The Significance of Vitamin B12 Deficiency
Vitamin B12 is an essential vitamin that plays a central role in many of the body’s metabolic processes. All cells require a constant supply of small amounts of B12 in order to function optimally. To this end, it is extremely important for humans and most animals to maintain a good supply of B12 to reap the benefits of this powerful vitamin.
Vitamin B12 is necessary for DNA synthesis, cell division, hematopoiesis (blood formation), synthesis of hormones and neurotransmitters, protection of nerve fibres in the spinal cord and brain (myelin sheaths) and the breakdown of homocysteine. If vitamin B12 deficiency occurs, health cannot be sustained in the long term, and a series of ever-worsening symptoms occur.
What Causes Vitamin B12 Deficiency?
The causes of B12 deficiency are mainly malabsorption and an increased need for the vitamin. Impairments of the gastrointestinal tract – as well as an increased strain through stress and pollution – severely impede the body’s ability to obtain enough B12 through the diet. Of course, this is particularly apparent if the diet contains little B12 anyway – e.g. vegetarian and vegan diets.
The main causes of B12 deficiency are thus gastrointestinal problems and excessive strain through stress and pollution. They are the consequences of both widespread poor diets and a generally unhealthy lifestyle in the modern world, which often lead to digestive disorders.
Whether a B12 deficiency is present can most easily be determined through a specific urine test. MMA acid increases due to B12 deficiency; it can therefore be measured through a urine test to determine whether or not the B12 supply is sufficient. This method is actually far more reliable than a usual blood test.
Vitamin B12 Deficiency Treatment and Prevention
Due to the complex absorption processes of vitamin B12, it is difficult in the above-discussed cases to cover the B12 requirement through the diet. As a result, the treatment of vitamin B12 deficiency, as well as its prevention in the first place, is today usually achieved through an intake of supplements.
For some time, artificial cyanocobalamin was used in B12 treatment, which has some significant disadvantages. Nowadays, however, many supplements are available which contain the natural B12 forms – methylcobalamin, adenosylcobalamin and hydroxocobalamin – which are found inherently in the body and in organic B12 food sources.
See here: Vitamin B12 Forms.
A usual prevention dose is 250-500 μg per day when taken orally. 500 μg is recommended if there is a deficiency or an increased need, 1000 μg if there are significant symptoms.
In case of a severe deficiency, high dose initial therapy is recommended: 5000 μg per day for a duration of 4 weeks.
More information: Vitamin B12 Dosages.
Finding Suitable Supplements Online
|Dosage/Day||Active Ingredients||Online Search|
|500µg||Methyl-, adenosyl- and hydroxocobalamin||B12 + methylcobalamin + adenosylcobalamin + hydroxocobalamin + 500µg + bioactive|
|1000µg||Methyl-, adenosyl- and hydroxocobalamin||B12 + methylcobalamin + adenosylcobalamin + hydroxocobalamin + 1000µg + bioactive|
|Initial Therapy 5000µg||Hydroxocobalamin||Hydroxocobalamin + high dosage + depot + 5000µg|
Further reading: Vitamin B12 Supplements.
Vitamin B12 Deficiency Symptoms
Vitamin B12 fulfils 5 essential functions in the body. It controls and influences:
- Synthesis of DNA ( -> cell division, blood formation)
- Energy metabolism (-> energy production in the mitochondria)
- Lipid metabolism (-> development of the cell membrane and myelin sheath, protection of the nerves in the central nervous system and brain)
- Synthesis of hormones and neurotransmitters
- Detoxification (-> homocysteine, cyanide, nitric oxide and more)
Due to these multiple functions of B12, a deficiency can lead to a whole host of sometimes severe physical and mental symptoms – ranging from fatigue and depression to severe anemia and nerve damage.
