Vitamin B12 depletion occurs when the body's stores of this essential nutrient become insufficient to support normal physiological functions. Understanding what causes B12 depletion is crucial for preventing potentially serious haematological and neurological complications. Common causes include dietary insufficiency, particularly in those following plant-based diets, malabsorption due to gastrointestinal conditions or surgery, autoimmune disorders such as pernicious anaemia, and long-term use of certain medications including proton pump inhibitors and metformin. Age-related changes in gastric acid production also increase risk. Early recognition and appropriate management are essential, as neurological damage from B12 deficiency can become irreversible if treatment is delayed.

What Is Vitamin B12 and Why Is It Essential?

Vitamin B12, also known as cobalamin, is a water-soluble vitamin that plays a crucial role in numerous physiological processes throughout the body. This essential micronutrient cannot be synthesised by the human body and must be obtained through dietary sources or supplementation.

B12 is fundamental for DNA synthesis, which is essential for cell division and growth. It works alongside folate in the production of red blood cells in the bone marrow, making it vital for preventing megaloblastic anaemia—a condition characterised by abnormally large, immature red blood cells. The vitamin is also critical for maintaining the integrity of the myelin sheath, the protective coating surrounding nerve fibres that enables efficient transmission of nerve impulses throughout the nervous system.

Additionally, vitamin B12 participates in the metabolism of homocysteine, an amino acid that, when elevated, is associated with increased cardiovascular risk. The vitamin acts as a cofactor for methionine synthase, an enzyme that converts homocysteine to methionine, thereby helping to maintain healthy homocysteine levels. B12 is also essential for the enzyme methylmalonyl-CoA mutase, which explains why methylmalonic acid (MMA) levels rise in B12 deficiency and can be used as a functional marker of deficiency status.

The body stores vitamin B12 primarily in the liver, with reserves typically sufficient to last several years. However, once these stores become depleted—whether through inadequate intake, malabsorption, or increased demand—deficiency can develop gradually. The consequences of B12 depletion can be significant, affecting haematological, neurological, and psychiatric health. Understanding what causes B12 depletion is therefore essential for prevention, early detection, and appropriate management of deficiency states.

Common Causes of B12 Depletion

Vitamin B12 depletion arises from several common mechanisms, with dietary insufficiency being a primary cause, particularly among certain population groups. B12 is naturally found almost exclusively in animal-derived foods, including meat, fish, eggs, and dairy products. Consequently, individuals following strict vegan or vegetarian diets are at increased risk of deficiency unless they consume fortified foods or take supplements. The prevalence of B12 deficiency in those following plant-based diets varies considerably depending on supplement use, fortified food consumption, and duration of the diet.

Malabsorption represents another major cause of B12 depletion. The absorption of vitamin B12 is a complex, multi-stage process that can be disrupted at various points. In the stomach, B12 must first be released from food proteins by gastric acid and pepsin, then bound to intrinsic factor—a glycoprotein secreted by gastric parietal cells. This B12-intrinsic factor complex travels to the terminal ileum, where it binds to specific receptors and is absorbed into the bloodstream.

Disruption of any stage in this process can lead to malabsorption. Reduced gastric acid production (hypochlorhydria or achlorhydria) becomes increasingly common with age and can lead to food-bound B12 malabsorption. Age-related atrophic gastritis is a significant cause of B12 deficiency in older adults in the UK, as it impairs the release of B12 from food proteins, though it typically does not affect absorption of crystalline B12 found in supplements.

Gastrointestinal surgery can also compromise B12 absorption. Procedures such as gastrectomy (partial or total stomach removal) or bariatric surgery reduce intrinsic factor production and decrease the absorptive surface area. Similarly, surgical resection of the terminal ileum removes the primary site of B12 absorption. According to UK bariatric surgery guidelines, patients who have undergone these procedures require lifelong B12 monitoring and often supplementation.

