Vitamin B12 is an essential nutrient that keeps your brain and blood cells healthy. If your diet is low in it or your gut absorption impaired, you are at risk of deficiency. This article looks into the controversial link between B12 levels and cancer, and carefully breaks down the causes, symptoms, and health effects of both low and high vitamin B12 levels.
What is Vitamin B12?
(Methyl)cobalamin, more commonly known as vitamin B12, is an essential dietary nutrient. It is crucial for:
- Producing red blood cells (hematopoiesis) [1, 2]
- Maintaining brain and nervous system health [3, 4, 5]
- Creating, copying, and repairing DNA [5, 6, 7]
Since your body cannot produce this vitamin, you need to obtain enough of it from your diet. The richest sources of vitamin B12 are animal products such as meat, fish, and dairy [8, 9].
Vitamin B12 Deficiency – Are You At Risk?
The body uses vitamin B12 very wisely, simultaneously using, recycling, and storing it. In fact, a healthy person can store up to 3 – 6 years’ worth of vitamin B12 in their liver. For this reason, vitamin B12 deficiencies are quite rare and usually result from a very long-term shortage [10].
You are at a higher risk of B12 shortage if you are:
- Vegan or vegetarian [11, 12, 13]
- Pregnant or breastfeeding [14, 15]
- A heavy alcohol drinker [16, 17]
- Obese [18, 19, 20]
- Suffering from a gut disorder that reduces your ability to absorb dietary B12 (such as Crohn’s disease) [21, 22, 23]
- Older, as the gut becomes less efficient at absorbing nutrients with age [24, 25, 22]
- Infected with HIV/AIDS [26, 27]
Total B12 vs. Active B12 and Methylmalonic Acid
Several tests can be used to determine if you are vitamin B12-deficient:
- Total vitamin B12
- Active vitamin B12, or holoTC (holotranscobalamin)
- Methylmalonic acid (MMA)
Although total vitamin B12 is the most commonly used test, these 2 additional markers may provide important insight into your B12 status in specific cases.
Active vitamin B12 makes up 6 – 20% of your total blood vitamin B12 levels [28, 29]. It has a short life and drops much faster than total vitamin B12 when your B12 supplies start running low. For this reason, some experts claim that active B12 is an earlier and more sensitive indicator of vitamin B12 deficiency [30].
However, measuring active vitamin B12 has several limitations. The lower limit is still unclear and this test may not be more accurate than total vitamin B12. In addition, it is rarely used because of its high cost and limited availability [31, 32, 28, 30].
Vitamin B12 normally breaks down methylmalonic acid (MMA), which builds up only when B12 is low. This is why MMA can be used as a functional indicator of vitamin B12 deficiency. But this test is not perfect either since it often gives false-positive results [32].
Neither active vitamin B12 nor MMA is reliable in people with damaged kidneys [33, 34].
Normal Range
The normal range for vitamin B12 (total) is between 200 – 1100 ng/L (nanograms per liter), 200 – 1100 pg/mL (picograms per milliliter), or 148 – 811 pmol/L (picomoles per liter).
The normal range for active vitamin B12 (holoTC) is around 20 – 134 pmol/L (picomoles per liter).
Levels differ slightly between labs, due to differences in techniques, equipment, and chemicals.
Low Levels of Vitamin B12
Causes
Causes listed below are commonly associated with low vitamin B12 levels. Work with your doctor or another health care professional to get an accurate diagnosis.
