULTS | ||||
|---|---|---|---|---|
| B12 < 75 pmol/L | B12 between 75 - 150 pmol/L | B12 between 150 - 220 pmol/L | B12 between 220 - 300 pmol/L | |
| Pregnant and breastfeeding women | 1000 µg/day for 4 months | 1000 µg/day for 3 months | 1000 µg/day for 2 months | 1000 µg/day for 1 month |
| Children 6 months to 3 years | 250 µg/day or 3 daily doses of 10 µg for 4 months |
250 µg/day or 3 daily doses of 10 µg for 3 months |
250 µg/day or 3 daily doses of 10 µg for 2 months |
250 µg/day or 3 daily doses of 10 µg for 1 month |
| Children 4 to 6 years | 500 µg 4 times a week for 4 months | 500 µg 4 times a week for 3 months | 500 µg 4 times a week for 2 months | 500 µg 4 times a week for 1 month |
| Children 7 to 10 years | 500 µg 6 times a week for 4 months | 500 µg 6 times a week for 3 months | 500 µg 6 times a week for 2 months | 500 µg 6 times a week for 1 month |
| Children >11 years | 1000 µg/day for 4 months | 1000 µg/day for 3 months | 1000 µg/day for 2 months | 1000 µg/day for 1 month |
| Adapted from: Baroni L, Goggi S, Battaglino R, et al. Vegan Nutrition for Mothers and Children: Practical Tools for Healthcare Providers. Nutrients. 2018;11(1):5. Published 2018 Dec 20. doi:10.3390/nu11010005 | ||||
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Note: Each case must be monitored individually and based on patient response/evolution. The authors acknowledge there is no exact or closed protocol, nor consensus. Please note that the values in this chart are expressed in pmol/L and not in pg/mL (to convert, multiply by 1.35). |
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6.2 VITAMIN B12 IN MOTHERS AND CHILDREN
This is a key point with extremely important and vital functions. In children, we have mentioned that the situation is even more complicated than in adults. They can suffer much earlier and more severe deficiencies from the outset, and the disaster that a B12 problem can cause for young children is well documented in the scientific literature through reported cases.
Some of these problems include neurological disorders, brain atrophy, demyelination, delayed cognitive development and growth, mental retardation, lack of emotional and communicative responses, lack of smiling and willingness to play, extreme fatigue, vomiting, tremors and convulsions, gait and motor coordination disorders, severe megaloblastic anemia, thrombocytopenia, pancytopenia, which can lead to coma, respiratory failure, and death. The following have also been described: hypotonia, muscle weakness, lack of response to stimuli, delayed speech development, lack of interaction with people, involuntary movements, hyperpigmentation, enlargement of the liver and spleen, and low bone mineral density. All of these have been documented in scientific literature.
The likelihood of residual symptoms remaining after treatment is much higher than in adults. It appears that between the fourth and tenth month is when the clinical picture is most likely to appear, but there are also cases reported earlier, as well as in older children.
7. VITAMIN B12 SUPPLEMENTATION
7.1 FORMS OF VITAMIN B12 IN SUPPLEMENTS: CYANOCobalamin, HYDROXOCobalamin, METHYLCobalamin
Regarding the different forms of B12, it is always advisable to supplement with cyanocobalamin, as it is the most studied form (and also inexpensive, since it is easily produced in the laboratory), as well as being very stable, resistant, and less photosensitive.
It has proven safety and the amount of cyanide it contains is low.
Cyanocobalamin has sometimes been proposed as the worst source because it must be converted to the two coenzymatic forms (methyl and adenosyl) before it can be used, but the reality is that the body can efficiently convert cyanocobalamin into methylcobalamin and adenosylcobalamin without any problems.
It is true that methyl- can have its uses, without a doubt, and it is not an incorrect form; it has also been said that once absorbed, it is better retained; but the doses to be used are not precisely known. However, when properly managed, anyone who wants to take the directly methylated form is an option.
Although methylcobalamin is the least common form when injected, recent studies are considering it as an option in some cases, such as in the early stages of amyotrophic lateral sclerosis, where a study by Ryosuke et al. worked with daily injections of 50 mg (which are extremely high doses).
Hydroxocobalamin is usually found in injectable form, although injectable cyanocobalamin is also more common, with Optovite (cyanocobalamin) being the most common drug in Spain for this use.
At low doses, from 1 μg to 25 μg, all forms are absorbed equally. At high doses, cyanocobalamin is better absorbed. Methylcobalamin in supplement form is converted very efficiently and without difficulty into adenosylcobalamin. It appears to be better retained once absorbed, but much higher doses are required. The necessary doses are currently unknown, and aspects of its metabolism are not fully understood. It is also a less stable form.
- Cyanocobalamin is only contraindicated in certain cases:
- People with kidney problems and renal failure have problems clearing and eliminating cyanide.
- People with cyanide metabolism defects or who have suffered cyanide poisoning.
- Smokers: they excrete more cyanocobalamin due to the affinity that cobalamin has for cyanide (which is why smoking is an additional risk factor as it affects B12 metabolism). The presence of cyanide in the body is increased in smokers. It is also known that administering hydroxocobalamin to people with cyanide poisoning is very effective in eliminating cyanide because it binds to cobalamin. This means that if a heavy smoker takes hydroxocobalamin (the most common dietary form), they may excrete more cyanocobalamin. For this reason, it is advisable to use methylcobalamin (some have suggested methylcobalamin combined with cyanocobalamin). However, there is no consensus, only hypotheses and recommendations.
- People who have shown adverse reactions to cyanide supplements (although this is usually more common with injections than with oral supplements) and even rare cases where recovery with injections is accompanied by neurological symptoms (in these cases, some authors suggest using cobalamin in hydroxy form, or cycling hydroxy with cyanide).
- Conditions such as tobacco amblyopia or Leber's disease.
- Specific cases where the professional wishes to use another type of form for different reasons or causes.
Among others, Leene A. Alane and Carlos Rojas-Fernández review studies with several groups of patients with B12 deficiency for different reasons (including dietary deficiency, atrophic gastritis, ileal resection, or medication use), where some received oral B12 and others received parenteral B12 (always at high pharmacological doses ranging from at least 500 μg to 2000 μg).
In one case, high-dose oral supplementation was found to be at least as effective as parenteral supplementation, and the authors venture to say —based on a study—that it is even superior when it comes to maintenance doses, since the levels of methylmalonic acid that remained slightly above the upper limit decreased more slowly in the group that received intramuscular injections. This would also represent a significant saving, since oral supplements based on cyanocobalamin are much cheaper than injectable preparations.
They comment that patients tend to prefer oral administration over injection for reasons of convenience and adherence. In the case of oral supplementation, there appears to be no difference between taking it sublingually or swallowing it. Among others, Amir Sharabi et al. compared the sublingual and oral (swallowed) routes with doses of 500 μg.
However, although there are studies on the effectiveness of high-dose oral supplementation when symptoms are present, in severe cases of neurological symptoms, B12 should be administered parenterally until the symptoms subside and normal levels are restored. In this case, maintenance oral supplementation may be continued if the patient wishes and finds it more convenient, always taking into account the personal needs of each individual and considering whether it may be an option for the clinical case in question.
In patients where levels are low, close to the lower limit, and where there are no symptoms, a loading dose can be given through oral supplementation. This dose may vary and will depend on many factors, but a minimum of 2-4 weeks with 2000 μg/day is usually recommended, followed by maintenance if levels have recovered well. It would also be useful for people who have not been taking supplements for some time or do not know their status, although it is always advisable in any case to have a check-up beforehand to assess the situation.
