1. Be aware of the limitations of laboratory tests.
Signs and symptoms of vitamin B12 deficiency can arise even when serum levels are borderline or in the low-normal range. There are several reasons for this. Current assays measure the total amount of B12 on two carrier proteins, haptocorrin and transcobalamin. However, only transcobalamin actively delivers B12 to tissues. In addition, current assays can give false normal results if the patient has a high titre of anti-intrinsic factor antibodies.1 If you have a high clinical index of suspicion of deficiency consider additional tests, such as holo-transcobalamin and metabolic markers of deficiency such as serum homocysteine and methylmalonic acid. You may have to discuss the availability of these with your local laboratory.
2. Vitamin B12 deficiency can exist in the absence of macrocytic anaemia.
It is important to remember that vitamin B12 deficiency is not synonymous with pernicious anaemia (PA). Autoimmune PA is just one cause of B12 deficiency. Low levels of B12 can exist in the absence of macrocytic anaemia. In fact, the neuropsychiatric and haematological features of deficiency are frequently dissociated. 2
3. Vitamin B12 deficiency can cause behavioural changes
Patients often complain of ‘waking up tired’ even after a good night’s sleep. They may also complain of a lack of mental clarity, nominal aphasia, short-term memory loss and repetition. Irritability, frustration and impatience with a desire for isolation and an aversion to bright lights are also common. All these can have an adverse impact on family life and workplace performance leading to anxiety and depression.
4. The anaemia of B12 deficiency can present in various ways
Breathlessness can manifest as panting during physical exertion or regular deep breaths. It can also present as continual sighing or yawning. The low red blood cell count may lead to an increased flow state perceived as pulsatile tinnitus. Patients may complain of ‘screaming’, ‘whistling’ ‘screeching’ or other strange sounds.
5. Remember that the gastrointestinal tract may be involved
Sudden and unaccountable bouts of diarrhoea are common. The tongue may appear swollen/beefy and smooth or red with cracks and will be larger than usual. This usually resolves rapidly with vitamin B12 replacement.
6. B12 deficiency produces many neurological signs and symptoms
Neurological signs usually generate a clinical picture of combined sclerosis of the spinal cord, but can vary across a wide clinical spectrum. Left undiagnosed and untreated, vitamin B12 deficiency leads to paraesthesia, numbness, gait disturbance, balance and coordination problems, and vertigo. Patients may experience burning legs and/or feet (Grierson-Gopalan syndrome) affecting one or both limbs, typically worse in the evenings. All patients with neurological symptoms should also be referred to a haematologist.
7. Check for concomitant medications that might interfere with vitamin B12 absorption
Medications that reduce stomach acid, such as H2-receptor antagonists or PPIs, may reduce vitamin B12 absorption from food and these patients might benefit from supplementation.
Metformin, slow-release potassium supplements, colchicine and AZT can also reduce absorption of vitamin B12 and may contribute to deficiency.
Although serum concentrations of B12 may be lowered by oral contraceptives, a recent study found no metabolic evidence of deficiency in such patients.
8. Remember the at-risk groups
Vitamin B12 deficiency is common in the elderly, but can occur at all stages of life including infancy. Additional risks are:
- Previous gastric and bowel surgery, which may reduce absorption.
- Other autoimmune diseases, which often co-exist with vitamin B12 deficiency, such as diabetes, thyroiditis, and psoriasis.
- Strict vegetarianism: up to 88% of vegans who do not take supplements can be deficient.
- Dietary intolerance: it is also important to be aware that bioavailability of vitamin B12 may be low in goat’s milk.
9. Check the injections schedule and dosage
In pernicious anaemia or malabsorption, hydroxocobalamin 1,000 mcg should be given initially three times a week for two weeks, then 1 mg every three months as long term maintenance. Importantly, where there is neurological involvement, initial dosage should be 1,000 mcg on alternate days until no further improvement is observed, then 1,000 mcg every two months according to the BNF 2013.
Some patients find that their symptoms return before their next injection. The reason for this is not yet known. It might relate to genetic polymorphisms of transcobalamin or its receptor.3 In such patients perhaps consider giving injections more frequently, or supplementing injections with daily high dose oral B12 supplementation (see below).
10. Do not overlook the role of oral vitamin B12
Oral cyanocobalamin is appropriate for people with proven dietary B12 deficiency. Small amounts of vitamin B12 can also be absorbed by passive diffusion in the absence of intrinsic factor, so haematological and neurological responses can be maintained with high daily doses (1,000-2,000 mcg) of an oral preparation.4 Oral vitamin B12 formulations may be preferred if patients cannot tolerate the transient pain and stinging from an injection. However, an injection may be more reliable for those who are unable to take an oral medication regularly. Oral formulation of cyanocobalamin should not be used for patients with Leber’s optic atrophy, tobacco-alcohol amblyopia or renal failure.
Dr Andrew McCaddon is a principal GP in Wrexham and honorary senior research fellow in the School of Medicine, Cardiff University. He has a research interest in vitamin B12 deficiency and dementia.
Competing interests: Dr McCaddon is a director of Cobalz Limited, a private company developing Betrinac and other high dose B vitamin and antioxidant supplements.
The Pernicious Anaemia Society is a registered charity that strives to improve current and future diagnosis and treatment of pernicious anaemia, whilst providing support, help and information to sufferers, their families and healthcare professionals. Helpline: 01656 769717.
1. Yang DT, Cook RJ. Spurious elevations of vitamin B12 with pernicious anemia. N Engl J Med 2012;366(18):1742-3 doi:
2. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988;318(26):1720-28.
3. McCaddon A. Vitamin B(12) in neurology and ageing; Clinical and genetic aspects. Biochimie 2013 95(5):1066-76
4. Butler CC, Vidal-Alaball J, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials.