Vitamin B12 deficiency remains a common and clinically significant condition, affecting hematologic, neurologic, and systemic health. Despite being preventable and easily treatable, its management continues to evolve as understanding of metabolism, absorption, and individualized therapy improves [1]. The principal therapeutic goal is to restore adequate vitamin B12 levels to reverse anemia, prevent neurological complications, and maintain metabolic balance. Modern strategies now integrate precision supplementation, focusing on bioavailability, patient compliance, and mechanistic understanding.

Vitamin B12 plays an essential role in DNA synthesis and red blood cell maturation. Its deficiency leads to defective thymidylate synthesis, resulting in nuclear-cytoplasmic asynchrony within erythroid precursors and causing megaloblastic anemia [1]. Peripheral blood smears typically reveal macrocytosis, anisopoikilocytosis, and hypersegmented neutrophils, while bone marrow aspirates show megaloblastic hyperplasia.

Recent hematological studies using digital imaging and machine learning techniques have enhanced early detection of macrocytosis and subclinical marrow dysplasia, allowing diagnosis before overt anemia occurs [1]. In elderly or chronically ill patients, vitamin B12 deficiency often coexists with inflammation or folate deficiency, producing mixed anemia syndromes. Therapeutic response is both rapid and diagnostic: reticulocytosis typically emerges within 5–7 days, followed by normalization of hemoglobin and MCV within several weeks [1]. Persistent cytopenias after replacement therapy should raise suspicion of myelodysplasia or secondary marrow disorders. Moreover, neurological damage may remain irreversible if treatment is delayed, underscoring the importance of early detection and intervention.

Advanced diagnostic algorithms combining hematologic parameters, metabolic biomarkers (methylmalonic acid, homocysteine, holotranscobalamin), and AI-assisted analysis improve diagnostic accuracy and help distinguish functional from true deficiency [1].

Therapeutic formulations of vitamin B12 include cyanocobalamin, hydroxocobalamin, and methylcobalamin, each with distinct pharmacokinetic and pharmacodynamic properties (Table 1) [2–4]. Cyanocobalamin, the synthetic form, remains widely used due to its stability and affordability, though it requires metabolic conversion into active coenzymes, which may be suboptimal in patients with absorption or enzymatic defects [1,4]. Hydroxocobalamin, a natural form with higher bioavailability and longer systemic retention, is preferred in pernicious anemia, malabsorption syndromes, and severe deficiency. It also allows less frequent dosing due to its prolonged plasma half-life [1]. Methylcobalamin, the active coenzyme form, directly participates in neuronal methylation processes and is particularly indicated in neurological complications such as peripheral neuropathy or cognitive decline [2,3]. Comparative trials indicate that methylcobalamin enhances neuroregeneration and improves functional recovery.

The choice of administration route is crucial for therapeutic efficacy, rate of correction, and adherence. Intramuscular (IM) and intravenous (IV) administration remain gold standards, especially for severe deficiency or impaired absorption [1,5]. Standard IM therapy—1000 µg daily for 1–2 weeks—ensures reliable absorption by bypassing gastrointestinal barriers, while IV delivery is reserved for acute or life-threatening presentations. For mild or moderate deficiency with intact absorption, oral supplementation (1000–2000 µg/day) provides effective and convenient treatment [1]. A 2023 network meta-analysis found that IM and sublingual routes achieved the fastest increases in serum vitamin B12, though oral therapy remained effective for long-term management [5]. Sublingual and intranasal formulations offer non-invasive alternatives for patients with malabsorption, gastrointestinal surgery, or injection intolerance [2]. Novel transdermal and intradermal systems are under investigation for sustained release and improved adherence [5]. In addition, Sucrosomial® B12, a new oral delivery system, has shown bioavailability comparable to parenteral therapy, expanding non-invasive options [1].

Treatment protocols vary with deficiency severity, route, and patient profile [1,5].

Mild to moderate deficiency: oral supplementation of 250–1000 µg/day for at least 4 months is recommended.

Severe or neurologically symptomatic deficiency: 1000–2000 µg/day IM or IV for 1–2 weeks, followed by weekly to monthly maintenance.

Long-term management: monthly IM or IV injections, or daily oral supplementation when absorption is adequate.

Special populations such as elderly individuals, pregnant women, vegetarians, and post-gastrointestinal surgery patients may require lifelong supplementation.

Allergic reactions to vitamin B12 are rare but clinically relevant, particularly with cyanocobalamin. In such cases, switching to hydroxocobalamin or methylcobalamin is advised [1,3]. When injection-related hypersensitivity occurs, oral, sublingual, or intranasal administration may be safer alternatives. Antihistamine pre-treatment may also be considered for mild reactions under medical supervision [1].

Emerging directions in vitamin B12 therapy focus on personalized medicine, accounting for genetic polymorphisms (MTRR, MTHFR), microbiome composition, and comorbidities affecting absorption and metabolism [1,6]. Future strategies will likely integrate multimodal monitoring—including hematologic, metabolic, and neurologic outcomes—to define individualized, precision supplementation protocols.

Artificial intelligence will play a growing role in screening and interpretation of diagnostic data, enhancing early recognition and treatment monitoring. The ultimate goal is to move from correction of deficiency to optimization of vitamin B12 metabolism as part of comprehensive metabolic health management.

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