Ralph Carmel published a paper in 2008 entitled “How I Treat Cobalamin Deficiency,” in which he discusses his extensive clinical experience treating patients with vitamin B12 deficiency.
He comments that in maintenance doses, it does not matter whether injectable cobalamin is used monthly or taken orally daily (each with its own specific protocols and doses), and that it is patient adherence that matters. If we are looking to optimize absorption, it is better to take the oral supplement on an empty stomach or between meals than after a meal, as the fraction absorbed is greater.
| Oral intake | Absorption μg | Ratio % |
| 500 μg on an empty stomach | 2.8-13.4 | 0.5-2.68 |
| 500 μg in the presence of food | 1.8-7.5 | 0.35-1.5 |
| Adapted from Carmel, R. (2008). How I treat cobalamin (vitamin B12) deficiency. Blood, 112(6), 2214-2221). Note that although there is greater absorption on average when fasting, there is considerable variability in the percentage. This tells us about the differences between individuals in the behavior of the vitamin. | ||
In cases with established neurological symptoms, and in line with other experts, he recommends treatment with injections rather than oral medication. A 1000 μg injection can result in the retention of up to 150 μg in the vast majority of patients in very severe and advanced cases. The doctor will determine the protocol, dose, and frequency. He also recommends conducting a preliminary study before starting treatment in patients with anemia and symptoms.
Hydroxocobalamin has been found to be more effective than cyanocobalamin in treating symptomatic conditions when administered by injection, although Carmel recommends cycling between the two. She is also surprised by the number of vegetarians who refuse or are reluctant to take supplements.
Brief summary of some points from Carmel's paper (which we recommend reading in its entirety as it is very interesting):
- Neurological symptoms: Parenteral treatment. Hydroxocobalamin is more effective than cyanocobalamin in these cases. Carmel cycles between them.
- At maintenance doses: No difference between injectable and oral (assess adherence/preference).
- Oral supplement best on an empty stomach or between meals.
A study by Bensky et al. that looked at oral versus intramuscular administration:
- It found that both B12 therapy with an oral protocol (sublingual oral in this case) and intramuscular therapy are valid for raising plasma levels of this vitamin.
- They reiterate what other authors have said repeatedly: intramuscular therapy is usually more uncomfortable and more expensive for patients, as well as requiring more clinic visits, and that regardless of the route of administration, patients with lower levels respond better and faster, with more efficient improvement of the hematological symptoms derived from their deficiency (although we should remember that in compromised and severe situations, parenteral protocols are usually used directly).
- The study used a higher cut-off point (300 ng/L or pg/mL) than the usual lower laboratory range values (200), which reminds us of another problem with these ranges, which are currently set at 200 ng/L and even lower. It is known that between 200-300 ng/L there may be some individuals already with associated problems or with a disaster slowly brewing.
In oral/sublingual replacement therapy, it is administered daily, while intramuscular administration follows weekly and then monthly patterns (or daily/weekly/monthly depending on the protocol and case).
Passive diffusion, although a much less efficient route, is the appropriate route for people with malabsorption problems due to any cause (including atrophic gastritis, gastrectomy, various autoimmunities—against intrinsic factor, against parietal cells, malabsorption associated with other autoimmune diseases, etc..-, use of interfering drugs...).
In children with macrocytic anemia, a clinical trial by Tandon et al found that the parenteral protocol achieved better levels of B12 and hemoglobin than the oral protocol.
7.3 ADVERSE REACTIONS
Possible adverse reactions, considered rare and exceptional, include:
- Swelling of the face, tongue, throat, dizziness, difficulty breathing, skin problems, diarrhea.
- Possibility of hypokalemia after initial treatment with injections: Observation/monitoring, especially after the first injection and 48 hours of follow-up.
- Not indicated in cases of allergy or hypersensitivity to cobalt.
- Arrhythmias, heart failure.
- May precipitate gout attacks in predisposed individuals.
- Supplements in cyanide form in people sensitive to cyanide or with kidney problems.
- Optic nerve atrophy (accelerated in Leber's disease).
- Transient mild diarrhea.
- Anaphylactic shock, death.
- Very high doses injected (especially in hydroxy form) may induce antibodies against TC2 and excessive levels of B12, resulting in a functional deficiency.
- Adverse reactions to other ingredients.
Acne is reported as a relatively common symptom when very high doses are administered at once. Cases of acne following protocols with high daily doses of B12 (5000-10000 mcg in a single dose) are not uncommon.
Regarding toxicity, oral cobalamin is considered very safe even at high doses, but according to Ralph Carmel himself, “toxicity is minimal, but not entirely non-existent,” and absurd and unjustified supplements should not be taken, especially not for long periods of time, as this does increase the risk of associated problems.
It is often said that B12 supplements do not cause problems, that there is no limit, that you can take as much as you want, that if you take too much it is eliminated in urine because it is water-soluble... This has even been heard from health professionals.
The fact that the IOM did not establish an upper level (UL) at the time, since, as the institute stated, “it cannot be determined due to a lack of data on adverse effects,” does not mean that there are none.
Even so—and we don't know why this is often omitted by those who support the 1998 IOM position, saying that “you can take as much B12 as you want”—they recommended that the source of this vitamin should only come from food to avoid high levels of intake (although logically this would not apply to vegetarians or in cases of vitamin malabsorption).
Some authors have already warned against “free supplementation.” In the words of Ralph Carmel: "People who really need B12 don't take it, and those who don't need it (e.g., athletes) usually take high doses (2000-5000 mcg/day). It is not known what such high daily doses sustained over time may cause. If an elderly person has low B12 levels, there is no problem with using 500-1000 mcg/day, but 5000 mcg is ridiculous."
It is true that problems are rare and tend to occur more with parenteral than oral administration, and more with forms of B12 other than cyanocobalamin, but this does not mean that indiscriminate supplementation should be allowed or that the doses to be used and the possible side effects should be ignored in recovery protocols. There is also a call for caution regarding proposals for mass fortification of products and foods with vitamin B12, as there may be more risks than benefits. On the other hand, folic acid supplementation in some products could aggravate problems associated with B12 in people with undetected deficiency, increasing the severity of neurological and psychiatric symptoms, which are uncertain in onset and in the vast majority of cases already in subclinical states.
7.4 RECOVERY PROTOCOLS
In replacement protocols, when there is low status, subclinical deficiency, asymptomatic deficiency, malabsorption that has led to deficiency without severe symptoms, established non-aggressive megaloblastic anemia, or mild symptoms, or when general repletion is sought, we have, orally:
- 500-1000-2000 mcg/day (oral, variable dose depending on the case and protocol, although all seem to work at a general level and not individually, 1000 or 2000 is usually chosen) for a variable period of time (normally 4-8 weeks, also subject to factors, and may be several months), assessing each situation and dose, taking into account the context, initial status, and clinical situation of the person.
- It can also be treated by injection (note: dosage and frequency vary).
- Greater adherence and comfort for the patient in these cases: oral supplement VS injection.
As a boost via parenteral route, when there is severe pernicious anemia and neurological symptoms, or if only a maintenance dose is sought, it is generally done as follows:
- Replacement phase: 1000 mcg/day for the first week + 1000 mcg/week for the following 4-8 weeks (some protocols do not use the daily phase and go straight to the weekly phase, depending on the case).
- Maintenance phase: 1000 mcg/month, as maintenance. If no prior recovery is sought, this is the standard maintenance dose to be followed by parenteral route (one injection per month of 1000 mcg).
- Note on megaloblastic anemia or repletion in asymptomatic patients: a first injection of 1000 mcg may be sufficient to reverse anemia/replenish levels and then continue with 1000 mcg/month. This should be decided by the professional in charge of each case.
