Vitamin B12 (also known as cobalamin due to its metal cobalt content) is an essential water-soluble vitamin. It is one of the nutrients in B complex vitamins, which is synthesised by bacteria primarily found in foods containing meat, fish, and dairy products. However, it is not naturally found in foods like grains, nuts, fruits, and vegetables. Therefore, vegan individuals may suffer from vitamin B12 deficiency (National Health Service 2020; British Nutrition Foundation 2021). Moreover, B12 is crucial for the production of red blood cells, nervous system function, and DNA synthesis during cell division (Arora et al. 2019; Hanna et al. 2009; Langan and Goodbred 2017).
Vitamin B12 deficiency is a condition resulted from inadequate intake or malabsorption of vitamin B12. This deficiency affects people at all ages including infants, children, men, women especially elderly people (Green et al. 2017). According to Gomollón et al. (2017), the diet of Western individuals consists of 3–30 micrograms of vitamin B12 daily, where only 1–5 micrograms are absorbed. The National Health Service (NHS, 2020) and British Nutrition Foundation (2021) recommended 1.5 micrograms daily intake of vitamin B12 for adults aged 19–64 years. Whilst the European Food Authority (2015, 2023) suggests an adequate intake of 4 micrograms daily cobalamin for adults aged over 18 years. They found that daily intake of 4 micrograms cobalamin was associated with serum cobalamin concentrations within normal range from healthy participants. In contrast, the Institute of Medicine in the United States (IOM, now National Academies Sciences Engineering Medicine) adopted the World Health Organization's recommended daily intake of 2.4 micrograms cobalamin daily (Otten et al. 2006; WHO 2004). Consequently, there is a substantial storage of vitamin B12 in a person's liver. Hence, it may take up to 10 years before symptoms of deficiency appear (Langan and Goodbred 2017).
Who is commonly affected by vitamin B12 deficiency?
According to World Health Organization (WHO 2023), vitamin deficiencies are a major global health concern. Although iron, vitamin A, and iodine deficiencies are the most common worldwide, vitamin B12 deficiency may also cause serious health problem as diminished absorption may lead to anaemia, a condition where there is a low haemoglobin concentration or insufficient red blood cells. National Institute for Health and Care Excellence (NICE 2023a) highlighted that the prevalence of vitamin B12 deficiency in the United Kingdom is ambiguous. Nevertheless, the data from Netherlands and USA suggest that it affects approximately 3% of people aged 20–39 years, and 4% of those aged 40–59 years. Whilst 6% of them were aged 60 years and over, and a dramatic rise to 20% amongst age group 85 years and older. Furthermore, vegan people or strict vegetarians, were 11% cobalamin deficient (Langan and Goodbred 2017; NICE 2023a).
Individuals at risk of vitamin B12 deficiency include infants, children, adolescents, pregnant and lactating women as their dietary intake of foods containing B12 were restricted (Green et al. 2017; WHO, 2004). However, vegans and people who underwent gastric resections are also susceptible to vitamin B12 deficiency, but most specifically elderly people (Green et al. 2017; Sukumar and Saravanan, 2019). Vitamin B12 consumed in the diet binds to intrinsic factor, a glycoprotein created by parietal cells located in gastrointestinal tract and is absorbed in the small intestine by the cubam receptor (receptor involved in absorption of B12) (Al-awami et al. 2023, David and Bell 2022; Stabler 2020). A randomised controlled trial by Lederer et al. (2019) found that there was a reduction in serum vitamin B12 with healthy participants on vegan diet compared to subjects on meat-rich diet. Moreover, a studyby Kornerup et al. (2019) showed that vitamin B12 absorption capacity was reduced following gastric surgery of morbidly obese patients, and significantly evident 6 months after surgery. Essentially, Nalder et al. (2020) reported that older individuals aged 60–85 years are prone to vitamin B12 deficiency.
Marchi et al. (2020) argued that there is limited evidence about the true prevalence of cobalamin deficiency in elderly even though it is known that cobalamin levels decline with advancing years. They explained that it could be due to broad differences amongst participants in research such as varying age, ethnicity, food consumption, and comorbidities.
Nevertheless, B12 deficiency in elderly was associated with malabsorption of vitamin B12 related to pernicious anaemia (autoimmune disease caused by cobalamin deficiency anaemia), atrophic gastritis (inflammation of gastric mucosa caused by bacteria called helicobacter pylori), and poor nutrition (Han Wee 2021; Htut et al. 2021; Naimovna et al. 2020). In fact, vitamin B12 deficiency is a common condition encountered by the general practice nurses in primary care settings most particularly with the elderly patients. Therefore, clinicians should be able to recognise this deficiency and treat appropriately (Saxena et al. 2021).
What are the clinical manifestations of vitamin B12 deficiency?
