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 [R]:

  • Producing red blood cells (hematopoiesis) [R, R]
  • Maintaining brain and nervous system health [R, R, R]
  • Creating, copying, and repairing DNA [R, R, R]

Since your body cannot produce this critical vitamin, you need to obtain enough of it from your diet. The richest and most common sources of vitamin B12 are animal products such as meat, fish, and dairy [R, R].

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 indicate a very long-term shortage [R].

You are at a higher risk of B12 shortage if you are:

  • Vegan or vegetarian [R, R, R]
  • Pregnant or breastfeeding [R, R]
  • A heavy alcohol drinker [R, R]
  • Obese [R, R, R]
  • Suffering from a gut disorder that reduces your ability to absorb dietary B12 (such as Crohn’s disease) [R, R, R]
  • Older, as the gut becomes less efficient at absorbing nutrients with age [R, R, R]
  • Infected with HIV/AIDS [R, R]

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 [R, R]. 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 [R].

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  R, R, R, R].

Vitamin B12 normally breaks down 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 [R].

Neither active vitamin B12 nor MMA are reliable in people with damaged kidneys [R, R].

Normal Range

The normal range for vitamin B12 (total) is between 200 – 900 ng/L (nanograms per liter), 200 – 900 pg/mL (picograms per milliliter), or 148 – 644 pmol/L (picomoles per liter).

The normal range for active vitamin B12 (holoTC) is around 20 – 134 pmol/L (picomoles per liter), but varies depending on the research and laboratory.

Low Levels of Vitamin B12

Causes

B12 deficiency may be caused by:

  • An B12-insufficient diet (such as a strict vegan diet) [R, R]
  • Pregnancy and breastfeeding (as essential nutrients are redirected to the developing fetus/baby) [R, R, R, R]
  • Gastric bypass surgery [R]

More rarely, B12 deficiency can be caused by chronic conditions such as:

  • Type-2 diabetes [R]
  • Helicobacter pylori infection [R, R, R]
  • Inflammatory Bowel Disease (IBD) [R, R, R]
  • Celiac disease [R, R]
  • Hypothyroidism and autoimmune thyroid disease [R, R, R, R, R]
  • Chronic inflammation of the pancreas (pancreatitis) [R]
  • Pernicious anemia, an autoimmune disease [R]
  • Multiple myeloma (a rare cancer that affects the bone marrow) [R, R]

Some drugs can decrease B12 levels, including:

  • Aspirin [R]
  • Drugs for acid reflux, which reduce stomach acid (such as prilosec, proton pump inhibitors, and H2 blockers) [R, R]
  • Diabetes medications (such as metformin) [R, R, R, R]
  • Anti-seizure medications [R]
  • Colchicine, used to treat gout [R]
  • Birth control pills [R]

Symptoms

Mild, subclinical deficiency affects between 2.5% and 26% of the general population (depending on the cut-off) [R].

Early symptoms of vitamin B12 deficiency include [R, R, R, R, R, R]:

  • Irritability
  • Fatigue
  • Loss of appetite
  • Dizziness
  • Twitchiness / involuntary movements
  • Muscle weakness
  • Headaches
  • Diarrhea

In more severe cases, B12 deficiency causes [R, R, R]:

  • 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) Low Vitamin B12 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) [R].

In diabetic vegetarians, those with higher B12 levels had higher antioxidant enzyme activity (catalase) [R].

2) Low Vitamin B12 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 [R, R, R].

3) Low Vitamin B12 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. Each 5 umol/L homocysteine increase above 10 umol/L in the blood is linked with a 20% increase in heart disease risk [R, R, R].

4) Low Vitamin B12 Increases 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 2k 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 9k people [R, R, R].

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 >3.5k people monitored over 7-12 years, each additional 10 ug of dietary vitamin B12 were associated with 2% lower odds of depression [R].

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 [R].

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)[R].

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 [R, R].

5) Low Vitamin B12 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 [R].

In 2.7k people monitored for over 10 years, a double increase in active B12 (holoTC, from 50 to 100 pmol/L) was linked with 30% slower rate of cognitive decline. A doubling in MMA (from 0.25 to 0.50 umol/L), indicating lower B12, was associated with more 50% more rapid cognitive decline [R].

B12 deficiency can temporarily cause dementia in the elderly. Since these changes are reversible in the long-term, it’s best if the deficiency is discovered early [R].

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 [R].

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 [R, R, R].

6) Low Vitamin B12 Can Cause Nerve Damage and Nerve Pain

vitamin B12 deficiency can cause impaired motor function (e.g. gait disturbances) and neuropathy or nerve pain. In over 2k elderly people, poor B12 status was associated with worse sensory and motor nerve function and decreased sensitivity to light and touch [R, R+, R, R].

In 90 patients with early type 2 diabetes, those on metformin had lower B12 levels and were more prone to nerve pain (peripheral neuropathy) [R].

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 [R].

7) Low Vitamin B12 May Increase the Risk of Osteoporosis

In a study of 2.5k adults, those with low B12 levels had lower bone mineral density [R].

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 [R].

8) Low Vitamin B12 Is Associated With Higher Cancer Risk

Vitamin B12-deficiency may increase the risk of cancer by impairing DNA synthesis and repair [R, R].