These can decrease vitamin B12 levels:
- An insufficient diet (such as a strict vegan diet) [35, 36]
- Pregnancy and breastfeeding. In these states, the essential vitamins and nutrients are redirected to the developing fetus/baby [37, 14, 15, 38]
- Pernicious anemia, an autoimmune disease which impairs vitamin B12 absorption in the gut [39]
- Other gut disorders that impair nutrient absorption, such as celiac disease, Crohn’s disease, or H. pylori infection [40, 41, 42, 43, 44, 45, 46, 47, 48]
- Gastric bypass surgery [39]
- Heavy drinking and alcoholism [17, 16, 49]
- Hypothyroidism or autoimmune thyroid disease [50, 51, 52, 53]
- Multiple myeloma (blood cell cancer) [54, 55]
Some common drugs can lower vitamin B12 levels, including:
- Diabetes medication (such as metformin) [56, 57, 58, 59]
- Anti-epileptic / anticonvulsant medications [60]
- Medications that reduce stomach acid (proton pump inhibitors, antacids, and H2 blockers) [56, 61]
- Contraceptives [62]
- Aspirin [63]
Symptoms
Mild, subclinical deficiency affects between 2.5% and 26% of the general population (depending on the cut-off) [64].
Early symptoms of vitamin B12 deficiency include [65, 66, 67, 68, 35, 69]:
- Irritability
- Fatigue
- Loss of appetite
- Dizziness
- Twitchiness / involuntary movements
- Muscle weakness
- Headaches
- Diarrhea
In more severe cases, B12 deficiency causes [39, 70, 71]:
- Anemia (fatigue, paleness)
- Dementia
- Mental health disturbances/psychosis
- Nerve pain
- Movement disorders (impaired balance and loss of muscle control)
Health Effects of Low Levels
1) Increases Oxidative Stress
In one study, 51 vitamin B12-deficient people had lower levels of the master antioxidant glutathione and reduced total antioxidant capacity, compared to 53 non-deficient people. Reflecting poor antioxidant defense, those who were B12-deficient also had higher levels of a marker of oxidative stress (malondialdehyde) [72].
In diabetic vegetarians, those with higher B12 levels had higher antioxidant enzyme activity (catalase) [73].
2) Causes Anemia
The bone marrow needs vitamin B12 to produce healthy red blood cells. B12 deficiency causes megaloblastic (macrocytic) anemia, which results in very large, oddly-shaped, immature red blood cells that can’t enter the bloodstream [74, 75, 70].
3) Increases the Risk of Heart Disease
Vitamin B12 is needed to break down homocysteine, a proven risk factor for heart disease. A lack of vitamin B12 will raise homocysteine levels [76, 77, 78].
4) May Increase the Risk of Depression
A lack of vitamin B12 may trigger mood imbalances and even depression. Some studies suggest that this link may hold true only in women.
In meta-analyses of studies with almost 2,000 people, low B12 levels were linked with depression among women but not men. Among 700 disabled women over 65, those deficient in vitamin B12 were 2X more likely to be severely depressed. Women who consumed more vitamin B12 had lower odds of being depressed in a study of over 9,000 people [79, 80, 81].
According to other studies, the potential benefits of B12 supplementation may extend to all people suffering from depression or those at an increased risk, regardless of sex. For example, in > 3,500 people monitored over 7 – 12 years, each additional 10 μg of dietary vitamin B12 was associated with 2% lower odds of depression [82].
In one study of 73 people with depression and low-normal B12 levels (190 – 300 pg/ml), all who received vitamin B12 as an add-on to antidepressants experienced improved symptoms after 3 months. In comparison, only 69% of those who took antidepressants alone improved [83].
Long-term vitamin B12 and folate use (several weeks to years) may prevent depression from coming back in those in recovery while also preventing depression in those at risk. Short-term supplementation (up to a few weeks), however, did not improve symptoms in depressed people on antidepressants (meta-analysis of 11 clinical trials) [84].
A possible explanation for the link between vitamin B12 and depression is that vitamin B12 is required for the production of SAM-e (S-adenosylmethionine). SAM-e is found naturally in the body, has antidepressant properties, and helps make mood-balancing neurotransmitters like serotonin [85, 86].
5) May Increase the Risk of Cognitive Decline and Dementia
In 100 people with mild cognitive impairment, those with low-normal B12 (< 300 pmol/L) had poorer learning abilities and memory than those with high-normal levels. Brain imaging (MRI) revealed that those with low-normal B12 levels had more damage to the hippocampus, the brain’s chief hub for learning and memory [87].