Medical Conditions That Lead to B12 Deficiency

Several medical conditions are strongly associated with vitamin B12 depletion, with pernicious anaemia being the most well-recognised cause. This autoimmune condition involves the production of antibodies against gastric parietal cells or intrinsic factor itself, resulting in impaired intrinsic factor production and subsequent B12 malabsorption. Pernicious anaemia typically affects older adults and is more common in individuals with other autoimmune conditions, such as autoimmune thyroid disease or type 1 diabetes. Diagnosis involves testing for intrinsic factor antibodies (and sometimes parietal cell antibodies). In the UK, the condition requires lifelong treatment with intramuscular hydroxocobalamin injections as first-line therapy.

Inflammatory bowel diseases (IBD), particularly Crohn's disease affecting the terminal ileum, can significantly impair B12 absorption. Chronic inflammation damages the intestinal mucosa where B12 absorption occurs, and surgical resection of diseased bowel segments further compounds the problem. Patients with extensive ileal disease or those who have undergone ileal resection require regular monitoring of B12 levels and often need supplementation.

Coeliac disease can lead to B12 deficiency through damage to the small intestinal mucosa, though this is less common than deficiencies of other nutrients such as iron or folate. The villous atrophy characteristic of untreated coeliac disease reduces the absorptive capacity of the small intestine. Adherence to a strict gluten-free diet typically allows mucosal healing and restoration of normal B12 absorption.

Other conditions associated with B12 depletion include chronic pancreatitis (which impairs the release of B12 from food proteins), small intestinal bacterial overgrowth (SIBO), where bacteria compete for available B12, and parasitic infections such as fish tapeworm (Diphyllobothrium latum). Additionally, Helicobacter pylori infection has been associated with B12 deficiency through its effects on gastric acid secretion and chronic gastric inflammation, though the strength of this association and its clinical significance in UK practice varies between patients.

Medications That Can Deplete B12 Levels

Several commonly prescribed medications can interfere with vitamin B12 absorption or metabolism, potentially leading to depletion over time. Proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, and esomeprazole are among the most frequently implicated drugs. These medications suppress gastric acid production, which is necessary for cleaving B12 from food proteins. Long-term or high-dose PPI use has been associated with increased risk of B12 deficiency, particularly in patients with additional risk factors, though the absolute risk remains relatively modest.

H2-receptor antagonists (H2RAs) such as famotidine also reduce gastric acid secretion, though typically to a lesser degree than PPIs. The risk of B12 depletion with H2RAs appears lower than with PPIs, but prolonged use may still contribute to deficiency, especially in vulnerable populations.

Metformin, the first-line medication for type 2 diabetes, has been consistently associated with reduced B12 levels. The mechanism is thought to involve interference with calcium-dependent B12-intrinsic factor uptake in the terminal ileum, as well as alterations in small bowel motility. According to a 2022 MHRA Drug Safety Update, reduced vitamin B12 levels are a common side effect of metformin treatment. The MHRA advises healthcare professionals to check B12 levels in patients with symptoms suggestive of deficiency and to consider periodic monitoring in those at risk of reduced B12 levels, particularly patients receiving long-term treatment or those with existing risk factors.

Other medications that may affect B12 status include colchicine (used for gout), which can impair intestinal absorption, and nitrous oxide (used in anaesthesia and increasingly misused recreationally), which irreversibly inactivates B12 by oxidising the cobalt ion in its structure. Chronic nitrous oxide exposure can cause severe, rapid-onset B12 deficiency with potentially devastating neurological consequences.

Patients who suspect they have experienced an adverse drug reaction should report it to the MHRA through the Yellow Card scheme.

Recognising the Symptoms of B12 Depletion

The clinical manifestations of vitamin B12 deficiency are diverse and can develop insidiously over months to years as hepatic stores become depleted. Haematological symptoms often appear first and include fatigue, weakness, and pallor due to megaloblastic anaemia. Patients may experience shortness of breath on exertion and palpitations as the oxygen-carrying capacity of the blood diminishes. However, it is important to note that anaemia is not always present, particularly in early deficiency or when folate intake is adequate.

