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Ten top tips - vitamin B12 deficiency

GP Dr Andrew McCaddon offers advice on how to identify and manage vitamin B12 deficiency

 

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.

References:

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.

 Fam.Pract. 2006;23(3):279-85

Readers' comments (15)

  • this is excellent piece of information....answers lot of previously unanswered questions..must read for all clinicians & their trainee(s.) .

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  • Dear Jayanta,
    Thank you for your kind comments!

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  • Absolutely brilliant thank you.

    Please ALL NOTE: The Pernicious Anaemia Society is holding a conference in Wales on

    Sat 19th October
    where there will be GUEST SPEAKERS and it is for Sufferers, their families and Health Professionals
    check out our website for more details or call us.

    Venue - The Pernicious Anaemia Society
    Level 4
    Brackla House
    Brackla Street
    BRIDGEND
    CF31 1BZ

    Tel: 44(0)1656769717
    Reg. Charity No. 1147839

    Hope to see you there :)

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  • informative-thank you

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  • Very informative thank you. All that is need now is for GPs to be aware and to have the confidence to treat their patients symptomatically instead of rigidly adhering to the 3-month rule - if they did that the outcomes for PA patients would be greatly improved. Withholding injections is, in my humble opinion, cruel at best and clinically dangerous at worst. Subjecting patients needlessly to the dangers of nerve damage needs to be eradicated throughout the UK as a matter of urgency so that PA patients can regain a decent quality of life. Thank you.

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  • Excellent article.
    However, unless this is changed to CAN give injections more frequently many GPs will still refuse to move from the 3-monthly rule. Many GPs routinely deny PA/B12 patients injections when they need them, when symptoms have returned, forcing them to wait for their 3-monthly injection, by which time symptoms are much worse.

    The medical profession wouldn't dream of allowing diabetic patients to suffer nerve damage by refusing them insulin, yet on a daily basis, all over the UK, many uninformed GPs are routinely refusing PA/B12 patients B12 injections when they need them, and this exposes them to the real dangers of nerve damage.

    PA/B12 patients need to be treated proactively which would prevent the reoccurrence of symptoms. They do not need to be treated reactively to try and get rid of the symptoms once they have reappeared. B12 levels need to be kept at a sufficiently high level to prevent the reappearance of symptoms, and the only way to do this is to give maintenance injections more regularly if necessary. Even patients with neuro symptoms are being refused appropriate treatment which is quite frankly unimaginable, but it happens, regularly.

    The current treatment of PA/B12 patients in the UK is, in many cases, woefully inadequate and needs to change. You only need to read some of the stories on the PAS website to see that misdiagnosis coupled with inappropriate treatment is having a major impact on the health of a significant proportion of PA/B12 patients.

    Correct diagnosis together with appropriate treatment tailored to the individual needs of each patient would save the NHS a fortune in long term care bills for patients who become nerve damaged and need long term care when all they really needed was the appropriate treatment for B12 deficiency (injections cost approx. 68p so this is not a costly medication). This is quite frankly a medical disaster of epic proportions and yet it continues to occur on a frighteningly regular basis.

    In order to protect the health of PA/B12 patients, and as a matter of some urgency, GPs now need to be issued with specific and detailed protocols giving them the information that they need and the confidence to treat their PA/B12 patients appropriately, to enable nerve damage to be repaired as much as possible in newly diagnosed patients and to help them to establish a maintenance programme tailored to the needs of the individual patient rather than the 'one size fits all' current regime of 3-monthly injections, which clearly does not suit every patient, and which is causing untold nerve damage and ruining the quality of life for countless PA/B12 patients across the UK.

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  • Really good to read.

    A few of points:

    The association of low B12 and thyroid disorder (primarily hypothyroidism) is very strong though reporting is highly variable as to numbers. I feel that could have been better emphasised.

    The only oral supplement mentioned is cyanocobalamin, whereas the majority of high dose supplements nowadays seem to be methylcobalamin. (Though there is no UK licensed form so far as I know.)

    Although lack of macrocytosis is mentioned, it does not specifically identify the issue of concurrent iron-deficiency anaemia with low B12 resulting in a seemingly unexceptional mean corpuscular volume. Elevated red blood cell distribution width might sometimes give a clue.

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  • Excellent article. Lets hope some GPs read it and more importantly act on it. They should consider this in all their patients that are not responding to standard thyroid treatments instead of dishing out anti depressants and labelling them with mental health conditions or diagnosing them with fibromyalgia CFS. The latter conditions are an invention by a medical profession to shut up chronically ill patients and doctors who now quite wrongly rely on the flawed thyroid function test TSH (ridiculous as it does not measure thyroid hormones) to treat and diagnose thyroid conditions.

    A point worth making is the travesty of diagnosing folate deficiency and treating that without heed to B12 deficiency. This masks a B12 deficiency whilst the neurological damage continues undetected. My sister is permanently disabled as a result of this negligence and missed diagnosis.

    Thank goodness for your report - someone needs to educate our medical profession and this is a great place to do it - are you reading and learning GPs out there?

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