Consultant haematologist Dr Priya Sriskandarajah advises on key aspects of the management of vitamin B12 deficiency in primary care, including when to suspect B12 deficiency, interpreting test results, how to investigate underlying causes and when urgent treatment is required.
Learning objectives
This module is designed to extend your knowledge of:
- Potential presentations of vitamin B12 deficiency.
- The underlying causes of vitamin B12 deficiency and how these are investigated.
- Appropriate serum testing to identify vitamin B12 and how test results should be interpreted, including use of second-line tests.
- When to initiate vitamin B12 replacement and appropriate dosing and routes of administration, including when urgent treatment is required.
- Appropriate follow-up and monitoring of patients on vitamin B12 replacement therapy.
1. How does vitamin B12 deficiency typically present?
Vitamin B12 deficiency can affect people differently and so a high index of suspicion is required when assessing patients for this. The recent NICE guidelines provide a long list of symptoms which are summarised below:1
- Unexplained fatigue.
- Glossitis.
- Visual changes: blurred vision; optic atrophy; visual field loss.
- Neurology: subacute combined degeneration of spinal cord – patients typically present with unsteadiness, paraesthesiae and impaired proprioception.2
- Symptoms and signs of anaemia including breathlessness on exertion and pallor.
Elderly patients may also present with neurocognitive deficit with multidomain cognitive impairment, in particular memory and attention. Furthermore, it can impact mental health with patients suffering with symptoms of anxiety, depression or psychosis. These cognitive and mood changes can be reversed following B12 supplementation, highlighting the importance of recognising B12 deficiency as early as possible.3
Rarely, B12 deficiency can present with haemolysis and can be misdiagnosed as a thrombotic microangiopathy (TMA), in particular thrombotic thrombocytopenic purpura (TTP).4 Patients typically present with low haemoglobin and low platelet counts associated with haemolysis characterised by low haptoglobin, raised lactate dehydrogenase (LDH) and elevated bilirubin levels. TTP is a known haematological emergency for which treatment with plasmapheresis is required. As a result, if patients with vitamin B12 deficiency are misdiagnosed they may receive unnecessary invasive intervention. It is therefore important in these cases to ensure a blood film is examined by a haematologist to differentiate between TTP and B12 deficiency, with the former typically associated with the presence of fragments (ie,schistocytes) while the latter is associated with oval macrocytes and hypersegmented neutrophils (see Figure 1).
2. What are the causes of B12 deficiency, and which groups are at particular risk?
The causes of vitamin B12 deficiency can be broadly divided into the following categories:
- Autoimmune: Pernicious anaemia is an autoimmune condition which particularly affects people over the age of 60 years.5 It is characterised by antibodies targeting intrinsic factor (IF), which plays a critical role in binding and facilitating the transport of B12 to the terminal ileum for absorption. Patients with pernicious anaemia also have a higher incidence of co-occurring autoimmune disorders including type 1 diabetes mellitus, vitiligo and autoimmune thyroid disease.6 In addition, it can be found in 25% of patients with autoimmune gastritis (AIG).5
- Malabsorption: Parietal cells in the stomach produce intrinsic factor which facilitate B12 absorption. Therefore, patients with a history of bariatric surgery (eg, Roux-en-Y gastric bypass or sleeve gastrectomy) OR those who have had gastrectomy for cancer management or terminal ileal resection for Crohn’s disease are at increased risk of developing B12 deficiency. Any other damage to the small intestine, such as previous abdominal or Coeliac disease, may also affect B12 absorption.
- Dietary insufficiency: This is commonly observed in people who follow a vegan diet or those who have an allergy to certain food types, including eggs, milk or fish. There should also be a high index of suspicion for B12 deficiency in those people who are finding it difficult to buy or prepare food due to dementia or frailty, or because of underlying mental health conditions.1,5
- Medications/toxins: Medications can be associated with reduced B12 levels including those which reduce gastric acid production (H2-receptor antagonists and proton pump inhibitors).2 Metformin is another well-known cause for B12 deficiency – the mechanism by which it does this is unclear although malabsorption may be a contributing factor. Previous studies have shown that increasing dose and prolonged duration of metformin treatment are major risk factors for developing B12 deficiency.7 As a result, the MHRA has published safety advice that patients receiving metformin should be tested for B12 deficiency if they develop symptoms. In addition, the MHRA recommended periodically monitoring B12 levels in those with other risk factors for developing B12 deficiency.8 At the present time, there is no evidence to support prophylactic B12 treatment in patients receiving metformin treatment.2 As well as medications, recreational nitrous oxide use is a well-known cause for B12 deficiency and should be excluded in patients presenting with neurological symptoms.1
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Dr Priya Sriskandarajah is Consultant Haematologist at Guy’s and St Thomas’ Hospital, London
I have had patients who have questioned the accuracy, i.e. false negative rates of the pernicious anaemia screen blood test, whats the evidence on that?