- The impaired formation of neurotransmitters and hormones can lead to mood swings and mental and cognitive disorders
- The disruption of blood formation and DNA synthesis can lead to pernicious anemia and severe impairments of the metabolism
- The increase in homocysteine levels can cause cardiovascular disease, retinal damage and vascular dementia
- Nerve damage can cause inexplicable pain, paralysis and coordination disorders
- Demyelination damage to the spinal cord causes symptoms similar to multiple sclerosis (MS)
Below is a selection of the typical symptoms of B12 deficiency. These symptoms can occur individually or in combination.
Mild to Medium Physical Symptoms
Severe Physical Symptoms
This is an overview of the typical symptoms of a vitamin B12 deficiency. Yet some symptoms may have other causes.
More information can be found in our article: Vitamin B12 Deficiency Symptoms.
The Progression of Vitamin B12 Deficiency
Although they can lead to serious symptoms in the long term, vitamin B12 deficiencies frequently remain undetected for a great deal of time. It can take up to 20 years from the start of a deficiency until serious physical or psychological symptoms develop. During this time the body is already suffering from a lack of B12, but this often goes undiagnosed.
This is usually because the early symptoms – such as tiredness, depression and mild inflammations – are rarely identified as symptoms of B12 deficiency, even by doctors. Unfortunately, tests are mostly only carried out when patients have developed more serious symptoms in the later stages of a deficiency, after they have already suffered from milder symptoms for many years.
Generally, vitamin B12 deficiencies progress in the following stages (1):
1. The B12 level drops in the blood serum
Due to a supply shortage or absorption problems, the concentration of the vitamin in the blood sinks. B12 is then mobilised from the body’s stores.
2. Store and cell depletion
The B12 stores in the liver and somatic cells become depleted, causing levels in the bloodstream to decrease continuously. This is when initial symptoms might be first experienced (psychological problems, depression, poor physical performance, tiredness, immunodeficiency, mouth inflammations etc.).
3. Impaired metabolic activity
When B12 is in its lowest range, multiple biological functions are significantly affected. DNA synthesis is impaired and homocysteine level in the blood increases significantly. Significant deterioration of general health and performance occur, and physical symptoms become apparent.
4. Clinical manifestation
This is when the most severe deficiency symptoms emerge. These can have very serious consequences, which can be irreversible (for instance, severe nerve damage) or even fatal (as with pernicious anemia).
How quickly these stages develop depends on the cause of the deficiency. If caused by malabsorption, the fourth stage may in some cases occur within a few years; whereas vegans, for example, with otherwise good health and nutrition can live up to 20 years with inconspicuous symptoms before more serious ones occur.
The ‘Vicious Circle’ of Vitamin B12 Deficiency
The gradual progression of B12 deficiency has resulted in the common misconception that people can survive healthily with only low levels of the vitamin. Recent studies indicate that latent B12 deficiency is extremely common but rarely identified (2, 3). In particular the psychological symptoms such as depression, which precede the more severe physical symptoms by a number of year, are rarely properly diagnosed as being the result of a B12 deficiency.
Due to the nature of the metabolic cycle, when a deficiency of the vitamin develops it tends to become a vicious circle. Some of the symptoms that occur as a result of B12 shortage can negatively impact our absorption capabilities, which in turn reinforces these symptoms.
It is extremely important that this vicious circle is broken as soon as possible through vitamin B12 therapy. This can be achieved by first administering a very high dose to rapidly replenish the body’s store of B12.
Interim Conclusion: Vitamin B12 Deficiency Key Points
Vitamin B12 Deficiency Causes
What causes vitamin B12 deficiency? Here there are three main areas:
1. Diet and deficiency
The daily requirement of vitamin B12 from food is estimated at 2.4 μg (significantly dependant on age, gender and situation). Over time, an insufficient intake of B12 from our diet can lead to deficiency. This could be due to an imbalanced or purely vegan or vegetarian diet (4).
Vitamin B12 can actually be made by intestinal bacteria in the human digestive tract. Unfortunately, this essential vitamin forms in a place where it can no longer be absorbed; it is simply produced in the intestine and excreted. Producing a B12 supply through the body’s own bacteria is only possible under very specific conditions and thus almost all people are dependent on obtaining the vitamin through the diet.