In 2,700 people monitored for over 10 years, a double increase in active B12 (holoTC, from 50 to 100 pmol/L) was linked with a 30% slower rate of cognitive decline. A doubling in MMA (from 0.25 to 0.50 μmol/L), indicating lower B12, was associated with a 50% more rapid cognitive decline [88].
B12 deficiency can temporarily cause dementia in the elderly. Since these changes are not always reversible in the long-term, it’s best if the deficiency is discovered early [89].
In a study of 181 demented adults, 25% were vitamin B12-deficient. Despite B12 supplementation, 85% still progressively worsened. Those who at least partially improved had mild dementia for less than 2 years [90].
Two studies found a link between low vitamin B12 and Alzheimer’s disease. However, many other studies have failed to find a link between vitamin B12 and cognitive decline, dementia, or Alzheimer’s disease [91, 92, 93].
6) Can Cause Nerve Damage and Nerve Pain
Vitamin B12 deficiency can impair motor function (e.g. gait disturbances) and cause neuropathy or nerve pain. In over 2,000 elderly people, poor B12 status was associated with worse sensory and motor nerve function and decreased sensitivity to light and touch [94, 95+, 96, 97].
In 90 patients with early type 2 diabetes, those on metformin had lower B12 levels and were more prone to nerve pain (peripheral neuropathy) [98].
In a study of 78 people with nerve pain, 83% improved with vitamin B12 treatment. Supplementation helped even when the nerve pain was caused by issues other than vitamin B12 deficiency [99].
7) May Increase the Risk of Osteoporosis
In a study of 2,500 adults, those with low B12 levels had lower bone mineral density [100].
In a study of 194 frail elderly, osteoporosis occurred more often among women with marginal or deficient B12 status. No association was found in men [101].
8) Associated With Stomach Cancer
Vitamin B12-deficiency may increase the risk of cancer by impairing DNA synthesis and repair [102, 103].
In a large study of smokers (almost 30,000 people), lower initial vitamin B12 levels were associated with a 5.8-fold higher risk of getting stomach cancer (gastric carcinoma). The association remained even >10 years after blood collection. Low-normal values were linked to a 3-fold increased risk [104].
However, rather than being a contributing factor, in this case, low vitamin B12 may be a consequence of stomach inflammation, which precedes stomach cancer and decreases B12 absorption [104].
Ways To Increase Vitamin B12
The most important thing is to work with your doctor to find out what’s causing your low vitamin B12 levels and to treat any underlying conditions.
Discuss the additional lifestyle changes listed below with your doctor. None of these strategies should ever be done in place of what your doctor recommends or prescribes!
1) Get More Vitamin B12 in Your Diet
If your diet is low in vitamin B12, try and boost your dietary B12 intake.
Common sources of B12 include animal products such as red meat, fish, poultry, yogurt, and milk. Vitamin B12 is poorly absorbed from eggs [8, 9, 105].
A couple of studies suggest that algae (such as chlorella) may also be a viable source of B12 [106].
However, keep in mind that vitamin B12 levels are often low due to underlying conditions, such as impaired nutrient absorption due to gut-associated disease. In these cases, a simple dietary change won’t help increase B12 levels.
2) Avoid Alcohol
Alcohol consumption can reduce B12. Avoiding it will prevent further decreases in B12 levels [17, 16, 49].
3) Avoid Smoking
Smoking (nicotine) can also lower B12 levels and should be avoided [57].
4) Alternative Drugs
Knowing that your drugs likely decrease B12 levels can help if you take action and supplement accordingly. Metformin in diabetics is a good example [98].
Review your medication with your doctor or another healthcare professional, and discuss alternatives for those that are decreasing your B12 levels.
5) Supplements
If you’re deficient, your doctor will likely prescribe vitamin B12 supplements or vitamin B12 shots [107, 108].
Natural or biologically active forms (hydroxocobalamin, methylcobalamin, and adenosylcobalamin) are a better option than synthetic cyanocobalamin.
A study suggests that calcium supplements may improve B12 absorption in diabetics taking metformin [109].
