Vitamin B12 is required for vital physiological functions, such as the development, myelination, and operation of the central nervous system, DNA synthesis, and red blood cell formation. Although B12 is found in various foods, insufficiency and deficiency are still relatively common.
Evidence indicates that up to 6% of adults below the age of 60 have vitamin B12 deficiency. That rate jumps to 20% in those over the age of 60. Furthermore, subclinical deficiency, defined as inadequate levels without overt signs or symptoms, might affect up to 26% of the general population. Since B12 deficiency is often overlooked or misdiagnosed, understanding this crucial nutrient can reduce your risk of developing side effects that, at times, could be irreversible.
Vitamin B12 Overview
Vitamin B12, or cobalamin, is an essential water-soluble nutrient everybody needs for proper functioning. B12 is found naturally in animal products such as fish, meat, poultry, eggs, and dairy. It can also be found in fortified grain products such as cereal, bread, and nutritional yeast.
B12 found in food is bound to protein and must be released before it can be absorbed and utilized. B12 can be released from its food matrix through the actions of several enzymes and acids throughout the gastrointestinal tract (GI) tract. Once B12 reaches the duodenum, it combines with intrinsic factor, a transport and delivery binding protein secreted by the stomach’s parietal cells. B12 and intrinsic factor joined can be absorbed by the gut.
Once absorbed, vitamin B12 is an essential cofactor for two vital enzymes in human metabolism. First, vitamin B12 is a cofactor for the enzyme methionine synthase, which is used in converting homocysteine to methionine and is required for DNA synthesis. Therefore, B12 deficiency may lead to elevated homocysteine levels, impaired DNA synthesis, macrocytic anemia, and other symptoms such as fatigue.
Second, vitamin B12 is a cofactor for the enzyme methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA and is required for myelin synthesis. Consequently, with B12 deficiency, methylmalonic acid (MMA) levels may accumulate, contributing to myelin damage, neurologic deficits, neuropathy, and ataxia.
The Recommended Dietary Allowance (RDA) for vitamin B12 is 2.4 mcg for men and women over 18, which increases to 2.6 mcg and 2.8 mcg in those who are pregnant or lactating, respectively. Deficiency can occur if vitamin B12 needs are unmet due to insufficient dietary intake or a situation in which B12 is not absorbed or utilized effectively.
Vitamin B12 deficiency can cause physical (fatigue, megaloblastic anemia, loss of hunger, etc.), psychological (depression, irritability, etc.), and neurological (numbness and tingling, cognitive disruption, etc.) problems if left untreated. Symptoms often develop slowly over the years and worsen if not corrected. The prognosis for people with vitamin B12 deficiency depends on how early it is discovered and treated. B12 treatment can include oral medication, intramuscular injections, nasal gels, or nasal sprays and may vary based on the cause of B12 deficiency.
Neurological Symptoms of B12 Deficiency
While most side effects of B12 deficiency can be reversed with nutrient correction, evidence indicates that some neurological effects, primarily caused by the disturbance of myelin synthesis and nervous system demyelination, can become permanent.
Therefore, it’s crucial to detect and treat suboptimal B12 levels before lasting effects occur. Some of the more common but often subtle neuropsychiatric manifestations related to vitamin B12 deficiency include peripheral neuropathy, dementia or cognitive impairment, and neuropsychiatric abnormalities.
Peripheral neuropathy refers to conditions that involve damage to the peripheral nervous system, which sends signals between the central nervous system (brain and spinal cord) and the rest of the body. According to the Mayo Clinic, signs and symptoms of peripheral neuropathy might include (1) gradual onset of numbness, prickling, or tingling of the feet and hands (paresthesia), (2) sharp, jabbing, throbbing, or burning pain, (3) extreme sensitivity to touch or during activities that shouldn’t cause pain, (4) lack of coordination and falling (ataxia), (5) muscle weakness, (6) or paralysis.
Related to cognitive function, research has found a correlation between dementia, cognitive impairment, and B12 status. A review of 43 studies shows that low vitamin B12 levels correlate with increased neurodegenerative disease and cognitive impairment.
Signs and symptoms of cognitive impairment result when once-healthy neurons in the brain stop working effectively. Some common signs include memory loss, confusion, difficulty speaking or expressing thoughts, getting lost in familiar places, taking longer to complete routine daily tasks, and losing interest in normal daily activities or events. Although correlation does not equal causation, available data suggest that preventing vitamin B12 deficiency may afford protection from neurological deterioration and that some, but not all, cognitive impairments respond to B12 therapy.
Other neuropsychiatric abnormalities associated with vitamin B12 deficiency include depression, anxiety, apathy, agitation, insomnia, and impaired concentration. Furthermore, while hematological manifestations, such as anemia, are considered classical presentations of B12 deficiency, multiple studies have reported that neuropsychiatric manifestations could be the initial, and sometimes a sole, manifestation of B12 inadequacy.
Are You at Risk for a B12 Deficiency?
