Vitamin B12 deficiency in adults: A contemporary guide to recognition, diagnosis, and evidence-based management

Aetiology and pathophysiology

The absorption of dietary B12 is a complex, multi-stage process requiring functional gastric, pancreatic, and ileal components. Deficiency arises from disruption at one or more of these stages, which can be categorised as follows.^[6]

Nutritional deficiency: Inadequate dietary intake is the primary cause in populations with limited consumption of animal-source foods. Strict vegans are at the highest risk, though deficiency typically manifests only after several years due to substantial hepatic stores (2-5 mg).^[7]

Clinical manifestations

The clinical presentation is notoriously nonspecific and can be categorised into haematological, neurological, psychiatric, and general systemic features. Importantly, these domains may be affected independently.

Haematological manifestations: The classic finding is megaloblastic anaemia, characterised by macro-ovalocytes and an elevated mean corpuscular volume (MCV >100 fL). However, a normal MCV does not exclude deficiency, especially in the presence of concurrent iron deficiency or thalassemia. Pancytopenia may occur. Laboratory signs of ineffective erythropoiesis include elevated lactate dehydrogenase (LDH) and indirect bilirubin, with a low reticulocyte count. Peripheral blood smear reveals hypersegmented neutrophils (≥6% with 5 lobes or any with 6 lobes).^[14,15]

Neurological manifestations: These are the most concerning due to their potential irreversibility.

• Peripheral neuropathy: Symmetrical, “stocking-glove” distribution sensory disturbances (numbness, paresthesias, loss of vibration and proprioception).

• Subacute combined degeneration (SCD): Demyelination of the dorsal and lateral spinal cord tracts leads to sensory ataxia, spastic paraparesis, and Romberg's sign. Magnetic resonance imaging (MRI) may show T2 hyperintensity in the posterior columns.^[16]

• Other: Optic neuropathy, autonomic dysfunction, and cognitive impairment ranging from mild executive dysfunction to overt dementia.^[17]

Psychiatric manifestations: Symptoms may include depression, apathy, irritability, psychosis, and personality changes, often overlapping with cognitive deficits.^[18]

Other systemic features: Glossitis (smooth, beefy-red tongue), fatigue, general weakness, and, rarely, skin hyperpigmentation.^[9]

Differential diagnosis

Given its varied presentation, B12 deficiency must be distinguished from several other conditions [Table 1].

Diagnostic approach

Diagnosis requires a combination of clinical suspicion and a strategic laboratory evaluation, moving beyond serum B12 alone.^[24]

Initial test: Serum B12 Level. A level <148 pmol/L (<200 pg/mL) is suggestive of deficiency. Levels between 148-221 pmol/L (200-300 pg/mL) are considered borderline and require further testing, as a significant proportion of patients in this range have functional deficiency.^[25]

Second-line metabolic biomarkers: These functional tests of B12-dependent enzymes are more reflective of cellular status.

• Methylmalonic acid (MMA): Serum MMA is the most specific indicator (>90%) of B12 deficiency. Elevations confirm metabolic deficiency even when serum B12 is borderline. Note that renal impairment can cause false elevations.^[26]

• Total homocysteine: Elevated in both B12 and folate deficiency (less specific). The pattern of elevated MMA with elevated homocysteine is strongly indicative of B12 deficiency, whereas elevated homocysteine with normal MMA suggests folate deficiency or other causes.^[19]

Determining the aetiology: Identifying the cause is essential for guiding long-term management.

• First-line: Test for anti-intrinsic factor antibodies. A positive result is highly specific (>95%) for pernicious anaemia and is diagnostic.^[8]

• Second-line: Anti-parietal cell antibodies have high sensitivity but low specificity. In patients with negative serology but strong suspicion for malabsorption, consider gastroenterology referral for further evaluation (e.g., endoscopy, H. pylori testing).^[27]

Recent guidelines, such as those from the UK National Institute for Health and Care Excellence (NICE), recommend against routine population screening and advocate for targeted testing based on clinical signs, symptoms, and risk factors.^[28]

Treatment pathways and management

The goals are to correct symptoms, replenish stores, and provide lifelong maintenance therapy where the cause is irreversible. A major shift in practice is the strong evidence for high-dose oral therapy [Table 2].

Initial/corrective therapy

• High-dose oral therapy: A 2024 systematic review and network meta-analysis concluded that high- dose oral cyanocobalamin (1000-2000 mcg daily) is as effective as intramuscular (IM) therapy in normalising haematological and clinical parameters, including in patients with pernicious anaemia or malabsorptive conditions.^[29] This is due to passive diffusion absorbing approximately 1% of any oral dose, which at this high dose is therapeutic. The 2024 NICE guideline recommends high-dose oral B12 as a first-line treatment for all causes.^[28]

• Parenteral (intramuscular) therapy: IM hydroxocobalamin (1000 mcg) retains a crucial role in cases of severe neurological involvement (e.g., SCD), where rapid, assured repletion is prioritised, or for patients unable to tolerate/adhere to oral regimens. A typical loading regimen is 1000 mcg on alternate days for 1-2 weeks.^[30]

Future directions

Despite clear diagnostic criteria and effective treatments, challenges persist. Diagnostic delays remain common due to nonspecific symptoms and over-reliance on serum B12 testing without follow-up functional assays. The paradigm shift toward high-dose oral therapy empowers patients and reduces healthcare costs but requires effective education to ensure adherence. Future research should focus on long-term outcomes of different maintenance regimens, the cost-effectiveness of first-line MMA testing, and a clearer definition of the role of holo-transcobalamin (active B12) in diagnostic algorithms.