Vitamin B12 is not found in all diets. It is produced exclusively by microorganisms and found in varying concentrations in all animal products, but is almost impossible to find in plant-based foods. Because of this vegans and vegetarians should pay particularly close attention to their vitamin B12 intake.
Dietary groups at risk:
2. Increased consumption of B12 (e.g. through stress)
In stressful situations our need for vitamin B12 greatly increases. Stress here refers to all types of high physical and mental strain, such as: heavy manual labour, loud and clamorous situations, competitive sport, psychologically stressful situations, fear, anxiety, sadness and grief, heartbreak, spiritual changes and crises, or an overworked immune systems, due to infection.
This increased demand is determined by two factors. Firstly, in stressful situations the absorption of B12 is made more difficult, because the blood supply to the intestinal organs is poor and the ratio of gastric acid to enzymes is affected. Secondly, the vitamin is required for the production of other hormones such as noradrenaline and serotonin. Due to the high release of norepinephrine in many stressful situations, B12 reserves are used up quickly; deficiency will develop if there is an insufficient supply.
A significantly increased need also occurs whilst pregnant and breastfeeding – a sufficient supply is particularly critical at this time, since a deficiency strongly influences the development of the child and can cause lasting damage (5).
Furthermore, exposure to pollutants/poisons can use up large quantities of vitamin B12. This is the case with smoking, for example, as B12 neutralises the cyanide in cigarette smoke (6). It is also particularly serious in the case of general anaesthetics – so much B12 is consumed in the detoxification of the nitrogen compounds used, that it can deplete body stores and result directly in a serious B12 deficiency (7). High strain through nitrogen radicals (i.e. nitrosative stress) leads to the significant consumption of B12.
Groups at risk due to an increased requirement:
- Pregnant and lactating women
- People with higher levels of stress
- Athletes and fitness enthusiasts
- People who have recently had operations using general anaesthetics
- Those exposed to environmental pollution and heavy metals
3. Malabsorption of B12
When suffering from digestive disorders the body cannot properly absorb vitamin B12, even when it has a sufficient supply. This could be caused by gastrointestinal infection/inflammation, or as a result of interaction with medications.
Vitamin B12 can only be absorbed via the oral mucosa and the final section of the small intestine (the ileum). A special glycoprotein called intrinsic factor (IF) is required for this process, which is secreted by the stomach’s parietal cells. Without the IF, only very small amounts of B12 will be absorbed through passive diffusion. Consequently, a very high dose of B12 would be necessary to ensure an adequate supply is obtained.
The health of the stomach and intestines is therefore of pivotal importance, as they enable the absorption of B12; various gastrointestinal conditions can impede the uptake of the vitamin, having a serious impact. Such illnesses are particularly widespread in industrialised countries due to poor eating habits – accordingly, B12 deficiencies are just as common.
Even small problems affecting the mucous membrane appear to reduce the absorption rate of the vitamin significantly, which can very easily result in a supply shortage. According to current findings, most of the B12 deficiency diseases are due to malabsorption – for example, due to gastritis/disturbed gastrointestinal mucosa. The exact nature of the relationship between nutrition and absorption remains uncertain, as the data on this topic is somewhat inconsistent.
Possible causes for malabsorption:
A further possible cause of deficiency is anesthetic with nitrous oxide (i.e. laughing gas), which uses up a lot of vitamin B12. For more details on this interrelation, click here.
How Common is Vitamin B12 Deficiency?
Just how commonplace B12 deficiencies are in various populations has not yet been fully investigated. This is partially due to the fact that there is not yet a precise method of measuring the body’s B12 levels and also because opinions regarding what defines a deficiency greatly differ.