- This is the standard protocol with cyanide-form B12. Some authors may differ in their approach, depending on each case, cycling different forms of cobalamin (cyanide + hydroxy) and even cycling injectable + oral.
- These are general guidelines. Each case must always be personalized.
- Always intramuscular/deep subcutaneous (gastrectomized patients).
- There are exceptional cases where it can be administered intravenously: extreme thrombocytopenia, some nutritional solutions.
This is a double-blind intervention involving vegetarian and vegan subjects with marginal (>220 pmol/L) or very low (>150 pmol/L) vitamin B12 levels but no symptoms.
- Inclusion criteria: Not participating: people with malabsorption, pathologies, smokers and drinkers, or those using supplements.
- B12 administered sublingually in the form of cyanocobalamin.
- The sample is n=36, divided into 2 groups.
- Group 1: 50 mcg/day of B12 (350 mcg/week).
- Group 2: 2000 mcg/week of B12 (1 dose of 2000 mcg in a single intake and placebo on the remaining days).
- No supplements, fortified products, or analogues (e.g., spirulina) were allowed.
- Note: No control group (vegetarians without supplements) or total placebo group, for ethical reasons (we know that not giving B12 to someone with a deficiency exposes them to serious problems; and knowing what would happen, we chose not to give placebos or have groups without supplements).
- The goal is achieved with daily doses.
- However, the 2000 mcg/week group had slightly better improvements (more efficient).
- Important: study applied to people without clinical symptoms, only low status.
It can therefore be concluded that for deficiencies that are beginning or suboptimal values in tests (and it would even be applicable to correct values but masked subclinical deficiencies), even a maintenance dose protocol could serve to avoid danger. However, it is always better to work with well-planned recovery protocols. But this leads us to see how starting supplementation in vegetarians at maintenance doses could save someone on the verge of deficiency from suffering from it, even if they have no symptoms and no blood tests. Taking B12 is crucial. Even if you are asymptomatic.
7.5 PERCENTAGES ABSORBED AND RETAINED IN DIFFERENT DOSES AND ROUTES
| SUMMARY OF ESTIMATED PERCENTAGES ABSORBED AND RETAINED AT DIFFERENT DOSES AND ROUTES | ||
|---|---|---|
| Normal Absorption | Malabsorption Cases (e.g. Pernicious Anemia) | |
| Estimated daily loss / Requirements | ~1 µg/day | ~2 µg/day |
| Recommended daily dose | 2.4 µg/day | Supplementation needed |
| Average cobalamin reserves | ~2500 µg | Depends on depletion phase |
| Reserve-to-loss ratio | 2500:1 | ~1200:1 |
| Amount (%) absorbed from an oral dose of: | ||
| 1 µg | 0.56 µg (56%) | 0.01 µg (1.2%) |
| 10 µg | 1.6 µg (16%) | 0.1 µg (1.2%) |
| 50 µg | 1.5 µg (3%) | 0.6 µg (1.2%) |
| 500 µg | 9.7 µg (2%) | 7.0 µg (1.3%) |
| 1000 µg | ~13 µg (1.3%) | ~12 µg (1.2%) |
| Amount (%) retained from a parenteral dose of: | ||
| 10 µg | 9.7 µg (97%) | Same as normal absorption |
| 100 µg | 55 µg (55%) | Same as normal absorption |
| 1000 µg | 150 µg (15%) | Same as normal absorption |
|
Adapted from: Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008 Sep 15;112(6):2214–21. doi: 10.1182/
blood-2008-03-040253. Epub 2008 Jul 7 And from: Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968 Oct;184(4):247–58. |
||
8. BIBLIOGRAPHY
A Garrido Pertierra. José María Teijon Rivera. Bioquímica metabólica. 2ºEd. Editorial Tebar.
A Kornic, Patricia & M J Harty, Margaret & Grant, Joshua. (2016). Influence of Treatment Parameters on Symptom Relief in Individuals with Vitamin B12 Deficiency. Annual Research & Review Biology. 11. 1-831711. 10.9734/ARRB/2016/31711.
Adams JF, Ross SK, Mervyn L, Boddy K and King P, 1971. Absorption of cyanocobalamin, coenzyme B12, methylcobalamin, and hydroxocobalamin at different dose levels. Scandinavian Journal of Gastroenterology, 6, 249–252.
Aguirre JA, Donato ML, Buscio M, Ceballos V, Armeno M, Aizpurúa L, Arpí L. [Serious neurological compromise due to vitamin B12 deficiency in infants of vegan and vegetarian mothers]. Arch Argent Pediatr. 2019 Aug 1;117(4):e420-e424.
Al Amin ASM, Gupta V. Vitamin B12 (Cobalamin). 2022 Jun 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.
Alenzuela B, Alfonso; Sanhueza C, Julio, Nieto K. Susana. Oxidos del Colesterol (oxisteroles): Factores que condicionan su formación, efectos biológicos y su presencia en los alimentoslRev. chil. nutr. 2002, vol.29, n.2, pp.116-124.
Allen RH, Stabler SP. Identification and quantitation of cobalamin and cobalamin analogues in human feces. Am J Clin Nutr. 2008 May;87(5):1324-35.
Andres E, Affenberger S, Vinzio S, Kurtz JE, Noel E, Kaltenbach G, Maloisel F, Schlienger JL and Blickle JF, 2005. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. American Journal of Medicine, 118, 1154–1159.
Andres E, Serraj K, Zhu J and Vermorken AJ, 2013. The pathophysiology of elevated vitamin B12 in clinical practice. QJM- Monthly Journal of the Association of Physicians, 106, 505–515.
Andrès E, Serraj K, Zhu J, Vermorken AJ. The pathophysiology of elevatedvitamin B12 in clinical practice. QJM. 2013 Jun;106(6):505-15. doi:10.1093/qjmed/hct051. Epub 2013 Feb 27. Review.
Ankar A, Kumar A. Vitamin B12 Deficiency. 2022 Jun 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.
Antoni AC. Megaloblastic anemias. En: Hematology basic principles and practice. 2nd ed. New York: Churchill Livingston,1995:552-86.
Antony AC. Prevalence of cobalamin (vitamin B-12) and folate deficiency in India--audi alteram partem. Am J Clin Nutr. 2001 Aug;74(2):157-9.
Anurag A. A Study on the Levels of Folic Acid, Vitamin B12 and Plasma Homocysteine in Patients with Chronic Kidney Disease. J Assoc Physicians India. 2022 Apr;70(4):11-12.
Aoyama T, Maezawa Y, Cho H, Saigusa Y, Tamura J, Tsuchida K, Komori K, Kano K, Segami K, Hara K, Senuki K, Suzuki Y, Yamakawa M, Tamagawa H, Oshima T, Yukawa N, Rino Y. Phase II Study of a Multi-center Randomized Controlled Trial to Evaluate Oral Vitamin B12 Treatment for Vitamin B12 Deficiency After Total Gastrectomy in Gastric Cancer Patients. Anticancer Res. 2022 Aug;42(8):3963-3970. doi: 10.21873/anticanres.15891.
Arendt JF, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS One. 2012;7(9):e45979.
Arendt JF, Pedersen L, Nexo E, Sørensen HT. Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study. J Natl Cancer Inst. 2013 Dec 4;105(23):1799-805.
Aslinia F, Mazza JJ, Yale SH. Megaloblastic anemia and other causes of macrocytosis. Clin Med Res. 2006 Sep;4(3):236-41. Review. Erratum in: Clin Med Res. 2006 Dec;4(4):342.