High Levels of Vitamin B12
Causes
Blood tests for B12 may show elevated levels in people who are (or have recently been) taking vitamin B supplements [110]. This is usually not of concern as vitamin B12 is not considered toxic.
High levels of vitamin B12 when not supplementing are important because they may indicate an underlying health condition, such as:
- Liver disease (e.g. cirrhosis or hepatitis) [111, 112, 113, 114]
- Diabetes [115]
- Myeloproliferative disorders (diseases of the bone marrow and blood), such as hypereosinophilic syndrome, polycythemia vera, or leukemia [111, 116]
- Kidney failure [117]
- Cancer [118]
Causes listed above are commonly associated with high vitamin B12 levels. Work with your doctor or another health care professional to get an accurate diagnosis.
In some cases, despite being elevated the body can’t use vitamin B12 effectively, in which case people can experience functional vitamin B12 deficiency [118].
Symptoms
High vitamin B12 levels are not associated with any particular symptoms.
Health Effects of High Levels
It was long thought that high vitamin B12 levels weren’t harmful, but a significant number of emerging studies have linked high B12 blood levels and B12 supplementation to higher cancer risk and mortality.
However, much like the studies linking folic acid to cancer, the studies below are not conclusive. Many point only to an association, not causation. More large-scale and well-designed research is needed.
1) Associated with Higher Risk of Cancer
In a study of over 333,000 people without cancer, the risk of cancer increased with higher B12 levels and was highest during the first year of follow-up. The risk was particularly elevated for blood-, smoking-, and alcohol-related cancers [119].
Similarly, in over 476,000 people without cancer or vitamin B12 prescriptions (injections), high B12 levels (> 1,200 pmol/L) were linked to a higher incidence of cancer [120].
A large-scale study looked at 5,000 lung cancer-control pairs and reviewed genetic data of 29k cancer patients and 56k healthy people. Higher blood vitamin B12 was associated with higher lung cancer risk. In addition, genetic variants linked to higher vitamin B12 levels were also linked with higher overall lung cancer risk [121].
Two meta-analyses of 6 and 7 studies, respectively, linked higher vitamin B12 levels to a small increase in the risk of prostate cancer [122, 123].
2) Associated with All-Cause, Heart Disease, and Cancer Mortality
In a single study with approximately 700 people aged 85+, women (but not men) with initially higher vitamin B12 levels had an increased risk of dying from any cause and from heart disease [124].
Several studies of hospitalized patients (over 5,000 in total) found a link between higher B12 levels and mortality [125, 126, 127, 128, 129].
In over 25,000 cancer patients, those with high B12 levels had lower chances of surviving. Patients with levels of > 600 pmol/L were 2 times less likely to survive than those with levels within 200 – 600 pmol/L [130].
Similarly, in two other studies, higher vitamin B12 levels were linked to shorter cancer survival time [131, 132].
The mechanism behind the association of B12 levels and death rates still remains a mystery [129].
Decreasing Vitamin B12
If your tests consistently show elevated levels of B12 even after stopping supplement use, work with your doctor to find out what’s causing your high B12 levels and to treat any underlying conditions.
Vitamin B12 and Cancer
Vitamin B12 Blood Levels
In several large observational studies, higher blood B12 levels were linked to an increased risk of cancer (described in more detail above) [119, 120, 121, 122, 123].
Blood vitamin B12 levels don’t necessarily reflect dietary intake and may result from issues such as liver damage.
Vitamin B12 Intake
Meta-analyses of 45 studies suggest an increased risk of esophageal cancer with higher vitamin B12 intake. In over 500,000 people, each 1ug/day increase in vitamin B12 intake increased the risk of esophageal cancer by 2% [133, 134].
However, two other studies show the opposite. In a meta-analysis of studies of over 1.2 million people, every 10 μg/d increase in vitamin B12 intake lowered the risk of pancreatic cancer by 27% [135].
Similarly, in another meta-analysis of 17 studies and over 10,000 people, higher total and dietary vitamin B12 intake were associated with lower colon cancer risk [136].
