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Background <p>Vitamin B12 deficiency is traditionally recognized through megaloblastic anemia, yet accumulating evidence shows a broad spectrum of non‑hematological manifestations and clinically relevant associations with elevated serum B12. Understanding these dimensions is essential for timely diagnosis and rational management across diverse populations.</p> Objective <p>To synthesize current evidence on the non‑hematological clinical manifestations, diagnostic challenges, and management implications of Vitamin B12 deficiency and excess, with emphasis on high‑risk groups and emerging therapeutic approaches.</p> Methods <p>A narrative review of human studies was conducted using PubMed, MEDLINE, Embase, Cochrane CENTRAL, Web of Science, Scopus, and Google Scholar from 1950 to 2024, supplemented by guideline documents and reference snowballing. Eligible publications examined non‑hematological outcomes or diagnostic and therapeutic aspects of vitamin B12 status; data were synthesized qualitatively with critical appraisal of study quality.</p> Findings <p>Vitamin B12 deficiency is linked to neurological, cognitive, psychiatric, cardiovascular, reproductive, renal, dermatological, and oncologic manifestations that may occur in the absence of anemia. Functional deficiency often arises despite serum Vitamin B12 concentrations within the conventional reference range, making methylmalonic acid, homocysteine, and holotranscobalamin valuable adjunctive biomarkers, although interpretation is influenced by renal function and assay availability. High‑dose oral supplementation is generally non‑inferior to intramuscular therapy for correcting biochemical deficiency, while severe neuropsychiatric presentations and malabsorptive states frequently warrant parenteral regimens. Persistent hypervitaminemia B12 more commonly reflects underlying systemic disease—such as malignancy, liver or kidney dysfunction—than true toxicity, underscoring the need for etiological investigation rather than dose reduction alone. Elderly individuals, vegetarians/vegans, pregnant women, and post‑bariatric surgery patients constitute key risk groups requiring proactive screening and long‑term follow‑up.</p> Conclusions <p>Vitamin B12 imbalance extends far beyond hematological abnormalities and should be considered in a wide range of neuropsychiatric, cardiometabolic, reproductive, and systemic presentations. Integrating functional biomarkers into diagnostic algorithms, individualizing replacement strategies, and prioritizing high‑risk populations may improve outcomes and align clinical practice with emerging evidence. Future research should focus on standardized diagnostic thresholds, long‑term neurocognitive and cardiovascular endpoints, and pharmacogenomic and novel delivery strategies to support precision supplementation.</p>

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Non-hematological manifestations of vitamin B12 deficiency and excess: clinical spectrum and management

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Amin R. Soliman,
  • Shaimaa Shaheen,
  • Rana Walid,
  • Ahmed Elamragy,
  • Ayman Hany,
  • Eslam Abu-Naeima,
  • Lobna Sedky,
  • Doaa M. Mahgoub,
  • Mona Hegazy,
  • Amira Khalifa,
  • Nadia M. Tawfik

摘要

Background

Vitamin B12 deficiency is traditionally recognized through megaloblastic anemia, yet accumulating evidence shows a broad spectrum of non‑hematological manifestations and clinically relevant associations with elevated serum B12. Understanding these dimensions is essential for timely diagnosis and rational management across diverse populations.

Objective

To synthesize current evidence on the non‑hematological clinical manifestations, diagnostic challenges, and management implications of Vitamin B12 deficiency and excess, with emphasis on high‑risk groups and emerging therapeutic approaches.

Methods

A narrative review of human studies was conducted using PubMed, MEDLINE, Embase, Cochrane CENTRAL, Web of Science, Scopus, and Google Scholar from 1950 to 2024, supplemented by guideline documents and reference snowballing. Eligible publications examined non‑hematological outcomes or diagnostic and therapeutic aspects of vitamin B12 status; data were synthesized qualitatively with critical appraisal of study quality.

Findings

Vitamin B12 deficiency is linked to neurological, cognitive, psychiatric, cardiovascular, reproductive, renal, dermatological, and oncologic manifestations that may occur in the absence of anemia. Functional deficiency often arises despite serum Vitamin B12 concentrations within the conventional reference range, making methylmalonic acid, homocysteine, and holotranscobalamin valuable adjunctive biomarkers, although interpretation is influenced by renal function and assay availability. High‑dose oral supplementation is generally non‑inferior to intramuscular therapy for correcting biochemical deficiency, while severe neuropsychiatric presentations and malabsorptive states frequently warrant parenteral regimens. Persistent hypervitaminemia B12 more commonly reflects underlying systemic disease—such as malignancy, liver or kidney dysfunction—than true toxicity, underscoring the need for etiological investigation rather than dose reduction alone. Elderly individuals, vegetarians/vegans, pregnant women, and post‑bariatric surgery patients constitute key risk groups requiring proactive screening and long‑term follow‑up.

Conclusions

Vitamin B12 imbalance extends far beyond hematological abnormalities and should be considered in a wide range of neuropsychiatric, cardiometabolic, reproductive, and systemic presentations. Integrating functional biomarkers into diagnostic algorithms, individualizing replacement strategies, and prioritizing high‑risk populations may improve outcomes and align clinical practice with emerging evidence. Future research should focus on standardized diagnostic thresholds, long‑term neurocognitive and cardiovascular endpoints, and pharmacogenomic and novel delivery strategies to support precision supplementation.