Barney AM, Danda S, Cherian AG, Aronraj J, Jayaprakash L, Abraham VJ, Christudass CS, Marcus TA. Association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with vitamin B12 deficiency and adverse perinatal outcomes among pregnant women of rural South India - a cross sectional longitudinal study. J Perinat Med. 2022 Jul 11. doi: 10.1515/jpm-2022-0119.
Batalha MA, Dos Reis Costa PN, Ferreira ALL, Freitas-Costa NC, Figueiredo ACC, Shahab-Ferdows S, Hampel D, Allen LH, Pérez-Escamilla R, Kac G. Maternal Mental Health in Late Pregnancy and Longitudinal Changes in Postpartum Serum Vitamin B-12, Homocysteine, and Milk B-12 Concentration Among Brazilian Women. Front Nutr. 2022 Jul 11;9:923569. doi: 10.3389/fnut.2022.923569.
Bell DSH. Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes. Diabetes Obes Metab. 2022 Aug;24(8):1423-1428. doi: 10.1111/dom.14734. Epub 2022 May 20.
Bensky MJ, Ayalon-Dangur I, Ayalon-Dangur R, Naamany E, Gafter-Gvili A, Koren G, Shiber S. Comparison of sublingual vs. intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency. Drug Deliv Transl Res. 2019 Jun;9(3):625-630. doi: 10.1007/s13346-018-00613-y.
Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968 Oct;184(4):247-58.
Blanco-Vaca F, Deulofeu R, Vilaseca MA, Chacón P, Dulin E. Determinación de homocisteína en plasma: metabolismo, metodología, interpretación de resultados y papel en la evaluación del riesgo cardiovascular. Química Clínica 2002;21:243-50.
Bobat H, Akyol M, Moradi P. Comment on: 'Patients with unexplained neurological symptoms and signs should be screened for vitamin B12 deficiency regardless of haemoglobin levels'. Eye (Lond). 2022 Jul 2. doi: 10.1038/s41433-022-02162-8.
Bondevik GT, Schneede J, Refsum H, Lie RT, Ulstein M, Kvåle G. Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalaminsupplementation be considered? Eur J Clin Nutr. 2001 Oct;55(10):856-64.
Brescoll J, Daveluy S. A review of vitamin B12 in dermatology. Am J Clin Dermatol. 2015 Feb;16(1):27-33. doi: 10.1007/s40257-014-0107-3. Review.
Carmel R, Gott PS, Waters CH, et al. The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities. Eur J Haematol. 1995;54:245–253.
Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea M, Azen C. Serum cobalamin, homocysteine and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities. Am J Clin Nutr. 1999;70:904–910.
Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology. 2003:62–81.
Carmel R, Karnaze DS, Weiner JM. Neurologic abnormalities in cobalamin deficiency are associated with higher cobalamin "analogue" values than are hematologic abnormalities. J Lab Clin Med. 1988 Jan;111(1):57-62.
Carmel R, Melnyk S, James SJ. Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Blood. 2003;101:3302–3308.
Carmel R, Sarrai M. Diagnosis and management of clinical and subclinical cobalamin deficiency: advances and controversies. Curr Hematol Rep. 2006;5:23–33.
Carmel R, Sinow RM, Karnaze DS. Atypical cobalamin deficiency: subtle biochemical evidence of deficiency is commonly demonstrable in patients without megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption. J Lab Clin Med. 1987;109:454–463.
Carmel R, Spencer CA. Clinical and subclinical thyroid disorders associated with pernicious anemia: observations on abnormal thyroid-stimulating hormone levels and on a possible association of blood group O with hyperthyroidism. Arch Intern Med. 1982;142:1465–1469.
Carmel R, Weiner JM, Johnson CS. Iron deficiency occurs frequently in patients with pernicious anemia. JAMA. 1987;257:1081–1083.
Carmel R. Cobalamin, the stomach, and aging. Am J Clin Nutr. 1997;66:750–759.
Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357–375.
Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357–375.
Carmel R. Efficacy and safety of fortification and supplementation with vitamin B12: biochemical and physiological effects. Food Nutr Bull. 2008 Jun;29(Suppl):S177-87. Review.
Carmel R. Efficacy and safety of fortification and supplementation with vitamin B12: biochemical and physiologic effects. Food Nutr Bull. 2008;29(suppl):S177–S187.
Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008 Sep 15;112(6):2214-21. doi: 10.1182/blood-2008-03-040253. Epub 2008 Jul 7.
Carmel R. Macrocytosis, mild anemia and delay in diagnosis of pernicious anemia. Arch Intern Med. 1979;139:47–50.
Carmel R. Malabsorption of food cobalamin. Baillieres Clin Haematol. 1995;8:639–655.
Carmel R. Nutritional vitamin B12 deficiency: possible contributory role of subtle vitamin B12 malabsorption. Ann Intern Med. 1978;88:647–649.
Carmel R. Pepsinogens and other serum markers in pernicious anemia. Am J Clin Pathol.
Carmel R. Pernicious anemia: the expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med. 1988;148:1712–1714.
Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med. 1996;156:1097–1100.
Çebi M, Metin B, Tarhan N. The association between vitamin B12 and plasma homocysteine levels with episodic memory and the volume of memory related brain structures in middle-aged individuals: a retrospective correlational study. Brain Struct Funct. 2022 Jul;227(6):2103-2109. doi: 10.1007/s00429-022-02499-6.
Cicero AF, Minervino A. Combined action of SAMe, Folate, and Vitamin B12 in the treatment of mood disorders: a review. Eur Rev Med Pharmacol Sci. 2022 Apr;26(7):2443-2459. doi: 10.26355/eurrev_202204_28479.
Clements M, Heffernan M, Ward M, Hoey L, Doherty LC, Hack Mendes R, Clarke MM, Hughes CF, Love I, Murphy S, McDermott E, Grehan J, McCann A, McAnena LB, Strain JJ, Brennan L, McNulty H. A 2-year randomized controlled trial with low-dose B-vitamin supplementation shows benefits on bone mineral density in adults with lower B12 status. J Bone Miner Res. 2022 Sep 21. doi: 10.1002/jbmr.4709.
Cohen H, Weinstein WM, Carmel R. The heterogeneity of gastric histology and function in food cobalamin malabsorption: absence of atrophic gastritis and achlorhydria in some patients with severe malabsorption. Gut. 2000;47:638–645.
Conocimientos actuales sobre nutrición editado por Ekhard E. Ziegler,L.J. Filer (Jr), V. Herbert.
Cortés MF, Hirsch BS, de la Maza CMP. Importancia del ácido fólico en la medicina actual. Rev Méd Chile. Scielo Chile [en línea] Febrero de 2000 [fecha de acceso Junio de 2007]; 128 (2):
Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12 from algae appears not to be bioavailable. Am J Clin Nutr. 1991 Mar;53(3):695-7.
Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12 from algae appears not to be bioavailable. Am J Clin Nutr. 1991 Mar;53(3):695-7.
de Paz R, Hernández-Navarro F. [Management, prevention and control of megaloblastic anemia, secondary to folic acid deficiency]. Nutr Hosp. 2006 Jan-Feb;21(1):113-9.
Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, New Delhi, India. Perturbing Status of Vitamin B12 in Indian Infants and Their Mothers. M Mittal et al. Food Nutr Bull 38 (2), 209-215. 2017 Mar 07.
Depuis Z, Gatineau-Sailliant S, Ketelslegers O, Minon JM, Seghaye MC, Vasbien M, Dresse MF. Pancytopenia Due to Vitamin B12 and Folic Acid Deficiency-A Case Report. Pediatr Rep. 2022 Mar 3;14(1):106-114. doi: 10.3390/pediatric14010016.