Vitamin B12 Supplementation
In over 77k people, B12 supplement use (but not multivitamins) was associated with a 40% increase in lung cancer risk among men, but not women. The risk was even higher among men who smoked [137].
In two studies (over 9,000 people), supplementing with folic acid + vitamin B12 increased cancer risk [138, 139].
Bottom Line
Higher blood levels of vitamin B12 have been linked to an increased risk of various cancers.
The impact of dietary B12 levels is less conclusive. Some studies suggest that higher dietary B12 is beneficial.
B12 supplements appear to have a negative effect, especially in men who smoke. Multivitamins seem to work better than B12 supplements in isolation. It’s possible that the effects of B12 are modified by other vitamins and dietary factors.
The mechanism linking B12 and cancer is still unknown. It’s possible that B12 affects methylation, and, therefore, the activity of certain cancer-related genes [140]. It’s also possible that there is no simple cause-and-effect explanation, and that both high B12 and cancer are caused by another underlying factor.
The takeaway:
- A balanced diet is better than supplements
- If supplementing, do so in moderation
- Avoid supplements if smoking (especially men)
Vitamin B12 Genetics
Many different genes impact vitamin B12 levels. They code enzymes/proteins that:
- Help create a more hospitable environment for gut flora and the “good” gut bacteria (e.g. FUT2). The gut environment impacts vitamin B12 absorption, and thereby vitamin B12 blood levels.
- Help transport vitamin B12 into cells (e.g. TCN1, TCN2, CUBN, CD320)
- Help transport B12 within the cell to the mitochondria (e.g. MMAA)
- Break down vitamin B12 (e.g. MMACHC, ABCD4, CLYBL)
| Gene/SNP | Higher vitamin B12 | Lower Vitamin B12 |
| FUT2 / rs6022662 | A (+ 44.2 pg/mL) [141, 142] | |
| FUT2 / rs492602 | G ( lower risk of vitamin B12 deficiency) [142] | A [142] |
| FUT2 / rs601338 | A [142] | G [142] |
| FUT2 / rs1047781 | T [142] | |
| FUT6 / rs3760776 | A [142] | |
| FUT6 / rs708686 | T (+0.2 pmol/l) [143] | |
| TCN1 / rs34324219 | A [144] | |
| TCN1 / rs526934 | G [142] | |
| TCN2 / rs1801198 | CC [142] | |
| CUBN / rs1801222 | G [142] | G [142] |
| CUBN / rs11254363 | G [145] | |
| CUBN / rs12780845 | G [142] | |
| MMACHC / rs12272669 | A [142] | |
| ABCD4 / rs4619337 | C [142] | |
| ABCD4 / rs3742801 | T [142] | |
| CD320 / rs2336573 | C, T [142] | |
| MTHFR / rs1801133 | T [142] | |
| MS4A3 / rs2298585 | T [142] | |
| MMAA / rs4835012 | C [142] | |
| MUT / rs9473558 | TT[142] | |
| MUT / rs9473555 | CC [142] | |
| CLYBL / rs41281112 | T [142] |
Takeaway
Vitamin B12 is a crucial nutrient, needed in balanced levels to keep your blood cells, brain, heart, and genetic material healthy. Since the body cannot make it, you need to ensure a proper diet with B12-rich foods, such as meat and fish. Plant-based diets are very low in vitamin B12. Gut issues and certain prescription medications can also impair B12 absorption and lower blood levels of this vitamin. The total vitamin B12 blood test is the most common way of assessing B12 levels. Two other tests can also provide additional useful information, although each has limitations. These include active vitamin B12 (or holoTC) and Methylmalonic acid (MMA). Although low vitamin B12 has many negative health consequences, high B12 has also been linked to health risks. These remain more controversial – such as the link between high B12 and increased cancer risk – but most research suggests over-supplementing should be avoided. Maintaining adequate dietary B12 intake (instead of supplementing), monitoring B12 levels, and addressing any underlying health issues you may have are the best strategies for reducing your overall disease risk.