Clinical signs and symptoms of vitamin B12 deficiency may persist to be implicit for years as cobalamin stores in liver are much higher than the daily vitamin loss (Langan and Goodbred 2017). Unless severe symptoms appear, vitamin B12 deficiency may not be easily diagnosed (van de Lagemaat et al. 2019). Conversely, clinical presentations may include features of anaemia such as atrophic glossitis (partial or complete absence of filiform papillae on the tongue surface), stomatitis (inflammation of the mucosa of the mouth), and changes in skin pigmentation (lemonyellow skin) because of anaemia and jaundice (Gould 2008; Saxena et al. 2021; Wu et al. 2022). Importantly, severe deficiency may lead to neurological symptoms (tingling in the feet and abnormal gait), mental impairment, or pernicious anaemia (Hanna et al. 2009; Saxena et al. 2021).
Yocum et al. (2023) suggest that the estimated incidence of pernicious anaemia was 0.1% for the general population, where 1.9% of them were older people aged over 60 years. Whilst 20–50% of cases were due to vitamin B12 deficiency. In addition, individuals with pernicious anaemia may present with clinical manifestations such as lethargy, pale appearance, inability to concentrate, headache, tingling sensation, depression, psychotic episodes, palpitations, and chest pain particularly in elderly people (Htut et al. 2021; Yocum et al. 2023). Thus, early recognition of these symptoms is vital as it could result in fatal irreversible neurological disorders (Marchi et al. 2020; Nawaz et al. 2020).
Although clinical symptoms may prompt the recognition of vitamin B12 deficiency, investigation for serum B12 level could be used to establish the diagnosis (Nawaz et al. 2020; Oo 2015). Hanna et al. (2009) explained that the expected range for serum B12 level should be 200–900 picograms/mL, but 300–350 picograms/mL was considered a threshold for elderly patients. Nonetheless, NICE (2023c) emphasised that the normal reference values for B12 is unclear. However, serum cobalamin of less than 148 picomol/L is considered sufficient to diagnose 97% of individuals with B12 deficiency. Further, clinicians should determine not only the laboratory findings but also the underlying cause of vitamin B12 deficiency to manage the condition effectively (Carmel 2008; NICE 2023c).
How to treat and manage vitamin B12 deficiency?
Management of vitamin B12 deficiency may be complex as there are inconsistencies in reference interval for the laboratory tests utilised to indicate B12 deficiency, and patients may present with non-specific clinical manifestations. Yet, immediate assessment and treatment are required when neurological and haematological features are observed (Sukumar and Saravanan, 2019).
Vitamin B12 deficiency is a common condition seen every day in primary care settings. General practice nurses administer vitamin B12 injections to patients with B12 deficiency (Saxena et al., 2021; Murrell, 2020). However, there was no clear guidelines on how long these patients require intramuscular injections to treat the deficiency. Clinical guidelines are recommendations developed to guide healthcare professionals in providing quality patient care and treat a specific health condition based on the best available evidence to optimise health outcomes (NICE 2012, NICE 2023b).
On the other hand, Shipton and Thachil (2015) stated that patients with vitamin B12 deficiency in the United Kingdom are treated with intramuscular B12 injections. They suggested that the routine procedure for patients with B12 deficiency, but no neurological symptoms include administration of hydroxocobalamin 1 milligram (mg) on alternating days for two weeks, then three-monthly B12 injections thereafter. This regimen may be given continuously for a lifetime if pernicious anaemia is suspected. Whereas patients with neurological symptoms, the same dose may be administered until there is an evident improvement in symptoms, then two-monthly B12 injections thereafter (British National Formulary and NICE 2023). However, patients with severe neurological features need to be referred to secondary care for appropriate management and treatment (Shipton and Thachil 2015). Currently, the same regimen is recommended by NICE (2023d) Guidelines, but they highlighted that B12 treatment for individuals with dietary deficiency may be stopped once their cobalamin levels and diet have improved.
Meanwhile, the guidelines from the British Society for Haematology were consistent with NICE (2023d) recommendations on cobalamin replacement treatment for vitamin B12 deficiency. However, they suggested that no further screening for B12 levels is required for patients with neurological deficit. Instead, patients may receive hydroxocobalamin 1000 micrograms intramuscular injection two-monthly (Devalia et al. 2014; British National Formulary and NICE 2023). Contrarily, a study by Arendt et al. (2019) found that individuals with B12 levels more than 1,000 pmol/L was significantly associated with a higher one-year cancer risk compared to individuals with normal B12 levels. Furthermore, Andrés et al. (2013) explained that high serum cobalamin levels due to long-term administration of cobalamin injections may result to the development of anti-transcobalamin II autoantibodies therefore reducing the transcobalamin II (TCB II, a protein that helps with the tissue and hepatic absorption of vitamin B12) clearance. Hence, careful evaluation and management of vitamin B12 deficiency in primary care are essential.
