• BMJ2024;385:q1019

Vitamin B₁₂ deficiency: NICE guideline summary

 Sands, T. Jawed, A. Stevenson E and Smith, M

Introduction

Vitamin B12 deficiency can occur if the body does not absorb enough vitamin B12 from the gastrointestinal tract or when there is not enough dietary intake of the vitamin, which is more common in people who have vegan diets and to a lesser extent, vegetarian diets (Devalia et al. 2014; Herrmann et al. 2003).

One cause of vitamin B12 deficiency in the UK is pernicious anaemia. Pernicious anaemia is an autoimmune disorder that results in inflammation and damage to the stomach lining, and loss of cells that produce stomach acid (parietal cells), digestive enzymes and mucus. The parietal cells also produce intrinsic factor, a protein needed for absorption of vitamin B12 in the gut. Destruction of parietal cells leads to a lack of intrinsic factor.

The exact cause of pernicious anaemia is unknown but, according to the NICE clinical knowledge summary on anaemia, about 30% of people with it have a family history of pernicious anaemia. The condition is more common in people over 60 years, and in women and in people with other autoimmune conditions, such as primary myxoedema, thyrotoxicosis, Hashimoto’s disease, Addison’s disease and vitiligo. People with pernicious anaemia have a higher risk of developing gastric cancer.

Malabsorption of vitamin B12 may occur in people with gastric, pancreatic or intestinal diseases (including removal of all or part of the stomach or gastric bypass surgery) and in people with HIV. Deficiency can also result from the long‑term use of drugs that affect gastric acid production (Kinn and Lantz 1984; Sneiders‑Keilholz et al. 1993) or radiotherapy of the abdomen or pelvis, which reduces vitamin B12 absorption from the diet.

The clinical consequences of vitamin B12 deficiency include:

• anaemia resulting from impaired red blood cell production
• loss of peripheral nerve function that can result in impaired sensation, movement or organ function
• visual disturbance
• memory loss
• psychiatric abnormalities.

Vitamin B12 deficiency can also lead to temporary infertility in women. Deficiency during pregnancy can result in foetal abnormalities, such as neural tube defects, according to the NICE clinical knowledge summary on anaemia.

There is uncertainty about the prevalence and incidence of vitamin B12 deficiency. This is partly because there is no established single measure of vitamin B12 deficiency or accepted definition of what constitutes a deficiency (Carmel 2011). Prevalence in the UK is estimated to be around 6% in people under 60 years and closer to 20% in people aged over 60 (Hunt et al. 2014).

There are several approaches to diagnosing vitamin B12 deficiency. These include:

• Tests to detect physiological correlates of vitamin B12 deficiency, for example blood film examination and elevated mean cell volume (MCV). Hypersegemented neutrophils, oval macrocytes and circulating megaloblasts are typical features of vitamin B12 deficiency. However, MCV is not specific to vitamin B12 deficiency and excess alcohol consumption, drug use and myelodysplastic syndrome may also cause increased levels. In addition, increased MCV is often a late indicator of vitamin B12 deficiency (Herrmann and Geisel 2002); 25% of people with vitamin B12‑related neurological impairment have normal MCV levels (Devalia et al. 2014).
• Functional tests for biochemical abnormalities associated with vitamin B12 deficiency, for example methylmalonic acid (MMA) or total homocysteine (Hcy) levels:
  • MMA is a substance produced when amino acids are metabolised. It is involved in a reaction that uses vitamin B12 (cobalamin) as a cofactor and so can be used as an indicator of vitamin B12 levels. High levels of plasma MMA may indicate cobalamin deficiency. However, levels may not accurately indicate a deficiency in people aged over 65 years with kidney disease, small bowel bacterial overgrowth or reduced fluid content of the blood because these conditions can also cause elevated MMA levels (Devalia et al. 2014; Hunt et al. 2014).
  • Total serum Hcy is an indicator of vitamin B12 deficiency because cobalamin is needed for the synthesis of methionine from Hcy, and low levels of vitamin B12 lead to increased total serum Hcy. However, its use as a sole confirmatory test is limited because Hcy levels are also higher in people with folate deficiency, vitamin B6 deficiency, renal failure and hypothyroidism (Devalia et al. 2014). Both MMA and Hcy are also late indicators of vitamin B12 deficiency (Herrmann and Geisel 2002).
• Direct tests of vitamin B12 status in its various forms are available (Hunt et al. 2014):
  • Serum total cobalamin or vitamin B12, the test most commonly used in the UK to measure vitamin B12 status, is known as the serum cobalamin level.
  • Serum holotranscobalamin (holoTC): in serum, vitamin B12 exists in 2 bound forms. It can be bound to haptocorrin to form holohaptocorrin; or bound to transcobalamin to form holoTC. Cells can only take up vitamin B12 in the form of holoTC (Hunt et al. 2014). Therefore, measuring holoTC is more reflective of vitamin B12 status than measuring total vitamin B12 or holohaptocorrin alone. Emerging evidence suggests that a low level of holoTC may be a more reliable marker of vitamin B12 deficiency than a low serum cobalamin level, particularly as an early marker (Hunt et al. 2014).

Testing of holoTC is being used more widely although there is a lack of consensus about the cut‑off values used to show vitamin B12 deficiency (Hunt et al. 2014), reflecting similar issues with other measures of vitamin B12 status. If the test result falls in the intermediate (borderline) range, a second test, such as measuring MMA levels, is recommended to confirm deficiency (Hunt et al. 2014). The British Society for Haematology guidelines (Devalia et al. 2014) recommend that reference ranges for holoTC are either based on manufacturers’ reference ranges or determined by the individual laboratory using the test.