Vitamin B12, or cobalamin, is a water-soluble nutrient obtained primarily from animal products. It is necessary for processes such as DNA synthesis, red blood cell formation, and maintaining a healthy nervous system. A deficiency occurs when the body does not ingest enough B12 or cannot properly absorb or utilize the amount it takes in. This shortage can lead to symptoms including fatigue, neurological problems, and megaloblastic anemia. The cause of B12 deficiency is complex, involving rare, severe inherited disorders, common genetic variations, and acquired environmental factors.
Inherited Disorders Affecting B12 Absorption and Use
Rare, severe inherited metabolic disorders follow a Mendelian pattern of inheritance and represent a direct genetic cause of B12 deficiency. These conditions are typically identified early in life and result from single-gene defects that severely impair the body’s B12 handling. One such group involves defects in the proteins required to absorb B12 from the gut.
Imerslund-Gräsbeck syndrome (IGS) is an example, caused by mutations in the $CUBN$ or $AMN$ genes. These genes encode components of the receptor complex responsible for absorbing the B12-intrinsic factor complex in the small intestine. A congenital form of pernicious anemia also exists, where a genetic defect prevents the stomach from producing intrinsic factor, the protein required to bind to B12 for absorption.
Another category affects the transport and intracellular use of B12 after absorption. Transcobalamin II deficiency is a rare disorder where the protein transporting B12 to the body’s cells is dysfunctional, limiting the vitamin’s availability for cellular metabolism. Defects in genes like $MMACHC$ (causing $cblC$ disorder) prevent the cell from converting B12 into its active forms, causing a functional deficiency.
Common Acquired Causes of B12 Deficiency
Most B12 deficiency cases are acquired through environmental, autoimmune, and lifestyle factors. Dietary inadequacy is a straightforward cause, especially for individuals following a vegan or strict vegetarian diet, as B12 is found almost exclusively in animal products. Since the liver can store B12 reserves for two to five years, a dietary deficiency can take significant time to develop.
The most common cause in adults is pernicious anemia, an autoimmune condition. This disorder involves the immune system attacking the parietal cells in the stomach that produce intrinsic factor, leading to a loss of B12 absorption capacity. Gastrointestinal issues also contribute, as surgical procedures like gastric bypass or the removal of the terminal ileum reduce the physical sites where B12 absorption occurs. Certain medications, including metformin and proton pump inhibitors (PPIs), can also interfere with B12 release from food and subsequent absorption.
Genetic Susceptibility and Common Risk Factors
Common variations in multiple genes can increase a person’s susceptibility to developing B12 deficiency when combined with specific lifestyle or environmental factors. These variations are known as single nucleotide polymorphisms (SNPs) and affect the efficiency of B12 absorption and metabolism without causing severe deficiency outright.
One well-studied example is the $FUT2$ gene, which produces a protein that influences the gut microbiome and subsequent B12 absorption. Individuals carrying certain variants of the $FUT2$ gene show a lower ability to absorb B12 and are at a heightened risk of deficiency, especially if they follow a vegetarian diet.
Another gene, $MTHFR$, is involved in the one-carbon metabolism cycle, where B12 acts as a cofactor to convert homocysteine into methionine. Variations in $MTHFR$, such as the c.677C>T polymorphism, can reduce the enzyme’s activity. This increases the body’s demand for the active form of B12, meaning a person with an $MTHFR$ variant may be more likely to experience symptoms of functional B12 deficiency.
Tailoring Diagnosis and Management Based on Cause
The underlying cause of B12 deficiency dictates the most effective long-term treatment strategy. For rare inherited disorders where the body cannot absorb or utilize B12, high-dose parenteral (intramuscular) injections are mandatory and must be maintained for life, often at more frequent intervals than for other causes. This is because the defect in the transport or utilization pathway cannot be overcome by simply increasing the oral dose.
In cases of acquired malabsorption, such as pernicious anemia or post-gastric surgery, injections are the standard of care for maintenance, usually given every two to three months for life. Conversely, if the deficiency is solely due to dietary inadequacy, a high-dose oral or sublingual supplement may be sufficient to replenish stores and maintain healthy levels. Genetic testing can confirm rare inherited disorders or assess a person’s polygenic risk, providing a personalized approach to prophylactic supplementation and informing individuals of their elevated risk.