Neurological symptoms can be particularly concerning and may occur even in the absence of anaemia. Peripheral neuropathy typically presents with paraesthesia (pins and needles) and numbness, usually beginning in the feet and progressing proximally in a symmetrical pattern. Patients may describe sensations of walking on cotton wool or difficulty with fine motor tasks such as buttoning clothes. More severe deficiency can lead to subacute combined degeneration of the spinal cord, affecting the dorsal and lateral columns. This manifests as sensory ataxia (unsteady gait), loss of proprioception and vibration sense, and in advanced cases, spastic weakness and bladder dysfunction. This condition is a medical emergency requiring urgent treatment with intramuscular hydroxocobalamin without waiting for test results.

Neuropsychiatric manifestations are increasingly recognised and can include depression, irritability, memory impairment, and cognitive decline. In severe cases, patients may experience confusion, psychosis, or dementia-like symptoms. Glossitis (a smooth, sore, red tongue) and angular cheilitis (cracks at the corners of the mouth) are characteristic mucocutaneous features.

It is crucial to understand that neurological damage from B12 deficiency can become irreversible if treatment is delayed, even though haematological abnormalities typically resolve with supplementation. The insidious nature of symptom onset means that deficiency may be quite advanced before patients seek medical attention. Additionally, symptoms are non-specific and can be attributed to numerous other conditions, making clinical suspicion and appropriate testing essential. Importantly, folic acid should never be given alone when B12 deficiency is possible, as it may improve anaemia while allowing neurological damage to progress.

When to Seek Medical Advice About B12 Levels

Individuals should consult their GP if they experience symptoms suggestive of B12 deficiency, particularly if they have risk factors for depletion. Persistent unexplained fatigue, especially when accompanied by other symptoms such as paraesthesia, cognitive changes, or glossitis, warrants medical evaluation. It is important not to self-diagnose or commence supplementation before testing, as this can interfere with diagnostic accuracy and mask underlying conditions such as pernicious anaemia.

Certain groups should be particularly vigilant and may benefit from proactive discussion with their healthcare provider about B12 status. These include individuals following strict vegan or vegetarian diets, those over 60 years of age (due to increased prevalence of malabsorption), patients with gastrointestinal conditions affecting absorption, and anyone taking medications known to interfere with B12 metabolism for extended periods. Pregnant and breastfeeding women following plant-based diets should seek advice, as maternal B12 deficiency can affect foetal neurological development and infant health.

Patients who have undergone gastrointestinal surgery, particularly gastric or ileal resection, should have regular B12 monitoring as part of their long-term follow-up care. Similarly, individuals with diagnosed pernicious anaemia require lifelong treatment and periodic review to ensure adequacy of replacement therapy.

Urgent medical attention is warranted if neurological symptoms develop rapidly or are severe, such as significant weakness, marked gait disturbance, or acute confusion. Whilst rare, rapid neurological deterioration can occur, particularly in cases of nitrous oxide misuse or in patients with unrecognised severe deficiency.

Diagnosis typically involves blood tests measuring serum B12 levels (with reference to local laboratory ranges), full blood count, and folate levels. Additional tests may include intrinsic factor antibodies to confirm pernicious anaemia, and in borderline cases, methylmalonic acid or holotranscobalamin if available. According to NICE Clinical Knowledge Summary (CKS): Anaemia – B12 and folate deficiency, treatment for confirmed deficiency typically involves intramuscular hydroxocobalamin injections (1 mg on alternate days for 2 weeks, then maintenance of 1 mg every 2-3 months, or every 2 months if neurological involvement is present). Patients with severe neurological symptoms should be referred urgently to a specialist while treatment is initiated. Early detection and treatment are essential to prevent irreversible complications, particularly neurological damage.

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