Many researchers today believe that the current suggested threshold for deficiency is far too low and that a more accurate minimum requirement of B12 would realistically be much higher. Currently B12 serum levels (B12 blood concentration) lower than 200 pg/mol are considered deficient; however, many scientists now consider levels under 350 pg/mol to signify an acute deficient. Recent studies even claim that a realistic value would be set at approximately 500-600 pg/mol – as the research of Mitsuyama and Kogoh (8), Tiggelen (9) and David Brownstein (10), among others, recommends.
The current deficiency definition indicates that around 2-7 % of the younger generation and 14-40 % of the older generation suffer from a lack of the vitamin (12-14). As well as the elderly, vegetarians and vegans are particularly at risk; various studies have found that about 20-70 % of vegetarians and 60-90 % of vegans suffer from acute vitamin B12 deficiency. (14 – 17)
In light of recent discussions regarding the accuracy of these figures, it is possible that deficiencies are even more common than believed. A study from Tufts University which evaluated the results from the Framingham Heart Study (involving 3000 test subjects) ascertained that levels of B12 lower than 350 pg/mol were deficient and that 39 % of those who were tested fell into this category (18). According to this study, vitamin B12 deficiency would affect more than a third of the entire population – a significantly higher value than the official projection of 2-7 %.
What is more, studies from 2013 and 2014 found vitamin B12 levels below 300 ng/ml in over 80 % of subjects – indicating latent shortages in an even larger portion of the population (18, 19).
Which Groups are Most at Risk of Vitamin B12 Deficiency?
Studies such as the one mentioned above show that a deficiency can occur in all age groups among meat eaters, vegans and vegetarians alike. However, certain groups of people are more at risk:
- Vegans and vegetarians
- People aged 50+
- Those with stomach and intestinal disorders
- Heavy smokers and coffee drinkers
- People on certain medication (see table above)
- Alcoholics and drug addicts
Vitamin B12 Tests and Diagnosis
Currently there is no absolutely certain means of diagnosing a B12 deficiency, but the following methods are used to determine information about the levels of the vitamin in our bodies:
Until recent years, deficiency was determined by measuring its concentration in the blood serum. However, this method has proven to be somewhat inaccurate, because blood tests also factor in forms of B12 that have little to no use in the body (i.e. vitamin B12 analogues).
Interpretation of test results:
|Severe Deficiency||Value < 150 pg/ml|
|Deficiency||Value < 200 pg/ml|
|Mild shortage||Value 200-300 pg/ml|
|Normal status||Value 300-900 pg/ml|
|Hypervitaminosis||Value > 1000 pg/ml|
More recently, other tests have been developed:
This method measures levels of the biologically usable B12 in the blood, but gives no indication of the B12 levels in the cells and body stores. Holo TC is the earliest marker of deficiency.
|Deficiency||Value < 35 pmol/l|
|Possible deficiency||Value 35 – 50 pmol/l|
|Unlikely deficiency||Value >50 pmol/l|
This test measures the homocysteine levels in the blood, which are typically raised due to B12 deficiency. The results are usually analysed in conjunction with a blood test, because there are other known factors that can cause high homocysteine levels.
|Probable deficiency||Value > 12 µmol/l|
|Improbable deficiency||Value 5 – 12 µmol/l|
MMA Urine Test
In cases of a cellular deficiency of vitamin B12, the body produces increased amounts of methylmalonic acid (MMA). This can be measured in the blood and urine and provides reliable information concerning existing deficiencies. Today a urine test is therefore the easiest means of testing and is recommended by many researchers.
|Deficiency||Value > 3,6 mmol MMA/mol creatinine 2 mg MMA/g creatinine|
|No Deficiency||Value < 3,6 mmol MMA/mol creatinine 2 mg MMA/g creatinine|
Researchers at the University of Florida have developed a breath test, which determines the levels of vitamin B12 through the CO2 content of the air we breathe. The test is currently being trialled (19).
For American healthcare patients who have taken tests already and have been diagnosed with vitamin B12 deficiency anemia, the vitamin B12 deficiency ICD 10 code is D51.9. This a specific reference that indicates a diagnosis for reimbursement purposes.
