Healthcare Professionals Information

Diagnosing B12 deficiency/Pernicious Anaemia

Important Points

• There is no gold standard test for B12 deficiency.
• Clinical features of vitamin B12 deficiency can occur without anaemia and without low serum levels of vitamin B12.
• A normal MCV or the absence of anaemia does not exclude the need for B12 testing, as neurological impairment occurs in many cases without one or either.
• Pernicious Anaemia is the most common cause of B12 deficiency.
• People with Pernicious Anaemia may present with symptoms of associated disorders, for example, thyroid disorders, vitiligo, diabetes, or Addison’s disease.

Key Points in the Diagnosis of B12 Deficiency

• The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status since there is no ‘gold standard’ test to define deficiency.
• Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues.
• Neurological symptoms due to cobalamin deficiency may occur in the presence of a normal MCV/Hb.
• Plasma tHcy and/or plasma MMA, depending on availability, may be considered as supplementary tests to determine biochemical cobalamin deficiency in the presence of clinical suspicion of deficiency but an indeterminate serum cobalamin level.
• Serum cobalamin level of greater than 148 pmol/L (200 ng/l) in the presence of a strong clinical suspicion of cobalamin deficiency should be evaluated further with MMA, tHcy or HoloTC and a trial of hydroxocobalamin given to ascertain any clinical improvement.

Key Points in the Diagnosis of Pernicious Anaemia

• All patients with anaemia, neuropathy or glossitis, and suspected of having pernicious anaemia, should be tested for anti-intrinsic factor antibody regardless of cobalamin levels.
• Patients found to have a low serum cobalamin level in the absence of anaemia, and who do not have food malabsorption or other causes of deficiency, should be tested for IFAB to clarify whether they have an early/latent presentation of pernicious anaemia.
• Antibodies to IF are very specific for pernicious anaemia, however they are only present in around 50% of patients.
• Patients found to be positive for intrinsic factor antibodies should have lifelong therapy with cobalamin.
• Patients negative for intrinsic factor antibody, with no other causes of deficiency, may still have pernicious anaemia as a result of poor sensitivity of the test and should be treated as anti-intrinsic factor antibody negative pernicious anaemia. Lifelong therapy should be continued in the presence of an objective clinical response.

Treatment of Pernicious Anaemia

Key Points in the treatment of PA

• Treatment of cobalamin deficiency is recommended in line with the British National Formulary:
  By intramuscular injection:
• With neurological involvement*: Initially 1 mg once daily on alternate days until no further improvement, then 1 mg every 2 months.
• Without neurological involvement: Initially 1 mg 3 times a week for 2 weeks, then 1 mg every 2–3 months.
• No further testing for cobalamin levels is required.¹
• Measuring cobalamin levels is unhelpful as levels increase with treatment regardless of how effective it is.²
• There is no proof in large prospective, double-blind studies that oral supplementation is as effective in reducing symptoms associated with vitamin B12 deficiency as parenteral treatment.³

* Note: The large majority of patients present with neurological/neuropsychiatric involvement at the time of diagnosis

References

1. Devalia V, Hamilton M, Molloy A; Guidelines for the Diagnosis and Treatment of Cobalamin and Folate Disorders; British Journal of Haematology, 2014, 166, 496-513
2. NICE Clinical Knowledge Summaries Anaemia – B12 and folate deficiency
3. Wolffenbuttel, Bruce H R et al. “The Many Faces of Cobalamin (Vitamin B12) Deficiency.” Mayo Clinic proceedings. Innovations, quality & outcomes vol. 3,2 200-214. 27 May. 2019, doi:10.1016/j.mayocpiqo.2019.03.002