Depuis Z, Gatineau-Sailliant S, Ketelslegers O, Minon JM, Seghaye MC, Vasbien M, Dresse MF. Pancytopenia Due to Vitamin B12 and Folic Acid Deficiency-A Case Report. Pediatr Rep. 2022 Mar 3;14(1):106-114. doi: 10.3390/pediatric14010016.
Dharmarajan TS, Norkus EP. Approaches to vitamin B12 deficiency. Early treatment may prevent devastating complications. Postgrad Med. 2001 Jul;110(1):99-105; quiz 106. Review.
Dobson R, Alvares D. The difficulties with vitamin B12. Pract Neurol. 2016 Aug;16(4):308-11.
Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008 May;66(5):250-5. doi: 10.1111/j.1753-4887.2008.00031.x. Review.
D'Souza SW, Glazier JD. Homocysteine Metabolism in Pregnancy and Developmental Impacts. Front Cell Dev Biol. 2022 Jun 30;10:802285. doi: 10.3389/fcell.2022.802285.
Effects of smoking on metabolism and excretion of vitamin B12. J. C. Linnell, A. D. Smith, C. L. Smith, J. Wilson, and D. M. Matthews. Br Med J. 1968 Apr 27; 2(5599): 215–216.
EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2015. Scientific Opinion on Dietary Reference Values for cobalamin (vitamin B12). EFSA Journal 2015;13(7):4150, 64 pp.
Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005 May 23;165(10):1167-72.
Fang H, Kang J, Zhang D. Microbial production of vitamin B(12): a review and future perspectives. Microb Cell Fact. 2017 Jan 30;16(1):15.
Farooq MD, Tak FA, Ara F, Rashid S, Mir IA. Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes. J Xenobiot. 2022 May 31;12(2):122-130. doi: 10.3390/jox12020011.
Ferré N, Gómez F, Camps J, Simó JM, Murphy MM, Fernández-Baelart J, et al. Plasma homocysteine concentrations in patients with liver cirrhosis. Clin Chem 2002;48:183-5.
Forsyth JC, Mueller PD, Becker CE, Osterloh J, Benowitz NL, Rumack BH, Hall AH. Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol. 1993;31(2):277-94.
Folatos y prevención de enfermedad cardiovascular D.A. de Luis Román y R. Aller de La Fuente.
Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98:204 - 210.
Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.
Forsyth JC, Mueller PD, Becker CE, Osterloh J, Benowitz NL, Rumack BH, Hall AH. Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol. 1993;31(2):277-94.
Gallego-Narbón A, Zapatera B, Álvarez I, Vaquero MP. Methylmalonic Acid Levels and their Relation with Cobalamin Supplementation in Spanish Vegetarians. Plant Foods Hum Nutr. 2018 Sep;73(3):166-171. doi: 10.1007/s11130-018-0677-y.
Garcia Lopez M, Baron JA, Omsland TK, Søgaard AJ, Meyer HE. Homocysteine-Lowering Treatment and the Risk of Fracture: Secondary Analysis of a Randomized Controlled Trial and an Updated Meta-Analysis. JBMR Plus. 2018 Mar 24;2(5):295-303. doi: 10.1002/jbm4.10045. eCollection 2018 Sep.
Gerrard A, Dawson C. Homocystinuria diagnosis and management: it is not all classical. J Clin Pathol. 2022 Sep 19:jclinpath-2021-208029. doi: 10.1136/jcp-2021-208029.
Gilsing AM, Crowe FL, Lloyd-Wright Z, Sanders TA, Appleby PN, Allen NE, Key TJ. Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians and vegans: results from a cross-sectional analysis of the EPIC-Oxford cohort study. Eur J Clin Nutr. 2010 Sep;64(9):933-9.
Gomollón F, Gargallo CJ, Muñoz JF, Vicente R, Lue A, Mir A, García-Alvarado M,Gracia M, García-López S. Oral Cyanocobalamin is Effective in the Treatment of Vitamin B12 Deficiency in Crohn's Disease. Nutrients. 2017 Mar 20;9(3). pii: E308. doi: 10.3390/nu9030308.
Grover IS, Bharti R, Kapahi R, Sodhi MK, Kapahi R. Correlations between serum vitamin B12 and folate levels among mother-infant dyads in Punjab state, North-West India. J Paediatr Child Health. 2022 Sep 13. doi: 10.1111/jpc.16207.
Guéant JL, Guéant-Rodriguez RM, Alpers DH. Vitamin B12 absorption and malabsorption. Vitam Horm. 2022;119:241-274. doi: 10.1016/bs.vh.2022.01.016.
Guéant JL, Guéant-Rodriguez RM, Alpers DH. Vitamin B12 absorption and malabsorption. Vitam Horm. 2022;119:241-274. doi: 10.1016/bs.vh.2022.01.016.
Guyton y Hall. Tratado de Fisiología Médica. Elsevier.
Halsted JA, Carroll J, Rubert S. Serum and tissue concentration of vitamin B12 in certain pathologic states. N Engl J Med. 1959;260:575-80.
Hanger HC, Sainsbury R, Gilchrist NL, Beard ME, Duncan JM. A community study of vitamin B12 and folate levels in the elderly. J Am Geriatr Soc. 1991;39:1155–1159.
Herbert V, Castle WB. Intrinsec factor. N Engl J Med 1964;270:118-26.
Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S. Review.
Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.
Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015 - 2022.
Howard JM, Azen C, Jacobsen DW, Green R, Carmel R. Dietary intake of cobalamin in elderly people who have abnormal serum cobalamin, methylmalonic acid and homocysteine levels. Eur J Clin Nutr. 1998;52:582–587.
Huang HH, Cohen AA, Gaudreau P, Auray-Blais C, Allard D, Boutin M, Reid I, Turcot V, Presse N. Vitamin B-12 Intake from Dairy But Not Meat is Associated with Decreased Risk of Low Vitamin B-12 Status and Deficiency in Older Adults from Quebec, Canada. J Nutr. 2022 Jun 23:nxac143. doi: 10.1093/jn/nxac143.
Huđek Turković A, Matovinović M, Žuna K, Škara L, Kazazić S, Bačun-Družina V, Durgo K. Association of Vitamins D, B9 and B12 with Obesity-Related Diseases and Oral Microbiota Composition in Obese Women in Croatia. Food Technol Biotechnol. 2022 Jun;60(2):135-144. doi: 10.17113/ftb.60.02.22.7478.
Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria) Orphanet Journal of Rare Diseases2006 Ralph Gräsbeck. Ingestas Dietéticas de Referencia para Población Española. FESNAD, 2010. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US); 1998.
Interrelación entre vitamina B12 y ácido fólico. Dr. Bernardo Condado Arenas. Ishtulin AF, Korotkova NV, Matveeva IV, Minaev IV, Polyakova PM. Vitamin B12 kak diagnosticheskiĭ marker snizheniia reproduktivnoĭ funktsii u muzhchin [Vitamin B12 is a diagnostic marker of decreased men reproductive function]. Biomed Khim. 2022 Jun;68(3):228-231. Russian. doi: 10.18097/PBMC20226803228.
Jack Norris. veganhealth.org
Jaeger B, Corpeleijn W, Dijsselhof M, Goorden S, Haverkamp J, Langeveld M, Waterham H, Westerbeek E, Bosch AM. Mind the B2: Life-Threatening Neonatal Complications of a Strict Vegan Diet during Pregnancy. Neonatology. 2022 Sep 19:1-4. doi: 10.1159/000526334.