In a large study of smokers (almost 30k), 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 [R].

However, rather than being a contributing factor, in this case low vitamin B12 may a consequence of stomach inflammation, which precedes stomach cancer and decreases B12 absorption [R].

Ways To Increase Vitamin B12

1) Get More Vitamin B12 in Your Diet

Increase your dietary intake of B12. Common sources of B12 include animal products such as red meat, fish, poultry, yogurt, and milk. Vitamin B12 is poorly absorbed from eggs [R, R, R].

A couple of studies suggest that algae (such as chlorella) may also be a viable source of B12 [R].

2) Avoid Alcohol

Alcohol consumption can reduce B12. Avoiding it will help with low B12 levels [R, R, R].

3) Avoid Smoking

Smoking (nicotine) can also lower B12 levels and should be avoided [R].

4) Alternative Drugs

In women, the use of oral contraceptives has been associated with lower B12 levels. Switching to an alternative form of birth control may help [R].

Also, knowing that your drugs likely decrease B12 levels can help if you take action and supplement accordingly. Metformin in diabetics is a good example [R].

5) Supplements

B-family vitamins are widely and commonly available over the counter as nutritional supplements.

Natural or biologically active forms (hydroxocobalamin, methylcobalamin, and adenosylcobalamin) are a better option than the synthetic cyanocobalamin.

Calcium can improve B12 absorption in diabetic patients taking metformin [R]

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 [R].

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) [R, R, R]
  • Hypereosinophilic syndrome, a blood disorder that occurs when you have high eosinophils [R]
  • Blood-related cancers (some forms of leukemia and polycythemia vera) [R, R]
  • Metastatic cancer [R]

High B12 levels can also sometimes be caused by taking anti-seizure medications [R].

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.

However, a significant number of emerging studies has linked high B12 blood levels and B12 supplementation to higher cancer risk and mortality.

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) High Vitamin B12 Levels are Associated with Higher Risk of Cancer

In a study of over 333k 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 [R].

Similarly, in over 476k people without cancer or vitamin B12 prescriptions (injections), high B12 levels (> 1,200 pmol/L) were linked to a higher incidence of cancer [R].

A large-scale study looked at 5k 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 [R].

Two meta-analyses of 6 and 7 studies, respectively, linked higher vitamin B12 levels to a small increase in the risk of prostate cancer [R, R].

2) High Vitamin B12 May Increase All-Cause, Heart Disease, and Cancer Mortality

In a single study with approximately 700 people aged 85+, women with higher vitamin B12 levels had an increased risk of dying from any cause and from heart disease [R].

Several studies of hospitalized patients (over 5k in total) found a link between higher B12 levels and dying [R, R, R, R, R].

In over 25k 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 200-600 pmol/L [R].

Similarly, in two other studies, higher vitamin B12 levels were linked to shorter cancer survival time [R, R].

The mechanism behind the association of B12 levels and death rates still remains a mystery [R+].

Ways To Decrease Vitamin B12

1) Cut Back on B12 Supplements

Cut back on any vitamin B12 supplements you may be taking, including multivitamins.

2) Address Any Potential Underlying Health Issues

If your tests consistently show high levels of B12 even after you stop taking supplements, it would be wise to consult a medical professional to rule out any more serious underlying problems.

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) [R, R, R, R, R].

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 500k people, each 1ug/day increase in vitamin B12 intake increased the risk of esophageal cancer by 2% [R, R].

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% [R].

Similarly, in another meta-analysis of 17 studies and over 10k people, higher total and dietary vitamin B12 intake was associated with lower colon cancer risk [R].

Vitamin B12 Supplementation

In over 77k people, B12 supplements 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 [R].

In two studies, supplementing with folic acid + vitamin B12 increased cancer risk [R, R].

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 [R]. It’s also possible that there is no simple cause-and-effect explanation, and that both high B12 and the 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 your 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/SNPHigher vitamin B12Lower Vitamin B12
FUT2 / rs6022662A (+ 44.2 pg/mL) [R, R]
FUT2 / rs492602G ( lower risk of vitamin B12 deficiency) [R]A [R]
FUT2 / rs601338A [R]G [R]
FUT2 / rs1047781T [R]
FUT6 / rs3760776A [R]
FUT6 / rs708686T (+0.2 pmol/l) [R]
TCN1 / rs34324219A [R]
TCN1 / rs526934G [R]
TCN2 / rs1801198CC [R]
CUBN / rs1801222G [R]G [R]
CUBN / rs11254363G [R]
CUBN / rs12780845G [R]
MMACHC / rs12272669A [R]
ABCD4 / rs4619337C [R]
ABCD4 / rs3742801T [R]
CD320 / rs2336573C, T [R]
MTHFR / rs1801133T [R]
MS4A3 / rs2298585T [R]
MMAA / rs4835012C [R]
MUT / rs9473558TT[R]
MUT / rs9473555CC [R]
CLYBL / rs41281112T [R]

 

Take-Away:

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 is far from useful. Maintaining adequate dietary B12 intake (instead of supplementing), monitoring B12 levels, and addressing any underlying health issues you may have is the best strategy for reducing your overall disease risk.

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