While vitamin B12 deficiency with classic hematologic and neurologic signs and symptoms is less common, low vitamin B12 status (200-300 pg/mL) without obvious symptoms affects nearly 40% of people in Western populations. You may be at higher risk for vitamin B12 deficiency if you:
Lack vitamin B12 in your diet: People who do not consume enough foods that contain vitamin B12 can develop a deficiency. Those who follow a vegan or vegetarian lifestyle must take particular care to include foods fortified with B12 in their diet since B12 is naturally found in animal products.
Have had gastrointestinal surgery: The absorption of vitamin B12 is mainly dependent on a healthy gastrointestinal tract. People with gastrointestinal surgery, such as gastric bypass, can limit their ability to digest and absorb vitamin B12. Intrinsic factor is produced by the parietal cells of the stomach. Therefore, if gastric bypass surgery forces a new pathway that bypasses the site of intrinsic factor production, B12 deficiency will likely occur.
Have conditions that interfere with nutrient absorption: Individuals with GI conditions which cause damage or inflammation to the GI tract may inhibit proper nutrient absorption and utilization and are at higher risk for vitamin B12 deficiency. Therefore, those with conditions like gastritis, Chron’s, Celiac, or IBS may be unable to absorb and use B12 efficiently, even if they consume it in adequate amounts.
Are taking certain medications: Certain drugs such as metformin (for diabetes management), proton pump inhibitors (used to treat heartburn), histamine H2 blockers (to reduce acidity in your stomach), and oral birth control pills (oral contraceptives) may increase the risk for vitamin B12 deficiency.
Are older than 60: As people age, the risk for vitamin B12 deficiency increases. This can be due to several reasons, from increased utilization of medications, increased incidence of Helicobacter pylori infection, increased gastric dysfunction, decreased production of intrinsic factor and hydrochloric acid, and reduced food intake.
Have pernicious anemia: People with this rare autoimmune condition produce antibodies to intrinsic factor. These antibodies bind to and inhibit the effects of intrinsic factor, limiting B12 absorption in the gut. Therefore, they are highly likely to experience vitamin B12 deficiency, even if adequate amounts are consumed in the diet.
Vitamin B12 Testing
Diagnosing B12 deficiency early on can be challenging since symptoms are often subtle, and possibly not present at all. For those concerned their B12 levels might be low, B12 testing is the most reliable way to determine so. Common diagnostic biomarkers for B12 status include serum or plasma vitamin B12, homocysteine, and methylmalonic acid (MMA).
Serum (or plasma) B12: When using serum (or plasma) vitamin B12 concentrations to determine nutrient status, serum B12 >300 pg/mL is considered normal, B12 between 200-300 pg/mL is considered borderline, and those with B12 <200 pg/mL are considered deficient. However, serum B12 levels may be unreliable, as one study found that measuring serum B12 only identified true deficiency in 22% of cases. The discrepancy between serum vitamin B12 levels and status is likely twofold. First, most circulating B12 is bound to other proteins and not bioavailable. Additionally, B12 can be stored in the liver, masking B12 deficiency for several years. Therefore, B12 levels in the blood don’t always reflect true B12 status.
Plasma total homocysteine levels: Plasma homocysteine levels can accumulate during B12 deficiency because of the diminished activity of methionine synthase. The normal range of total homocysteine in human plasma is 5-15 micromol/L, and values >13 micromol/L may be considered elevated and indicate insufficient B12 status. While using total homocysteine levels is a sensitive indicator of vitamin B12 deficiency, it is not specific. Total homocysteine levels can also be elevated with other conditions, such as deficiencies in folate, riboflavin, and vitamin B6, as well as with conditions like hypothyroidism or kidney disease.
Methylmalonic acid (MMA): MMA accumulates with vitamin B12 deficiency due to the diminished activity of methylmalonyl-CoA mutase. Although MMA levels can also be elevated with kidney dysfunction, elevated serum or urinary MMA is the most specific indicator of vitamin B12 deficiency, and many regard it as the most accurate marker. Although historically, MMA was considered expensive to measure, that has changed more recently with the use of urinary MMA (uMMA) testing. Studies have found that fasting uMMA concentrations corrected for creatinine (to rule out kidney dysfunction) are highly linearly correlated with serum MMA samples and have high sensitivity and specificity for subnormal B12 concentrations. When using uMMA to measure B12 status, levels below 2.0 mmol/mol creatinine are considered optimal. If higher than 3.8 mmol/mol creatinine, B12 status is likely very low and should be discussed with a trusted healthcare provider.
Vitamin B12 is an indispensable nutrient required for normal physiological functioning. Although it is found in a variety of foods, subclinical deficiencies still affect about a quarter of the Western population. B12 deficiency can cause various symptoms, including fatigue, depression, difficulty concentrating, paresthesia in hands and feet, and impaired coordination.
Unfortunately, if left untreated, some of the neurological symptoms of vitamin B12 deficiency can become irreversible. If you are concerned about your B12 levels, testing your B12 status regularly can help drive healthcare decisions and symptom correction. Currently, urinary MMA (uMMA) testing is a sensitive, specific, and cost-effective way to determine B12 status. If your B12 levels are low, work with a trusted healthcare provider to determine the cause so that proper treatment can be provided. To read more about B12 treatment options, check out the article: How to choose a B12 supplement.