To the Editor—A 79-year-old Chinese male presented in January 2023 with a 2-week history of depressed mood and a 2-year history of forgetfulness. He had no recollection of his COVID-19 illness in December 2022, after which his memory further worsened. He had been experiencing intermittent dyspepsia since May 2012, with a finding of Helicobacter pylori–negative inactive mild chronic antral gastritis in September 2015, for which he took antacids, famotidine, and pantoprazole as required. Review of his history revealed a diagnosis of vitamin B₁₂ deficiency anaemia 10 years earlier in September 2013 when he presented with depression, tiredness, dizziness, weight loss, hand numbness, and laboratory findings of macrocytic anaemia (haemoglobin level: 8.2 g/dL, mean cell volume [MCV]: 130.9 fL) along with a low serum vitamin B₁₂ level (<37 pmol/L). He was treated with intramuscular cyanocobalamin for 1 year followed by oral cyanocobalamin 100 mcg twice a day for 2.5 years. His symptoms improved and haemoglobin level, MCV (13.7 g/dL and 93.2fL, respectively, June 2014; 15.1g/dL and 93.7 fL, respectively, December 2016) and serum vitamin B₁₂ level (513 pmol/L, September 2014) normalised. Examination in January 2023 revealed mildly impaired cognition, depressed mood and positive Romberg test, but no pallor or glossitis. A clinical diagnosis of relapsed pernicious anaemia with neuropsychiatric presentation was made and confirmed by a low serum vitamin B₁₂ level (<109 pmol/L, January 2023) and a positive intrinsic factor antibody, although his haemoglobin level and MCV were normal (14.0 g/dL and 97.3 fL, respectively). His mood improved but cognition remained unchanged after high-dose oral vitamin B₁₂ (mecobalamin 500 mcg 3 times a day), with normalisation of serum vitamin B₁₂ level (318 pmol/L, April 2023). The patient was treated in accordance with the Declaration of Helsinki. Informed consent was obtained for publication of this case.

This case illustrates the importance of determining the aetiology of vitamin B₁₂ deficiency, failure to do so may lead to under-treatment and disease relapse or progression. Pernicious anaemia requires lifelong treatment with either parenteral or high-dose (≥1 g daily) oral vitamin B₁₂. Clinicians and pathologists should be familiar with both classic and non-classic presentations, causes, and laboratory diagnosis of vitamin B₁₂ deficiency, a common treatable disorder (Table).1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Neuropsychiatric presentations can occur in the absence of anaemia or macrocytosis and may be non-classic (eg, depression, long COVID-19, hallucinations).1 2 3 4 5 6 Underlying causes, often multiple in an individual, need to be diagnosed, and persistent cause(s) require lifelong treatment.1 Although acid-suppressive drugs may have contributed to this patient’s vitamin B₁₂ deficiency (food-cobalamin malabsorption),7 intrinsic factor antibody positivity and dyspepsia history point to an additional cause in autoimmune atrophic gastritis. The classic histopathology of this condition should be confirmed by gastric biopsy, including both corpus and antrum.8 Periodic screening for metformin-induced vitamin B₁₂ deficiency in diabetes, though proposed over 50 years ago,9 has only recently been incorporated into guidelines,1 10 but is not widely practised.

Vitamin B₁₂ deficiency can occur in individuals with apparently normal or supernormal serum vitamin B₁₂ or active vitamin B₁₂ levels, and clinicians should be aware of factors that affect test results (Table).1 2 4 11 12 The 2024 National Institute for Health and Care Excellence guideline1 introduced an indeterminate range for low-normal serum vitamin B₁₂ or active vitamin B₁₂ levels that necessitates further tests for raised serum homocysteine or methylmalonic acid (Table) to confirm the diagnosis in those with risk factors and compatible manifestations of vitamin B₁₂ deficiency. Because of the limitations of vitamin B₁₂ levels, the diagnosis and monitoring of treatment adequacy should not depend solely on its level, but should instead be guided by clinical judgement and response.1 Although a low vitamin B₁₂ level in patients on replacement therapy suggests poor adherence or inadequate dosing, a normal or high level does not necessarily indicate adequate treatment and should not prompt reduction discontinuation.1 The clinical response should be assessed at follow-up instead of merely repeating vitamin B₁₂ levels.1 Individual variability in vitamin B₁₂ treatment response and dose requirement has been observed, possibly due to genetic variants of transcobalamin and its receptor. These variants may reduce vitamin B₁₂ availability and reduce energy metabolism, ultimately contributing to frailty.1 2 13

The author solely contributed to the concept or design of the paper, acquisition of the data, analysis or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. The author had full access to the data, contributed to the paper, approved the final version for publication, and takes responsibility for its accuracy and integrity.

The author has disclosed no conflicts of interest.

This letter received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

1. National Institute for Health and Care Excellence. Vitamin B₁₂ deficiency in over 16s: diagnosis and management. NICE guideline; 2024. Available from: https://www.nice.org.uk/guidance/ng239. Accessed 10 Aug 2025.

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