Alternatively, vitamin B12 deficiency may also be wellcontrolled with oral B12 therapy. Correcting this deficiency with oral cobalamin supplements is uncomplicated, provided that patients adhere to treatment (Htut et al. 2021; Moll and Davis 2017). NICE (2023d) suggests treating patients with oral cyanocobalamin 50–150 micrograms daily between meals only if their deficiency is diet related, or they may have six-monthly hydroxocobalamin 1 mg injection (British National Formulary and NICE 2023). Although management of vitamin B12 deficiency in the UK relies on parenteral treatment, there are several strong evidence that oral B12 supplementation maybe just as effective (Nawaz et al. 2020; Shipton and Thachil 2015).
A systematic review of randomised controlled trials by Butler et al. (2006) showed that high doses of oral B12 (1000 micrograms and 2000 micrograms oral B12 daily) were as effective as vitamin B12 injections in relation to improvement in haematological and neurological reactions. Additionally, a study in Canada by Masucci and Goeree (2013) found that switching parental B12 treatment to oral cobalamin supplements lead to savings of $14.2 million to their health care system. However, there was no report on patients’ physiological or neurological responses to medications.
In contrast, a Cochrane review by Wang et al. (2018) revealed that there was very low-quality evidence that oral B12 supplementation appear as safe as B12 injections including both treatments having similar effects in normalising serum B12 levels. Nevertheless, oral treatment was cost-effective. Moreover, a randomised clinical trial by Sanz-Cuesta et al. (2020) found that oral B12 administration for cobalamin deficiency in patients aged over 65 years was as effective as parenteral administration. Although only Canada and Sweden use oral vitamin B12 supplementation as treatment for B12 deficiency, the benefits of oral supplements from previous studies may be applied in the UK (Shipton and Thachil 2015).
For example, taking oral B12 medication is safe, effective, cost-efficient, and painless (Devalia et al. 2014; Langan and Goodbred 2017; Vidal-Alaball et al. 2009). Also, it gives patients an alternative option, and oral B12 treatment means that no necessary involvement of nurses at home or at the general practice for B12 injection therapy. Therefore, producing substantial savings for the primary care (Nyholm et al. 2003).
Of note, vitamin B12 injection therapy may still be required for urgent treatment, vitamin B12 deficiency with neurological involvement, pernicious anaemia, gastric malabsorption, diabetes, and comorbidities (Marchi et al. 2020; NICE 2023d; Sukumar and Saravanan, 2019; Shipton and Thachil 2015). Chapman et al. (2016) found that metformin lowers B12 levels by 57 pmol/L leading to cobalamin deficiency in patients with type 2 diabetes. Hence, careful monitoring of cobalamin levels for these patients is pivotal. Though, laboratory testing such as methylmalonic acid (MMA, shows tissue level deficiency) and fasting plasma homocysteine levels (sensitive indicator of cobalamin deficiency) may still be performed if there is uncertainty of the diagnosis of vitamin B12 deficiency as these tests are over 95% sensitive in detecting cobalamin deficiency. Furthermore, holotranscobalamin is also another serum testing that is more accurate than serum cobalamin levels (Devalia et al. 2014; Nawaz et al. 2020; Htut et al 2021; Saxena et al. 2021).
What are the implications for future practice?
The possible causes of clinicians’ hesitancy to prescribe oral cobalamin supplements could be uninformed about the alternative options, uncertainty of its effectiveness due to unpredictable uptake of medication, or assumption that patients were unable to tolerate oral supplementation (Butler et al 2006; Murrell 2020). Regardless, general practitioners, general practice nurses, and other clinicians could be informed that this alternative therapy is safe, effective, and cost-efficient (Nyholm et al. 2003). Perhaps oral B12 supplementation may be offered to asymptomatic patients with B12 deficiency and obtain serum B12 levels every 6 to 12 months to assess patients’ response to treatment (Sukumar and Saravanan, 2019). Moreover, further clinical trial in the UK is needed to evaluate the effectiveness of high doses oral B12 treatment for vitamin B12 deficiency (Wolffenbuttel et al. 2019).
Conclusion
Vitamin B12 deficiency is a condition that affects people at all ages particularly the elderly individuals due to malabsorption of cobalamin. Serious B12 deficiency may lead to pernicious anaemia or irreversible neurological impairment. Therefore, early recognition and treatment of this condition are essential. It may be treated with oral B12 supplements or parenteral therapy. Although B12 injections are the preferred treatment for vitamin B12 deficiency in the UK, oral supplementation was also found as effective based on several strong evidence. Therefore, it may be offered to asymptomatic patients as an alternative treatment. However, symptomatic patients may still require B12 injections. High B12 levels were significantly related to risk of cancer. Hence, general practice nurses and other clinicians need to carefully assess the patients. Nevertheless, further research is needed to adequately evaluate the effectiveness of oral B12 treatment.
KEY POINTS
- Early detection and treatment of vitamin B12 deficiency may prevent irreversible neurological impairment.
- Individuals at risk of vitamin B12 deficiency include infants, children, adolescents, pregnant and lactating women, vegans, people who underwent gastric resections, but most especially the elderly patients.
- Vitamin B12 deficiency may be treated with oral B12 supplements or cobalamin injections.
- Vitamin B12 deficiency may present with non-specific clinical features, but severe deficiency may need secondary care referral.