Kacharava T, Giorgadze E, Janjgava S, Lomtadze N, Iamze T. Correlation between Vitamin B12 Deficiency and Autoimmune Thyroid Diseases. Endocr Metab Immune Disord Drug Targets. 2022 Jun 27. doi: 10.2174/1871530322666220627145635.
Kalkan Ç, Karakaya F, Tüzün A, Gençtürk ZB, Soykan I. Factors related to low serum vitamin B12 levels in elderly patients with non-atrophic gastritis in contrast to patients with normal vitamin B12 levels. Geriatr Gerontol Int. 2016 Jun;16(6):686-92.
Karnaze DS, Carmel R. Neurologic and evoked potential abnormalities in subtle cobalamin deficiency states, including deficiency without anemia and with normal absorption of free cobalamin. Arch Neurol. 1990 Sep;47(9):1008-12.
Khattab R, Albannawi M, Alhajjmohammed D, Alkubaish Z, Althani R, Altheeb L, Ayoub H, Mutwalli H, Altuwajiry H, Al-Sheikh R, Purayidathil T, Abuzaid O. Metformin-Induced Vitamin B12 Deficiency among Type 2 Diabetes Mellitus' Patients: A Systematic Review. Curr Diabetes Rev. 2022 Apr 18. doi: 10.2174/1573399818666220418080959.
Kim HI, Hyung WJ, Song KJ, Choi SH, Kim CB, Noh SH. Oral vitamin B12 replacement: an effective treatment for vitamin B12 deficiency after total gastrectomy in gastric cancer patients. Ann Surg Oncol. 2011 Dec;18(13):3711-7.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR C77CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288:2023-31.
Kolhouse JF, Kondo H, Allen NC, Podell E, Allen RH. Cobalamin analogues are present in human plasma and can mask cobalamin deficiency because current radioisotope dilution assays are not specific for true cobalamin. N Engl J Med. 1978 Oct 12;299(15):785-92.
Kostick N, Chen E, Eckert T, Sirotkin I, Baldinger E, Frontera A. Clinical Presentation of Subacute Combined Degeneration in a Patient With Chronic B12 Deficiency. Fed Pract. 2022 Mar;39(3):142-146. doi: 10.12788/fp.0228. Epub 2022 Mar 14.
Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N. Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant. 1997 Aug;12(8):1622-8.
Koyyalamudi SR, Jeong SC, Cho KY, Pang G. Vitamin B12 is the active corrinoid produced in cultivated white button mushrooms (Agaricus bisporus). J Agric Food Chem. 2009 Jul 22;57(14):6327-33.
Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998 Aug 15;92(4):1191-8.
L.Kathleen Mahan y Janice L. Raymond. Krause Dietoterapia. Lamers Y. Vitamin B-12 Requirements in Older Adults-Increasing Evidence Substantiates the Need To Re-Evaluate Recommended Amounts and Dietary Sources. J Nutr. 2022 Sep 22:nxac179. doi: 10.1093/jn/nxac179.
Lane LA, Rojas-Fernandez C. Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy. Ann Pharmacother. 2002 Jul-Aug;36(7-8):1268-72. Review.
Lanzkowski P. Anemias megaloblásticas y otras anemias nutricionales. En: Hematología pediátrica. 3a ed. La Habana, 1983:195-237. (Edición Revolucionaria).
Lawhorne L, Ringdahl D. Cyanocobalamin injections for patients without documented deficiency: reasons for administration and patient responses to proposed discontinuation. JAMA. 1989;261:1920–1923.
Lawrence AC, Bevington JM, Young M. Storage of blood and the mean corpuscular volume. J Clin Pathol. 1975 May;28(5):345-9.
Lee YK, Kim HS, Kang HJ. Holotranscobalamin as an indicator of vitamin B12 deficiency in gastrectomized patients. Ann Clin Lab Sci. 2009 Fall;39(4):361-6.
Lerman TT, Cohen E, Sochat T, Goldberg E, Goldberg I, Krause I. Proton pump inhibitor use and its effect on vitamin B12 and homocysteine levels among men and women: A large cross-sectional study. Am J Med Sci. 2022 Jul 24:S0002-9629(22)00313-5. doi: 10.1016/j.amjms.2022.07.006.
Lesbia Meertens R, Liseti Solano R. Vitamina B12, ácido fólico y función mental en adultos mayores. Invest. Clin. Scielo Chile. [en línea] Marzo de 2005 [fecha de acceso 4 de Octubre de 2017]; 46 (1).
Lic. Mariela Forrellat Barrios, Lic. Irma Gómis Hernández y Dra. Hortensia Gautier du Défaix Gómez, Vitamina B12, metabolismo y aspectos clínicos de su deficiencia. Rev Cubana Hematol Inmunol Hemoter 1999;15(3):159-74.
Linnell JC, Matthews DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.
Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50.
Martens JH, Barg H, Warren MJ, Jahn D. Microbial production of vitamin B12. Appl Microbiol Biotechnol. 2002;58:275–285.
Martínez Sánchez P. Anemias por alteración de la síntesis de ADN. Anemias megaloblásticas. Medicine. Doyma. [en línea] Septiembre de 2001.
Martín-Rivada Á, Cambra Conejero A, Martín-Hernández E, Moráis López A, Bélanger-Quintana A, Cañedo Villarroya E, Quijada-Fraile P, Bellusci M, Chumillas Calzada S, Bergua Martínez A, Stanescu S, Martínez-Pardo Casanova M, Ruíz-Sala P, Ugarte M, Pérez González B, Pedrón-Giner C. Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns. J Pediatr Endocrinol Metab. 2022 Sep 19. doi: 10.1515/jpem-2022-0340.
Mascarenhas R, Gouda H, Ruetz M, Banerjee R. Human B12-dependent enzymes: Methionine synthase and Methylmalonyl-CoA mutase. Methods Enzymol. 2022;668:309-326. doi: 10.1016/bs.mie.2021.12.012. Epub 2022 Jan 30.
McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006 Jun 29;354(26):2764-72.
Merchant RE, Phillips TW, Udani J. Nutritional Supplementation with Chlorella pyrenoidosa Lowers Serum Methylmalonic Acid in Vegans and Vegetarians with a Suspected Vitamin B₁₂ Deficiency. J Med Food. 2015 Dec;18(12):1357-62.
Mizrahi EH, Jacobsen DW, Friedland RP. Plasma homocysteine: a new risk factor for Alzheimer's disease? Isr Med Assoc J. 2002;4:187 - 190.
Moghadasian MH, McManus BM, Frohlich JJ. Homocyst(e)ine and coronary artery disease. Arch Intern Med. 1997;157:2299 - 2308.
Mok KC, Hallberg ZF, Taga ME. Purification and detection of vitamin B12 analogs. Methods Enzymol. 2022;668:61-85. doi: 10.1016/bs.mie.2021.11.023. Epub 2021 Dec 30.
Morado, M., & Paz, R. de. (2011). Anemia megaloblástica y gastritis atrófica. Revista Española de Enfermedades Digestivas, 103(6), 332.
Morales-Gutierrez J, Díaz-Cortés S, Montoya-Giraldo MA, Zuluaga AF. Toxicity induced by multiple high doses of vitamin B(12) during pernicious anemia treatment: a case report. Clin Toxicol (Phila). 2019 Apr 24:1-3. doi: 10.1080/15563650.2019.1606432.
Mounsey A, Brendle DC, Flowers K. Oral vs. Intramuscular Vitamin B12 for Treating Vitamin B12 Deficiency. Am Fam Physician. 2022 Jun;105(6):663-664.
N RS, Sharma R, Madhulata, Sharma R. Pancytopenia: Etiology and it's Variables. J Assoc Physicians India. 2022 Apr;70(4):11-12.
Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr. 2011 Jul;94(1):359S-365S. doi: 10.3945/ajcn.111.013458. Epub 2011 May 18. Review.
Niiyama S, Mukai H. Reversible cutaneous hyperpigmentation and nails with white hair due to vitamin B12 deficiency. Eur J Dermatol.2007 Nov-Dec;17(6):551-2. Epub 2007 Oct 19.
Nyholm E., Turpin P., Swain D., Cunningham B., Daly S., Nightingale P., Fegan C. Oral vitamin B12 can change our practice. Postgrad. Med. J. 2003;79:218–220. doi: 10.1136/pmj.79.930.218.
Oki R,et al. Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators. Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2022 Jun 1;79(6):575-583. doi: 10.1001/jamaneurol.2022.0901.
O'Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010 Mar;2(3):299-316. doi: 10.3390/nu2030299. Epub 2010 Mar 5. Review.
Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr. 2014 May;68(5):541-8. doi: 10.1038/ejcn.2014.46. Epub 2014 Mar 26. Review.
Pecikoza U, Tomić M, Nastić K, Micov A, Stepanović-Petrović R. Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy. Biomed Pharmacother. 2022 Sep;153:113441. doi: 10.1016/j.biopha.2022.113441.
Pfnür IAH. Vitamin B12 Deficiency as the Cause. Dtsch Arztebl Int. 2022 Mar 25;119(12):216. doi: 10.3238/arztebl.m2022.0053.
Praveen G, Sivaprasad M, Reddy GB. Telomere length and vitamin B12. Vitam Horm. 2022;119:299-324. doi: 10.1016/bs.vh.2022.01.014.
Praveen G, Sivaprasad M, Reddy GB. Telomere length and vitamin B12. Vitam Horm. 2022;119:299-324. doi: 10.1016/bs.vh.2022.01.014.
R Muhammad, MD, P Fernhoff, MD, Dept of Pediatrics, Emory Univ, Atlanta, Georgia. S Rasmussen, MD, Div of Birth Defects and Developmental Disabilities; B Bowman, PhD, Div of Diabetes Translation; K Scanlon, PhD, L Grummer-Strawn, PhD, L Kettel Khan, PhD, Div of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion; M Jefferds, PhD, EIS Officer, CDC.
Rasmussen K, Moelby L, Jensen MK. Studies on methylmalonic acid in humans. II. Relationship between concentrations in serum and urinary excretion, and the correlation between serum cobalamin and accumulation of methylmalonic acid. Clin Chem. 1989 Dec;35(12):2277-80.
Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41.
Reischl-Hajiabadi AT, Garbade SF, Feyh P, Weiss KH, Mütze U, Kölker S, Hoffmann GF, Gramer G. Maternal Vitamin B12 Deficiency Detected by Newborn Screening-Evaluation of Causes and Characteristics. Nutrients. 2022 Sep 13;14(18):3767. doi: 10.3390/nu14183767.
Rhode BM, Tamim H, Gilfix BM, Sampalis JS, Nohr C, MacLean LD. Treatment of vitamin B12 deficiency after gastric surgery for severe obesity. Obes Surg. 1995;5:154–158.
Rizzo G, Laganà AS, Rapisarda AM, La Ferrera GM, Buscema M, Rossetti P, Nigro A, Muscia V, Valenti G, Sapia F, Sarpietro G, Zigarelli M, Vitale SG. Vitamin B12 among Vegetarians: Status, Assessment and Supplementation. Nutrients. 2016 Nov 29;8(12).
Rodriguez NM, Shackelford K. Pernicious Anemia. 2022 Jul 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan
Rodriguez-Carnero G, Lorenzo PM, Canton-Blanco A, Mendizabal L, Arregi M, Zulueta M, Simon L, Macia-Cortiñas M, Casanueva FF, Crujeiras AB. Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Pregnant Women of a Homogeneous Spanish Population: The Need for Revisiting the Current Vitamin Supplementation Strategies. Nutrients. 2022 Jun 29;14(13):2702. doi: 10.3390/nu14132702.
Sadagopan N. Severe Hemolytic Anemia due to Vitamin B12 Deficiency in Six Months. Hematol Rep. 2022 Jun 22;14(3):210-212. doi: 10.3390/hematolrep14030028.
Samson ME, Yeung LF, Rose CE, Qi YP, Taylor CA, Crider KS. Vitamin B-12 malabsorption and renal function are critical considerations in studies of folate and vitamin B-12 interactions in cognitive performance: NHANES 2011-2014. Am J Clin Nutr. 2022 Jul 6;116(1):74-85. doi: 10.1093/ajcn/nqac065.
Sarode R, Garewal G, Marwaha N, Marwaha RK, Varma S, Ghosh K, Mohanty D, Das KC. Pancytopenia in nutritional megaloblastic anaemia. A study from north-west India. Trop Geogr Med. 1989 Oct;41(4):331-6.
Sechi LA, De Carli S, Catena C, Zingaro L, Bartoli E. Benign familial macrocytosis. Clin Lab Haematol. 1996 Mar;18(1):41-3.
Shankar PR. VigiAccess: promoting public access to VigiBase.Indian J Pharmacol. 2016;48:606–607. y vigiaccess.org/
Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003 Dec;56(6):635-8.
Shen Y, Huang L, Zou Y, Su D, He M, Fang Y, Zhao D, Wang W, Zhang R. Intake of Vitamin B12 and Folate and Biomarkers of Nutrient Status of Women within Two Years Postpartum. Nutrients. 2022 Sep 19;14(18):3869. doi: 10.3390/nu14183869. P
Shivkar RR, Gawade GC, Padwal MK, Diwan AG, Mahajan SA, Kadam CY. Association of MTHFR C677T (rs1801133) and A1298C (rs1801131) Polymorphisms with Serum Homocysteine, Folate and Vitamin B12 in Patients with Young Coronary Artery Disease. Indian J Clin Biochem. 2022 Apr;37(2):224-231. doi: 10.1007/s12291-021-00982-1.
Shorb, M. S. (1947). Unidentified Essential Growth Factors for Lactobacillus-Lactis Found in Refined Liver Extracts and in Certain Natural Materials. Journal of Bacteriology 53, 669-669.
Shorb, M. S. (1948). Activity of Vitamin-B12 for the Growth of Lactobacillus-Lactis. Science 107, 397-398.
Silverstein WK, Cheung MC, Lin Y. Vitamin B12 deficiency. CMAJ. 2022 Jun 20;194(24):E843. doi: 10.1503/cmaj.220306.
Silverstein WK, Cheung MC, Lin Y. Vitamin B12 deficiency. CMAJ. 2022 Jun 20;194(24):E843. doi: 10.1503/cmaj.220306.
Simeone G, Bergamini M, Verga MC, Cuomo B, D'Antonio G, Iacono ID, Mauro DD, Mauro FD, Mauro GD, Leonardi L, Miniello VL, Palma F, Scotese I, Tezza G, Vania A, Caroli M. Do Vegetarian Diets Provide Adequate Nutrient Intake during Complementary Feeding? A Systematic Review. Nutrients. 2022 Aug 31;14(17):3591. doi: 10.3390/nu14173591.
Singh J, Dinkar A, Gupta P, Atam V. Vitamin B12 deficiency in northern India tertiary care: Prevalence, risk factors and clinical characteristics. J Family Med Prim Care. 2022 Jun;11(6):2381-2388. doi: 10.4103/jfmpc.jfmpc_650_21.
Stabler SP, Allen RH. Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr. 2004;24:299-326. Review.
Susan E. Mulroney. Adam K. Myers. Netter Fundamentos de Fisiología. 2da edición. Elsevier.