Vitamin B12 Deficiency Treatment
Whether deficiency has emerged due to malabsorption, lack of dietary intake or stress – deficiency treatment takes place through the administration of B12 supplements. Depending on the severity of the deficiency, treatment follows these guidelines:
|State of Deficiency||Treatment||Recommended Active Ingredient|
|Deficient supply (slightly low values, no symptoms )||250 µg /day (oral)||Combination of the natural forms|
(Methyl, Hydroxo, Adenosyl)
|Mild deficiency (low values, mild symptoms)||500-1000 µg /day (oral)||Combination of the natural forms |
(Methyl, Hydroxo, Adenosyl)
|Severe deficiency (very low values, significant symptoms)||Replenishment treatment: |
Injection: 4-8 weeks 1000µg/week
Oral: 4-6 weeks 5000µg/week
Followed by maintenance treatment (see above)
Vitamin B12 supplements can contain various forms of the vitamin as active ingredients, each with specific advantages and disadvantages. In general, avoiding synthetic cyanocobalamin is recommended, as preference is instead given to the natural forms of hydroxocobalamin, adenosylcobalamin and methylcobalamin.
More information on this topic: Vitamin B12 Forms.
Vitamin B12 Deficiency – Are Injections Required?
A replenishment treatment with injections or infusions is common in cases of severely low levels or severe symptoms, as it quickly resolve the deficiency and refills the body’s store of vitamin B12. In this way, absorption is higher than with oral supplements, so that B12 reserves recover faster.
With a correspondingly high dose (1000-5000μg), the same results can be achieved through oral supplements as with injections. Oral supplements are therefore absolutely sufficient and are even recommended today for cases of severe anemia, since the efficacy at high dosages through supplements can almost approach those of injections.
When choosing supplements, several criteria should be considered:
- Active ingredient
- Pharmaceutical form (pills, capsule, spray)
Vitamin B12 Deficiency – Which Active Ingredient to Choose?
Vitamin B12 exists in various forms that function in the body through completely different metabolic pathways and therefore have divergent effects. In particular, the two bioactive coenzymes of B12 are of great importance. These are the forms that fulfil vital functions in the body in various reactions: methylcobalamin and adenosylcobalamin.
Both coenzyme forms have a completely independent effect and work in different parts of the body: methylcobalamin functions in the methylation cycle in the cytoplasm; adenosylcobalamin in the citrate cycle in the mitochondria. Humans need both coenzymes to stay healthy.
Of course, humans intake three different cobalamins through the diet: the coenzymes methylcobalamin and adenosylcobalamin, as well as their natural precursor, hydroxocobalamin. Hydroxocobalamin itself is not directly involved in metabolic processes, but on the one hand can be converted into either of the other two coenzymes. It is also an important detoxifier and can be stored in the blood for a particularly long time.
Theoretically, all forms of B12 can be converted into each other. Ideally, however, the content of supplements should be based on the natural composition of B12 in foods, providing a blend of all the major vitamin forms (21).
The Right Dosage of Vitamin B12
A rough orientation for dosing can already be found in the above table for B12 treatment. Here are some further notes:
In the case of an inadequate intake – for example, due to a vegan diet – larger doses (~ 1000 μg) should first be taken in order to replenish the body stores. Thereafter, maintenance dosages can be used to cover the daily requirement. To this end, the vitamin should always be overdosed, since not all ingested vitamin B12 is absorbed. The recommended >>basic dose<< to meet the single dose B12 requirement is 250 μg for normal use, and 500 μg for a small increase in demand.
In the case of an absorption disorder – as well as taking B12 supplements, the search for the root of the problem is the major part of treatment. Until this is found, B12 should be taken in fairly high doses. When taken orally, B12 tablets or capsules contain about 500-1000 μg/day.
In the case of an increased need and for older people – 500 to 1000 μg are also recommended as a daily dose.
More information: Vitamin B12 Dosages.
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