Susanti D, Ruslan FS, Shukor MI, Nor NM, Aminudin NI, Taher M, Khotib J. Optimisation of Vitamin B12 Extraction from Green Edible Seaweed (Ulva lactuca) by Applying the Central Composite Design. Molecules. 2022 Jul 12;27(14):4459. doi: 10.3390/molecules27144459.
Talari HR, Molaqanbari MR, Mokfi M, Taghizadeh M, Bahmani F, Tabatabaei SMH, Sharifi N. The effects of vitamin B12 supplementation on metabolic profile of patients with non-alcoholic fatty liver disease: a randomized controlled trial. Sci Rep. 2022 Aug 18;12(1):14047. doi: 10.1038/s41598-022-18195-8.
Tandon R, Thacker J, Pandya U, Patel M, Tandon K. Parenteral vs Oral Vitamin B12 in Children With Nutritional Macrocytic Anemia: A Randomized Controlled Trial. Indian Pediatr. 2022 Sep 15;59(9):683-687.
Taneja S, Chowdhury R, Kvestad I, Bhandari N, Strand TA. Vitamin B12 and/or folic acid supplementation on linear growth; a 6 years follow-up study of a randomised controlled trial in early childhood in North India. Br J Nutr. 2022 Jul 25:1-22. doi: 10.1017/S0007114522002343.
Ting RZ, Szeto CC, Chan MH, Ma KK and Chow KM. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Archives of internal medicine. 2006 Oct 9; 166 (18) :1975-9.
Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, Wilson PW, Selhub J. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr. 2000 Feb;71(2):514-22.
Ueno A, Hamano T, Enomoto S, Shirafuji N, Nagata M, Kimura H, Ikawa M, Yamamura O, Yamanaka D, Ito T, Kimura Y, Kuriyama M, Nakamoto Y. Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment. Nutrients. 2022 Apr 2;14(7):1494. doi: 10.3390/nu14071494.
Ueno A, Hamano T, Enomoto S, Shirafuji N, Nagata M, Kimura H, Ikawa M, Yamamura O, Yamanaka D, Ito T, Kimura Y, Kuriyama M, Nakamoto Y. Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment. Nutrients. 2022 Apr 2;14(7):1494. doi: 10.3390/nu14071494.
Üstün Özek S. A study on the correlation between pain frequency and severity and vitamin B12 levels in episodic and chronic migraine. Arq Neuropsiquiatr. 2022 Jun;80(6):586-592. doi: 10.1590/0004-282X-ANP-2021-0192.
Vademecum. Prospecto Optovite. vademecum.es
van Loon SL, Wilbik AM, Kaymak U, van den Heuvel ER, Scharnhorst V, Boer AK. Improved testing for vitamin B(12) deficiency: correcting MMA for eGFR reduces the number of patients classified as vitamin B(12) deficient. Ann Clin Biochem. 2018.
Vidal-Alaball J, Butler CC, Cannings-John R, Goringe A, Hood K, McCaddon A,McDowell I, Papaioannou A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004655. Review.
Vitamin Supplementation as Possible Prophylactic Treatment against Migraine with Aura and Menstrual Migraine Munvar Miya Shaik and Siew Hua Gan. Biomed Res Int. 2015; 2015: 469529.
Wang C, Zhang Y, Shu J, Gu C, Yu Y, Liu W. Association Between Methylmalonic Acid and Cognition: A Systematic Review and Meta-Analysis. Front Pediatr. 2022 Jun 29;10:901956. doi: 10.3389/fped.2022.901956.
Wang C, Zhang Y, Shu J, Gu C, Yu Y, Liu W. Association Between Methylmalonic Acid and Cognition: A Systematic Review and Meta-Analysis. Front Pediatr. 2022 Jun 29;10:901956. doi: 10.3389/fped.2022.901956.
Watanabe F, Schwarz J, Takenaka S, Miyamoto E, Ohishi N, Nelle E, Hochstrasser R, Yabuta Y. Characterization of vitamin B₁₂compounds in the wild edible mushrooms black trumpet (Craterellus cornucopioides) and golden chanterelle (Cantharellus cibarius).
Watanabe F, Takenaka S, Kittaka-Katsura H, Ebara S, Miyamoto E. Characterization and bioavailability of vitamin B12-compounds from edible algae. J Nutr Sci Vitaminol (Tokyo). 2002 Oct;48(5):325-31. Review.
Wei J, Wei Y, Huang M, Wang P, Jia S. Is metformin a possible treatment for diabetic neuropathy? J Diabetes. 2022 Sep 18. doi: 10.1111/1753-0407.13310
White ND. Vitamin B12 and Plant-Predominant Diets. Am J Lifestyle Med. 2022 May 4;16(3):295-297. doi: 10.1177/15598276221076102.
Wong S, Ahmad N, Rossetti AL. Vomiting as a Presenting Symptom of Infantile Vitamin B12 Deficiency. Cureus. 2022 May 19;14(5):e25134. doi: 10.7759/cureus.25134.
Wu HHL, Wang AY. Vitamin B12 and chronic kidney disease. Vitam Horm. 2022;119:325-353. doi: 10.1016/bs.vh.2022.01.011.
Wu HHL, Wang AY. Vitamin B12 and chronic kidney disease. Vitam Horm. 2022;119:325-353. doi: 10.1016/bs.vh.2022.01.011.
Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Steouwer CD. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003 Nov;254(5):455-63.
Xu B, Zhang L, Chen Q, Wang Y, Peng Y, Tang H. Case Report: A Case of Late-Onset Combined Methylmalonic Acidemia and Hyperhomocysteinemia Induced by a Vegetarian Diet. Front Pediatr. 2022 Jul 12;10:896177. doi: 10.3389/fped.2022.896177.
Yan S, Liu H, Yu Y, Han N, Du W. Changes of Serum Homocysteine and Vitamin B12, but Not Folate Are Correlated With Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis of Case-Control Studies. Front Psychiatry. 2022 May 9;13:754165. doi: 10.3389/fpsyt.2022.754165.
Yu YM, So SKC, Khallouq BB. The effect of metformin on vitamin B12 levels in pediatric patients. Ann Pediatr Endocrinol Metab. 2022 May 16. doi: 10.6065/apem.2142210.105.
Yuan X, Han X, Zhou W, Long W, Wang H, Yu B, Zhang B. Association of folate and vitamin B12 imbalance with adverse pregnancy outcomes among 11,549 pregnant women: An observational cohort study. Front Nutr. 2022 Jul 25;9:947118. doi: 10.3389/fnut.2022.947118.
Zhang B, Dong H, Xu Y, Xu D, Sun H, Han L. Associations of dietary folate, vitamin B6 and B12 intake with cardiovascular outcomes in 115664 participants: a large UK population-based cohort. Eur J Clin Nutr. 2022 Sep 13. doi: 10.1038/s41430-022-01206-2.
Zibold J, von Livonius B, Kolarova H, Rudolph G, Priglinger CS, Klopstock T, Catarino CB. Vitamin B12 in Leber hereditary optic neuropathy mutation carriers: a prospective cohort study. Orphanet J Rare Dis. 2022 Aug 9;17(1):310. doi: 10.1186/s13023-022-02453-z.
Zou R, Dai Y, Wang D, Zhang X. Association between MTHFR polymorphism and seizure control in epileptic patients with hyperhomocysteinaemia. Epileptic Disord. 2022 Oct 1;24(5):1-9. English. doi: 10.1684/epd.2022.1470.
Cite as: Robledo V. All about vitamin B12. Biochemistry, diagnosis, clinical aspects, and supplementation. ICNS. Available at https://www.icns.es/en/news/vitamin-b12
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