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Vitamin B12 Deficiency

Epidemiology varies based on etiology
Three commonest reasons being ○ autoimmune ○ malabsorption and dietary There is widespread global prevalence of Vitamin B12 deficiency resulting in considerable morbidity Can manifest at any age but prevalence generally increases with age In the UK and USA the prevalence is approximately 6 % in people < 60 and about 20 % in those older than 60.

Also referred to as cobalamin Two important roles
○ DNA synthesis
○ neurological functioning Absorbed in terminal ileum where it binds to intrinsic factor produced by gastric parietal cells Once absorbed B12 is used as a co-factor for enzymes that are involved in the synthesis of DNA , fatty acids and myelin Foods containing B12 derived only from animal products
○ meat
○ fish
○ dairy B12 is stored in liver Body stores generally enough ( last 2-4 yrs ) –> deficiency from diminished intake may not manifest for few yrs If B12 is not absorbed for prolonged periods – hepatic stores would be eventually depleted leading to deficiency Recommended daily dose in small

Risk factors B12 deficiency Vegans / vegetarians H/O gastric or intestinal surgery H/O atrophic gastritis Pernicious anaemia Gastric malabsorption Intake of medications which can interfere with absorption of Vit B12 e.g metformin , PPI use People aged > 65 type 2 diabetes use of anticonvulsants as carbamazepine pregnancy

Causes of B12 deficiency-Dietary – inadequate intake Malabsorption
○ pernicious anaemia
○ medications e.g long term PPI use
○ chronic alcoholism
○ pancreatic failure
○ coeliac disease ( more commonly causes Fe and Folate deficiency than B12 )
○ gastrectomy
○ small bowel surgery ( e.g terminal ileal )
○ generalised malabsorption
 tropical sprue
○ inflammatory bowel disease particularly that affecting the terminal ileum e.g Crohn’s disease
○ blind loop syndrome and or small bacterial overgrowth Medications e.g metformin, PPIs , hydroxyurea , methotrexate , trimethoprim , zidovudine Pregnancy Rare causes as disorders of cobalamin transport


Anaemia –exclude other causes including haematological disorders eg malignancy , myelodisplasia , haemolysis exclude hypothyroidism , chronic liver disease etc


Diet-dietary deficiency ? vegan or vegetarian ? anorexic or has food fads / poor diet

Family or personal h/o autoimmune disorders –positive family h/o personal auto-immune disorders ? the patient ,parents , sibling have vitiligo ? hypothyroidism or pernicious anaemia 

This increases the pre-test probability of pernicious anaemia

Tongue –glossitis or mouth ulceration ? glossitis is common with low cobalamin and mouth ulcers may reflect folate deficiency

Neurological changes –ask about h/o paraesthesia , unsteadiness , peripheral neuropathy several conditions can be responsible for these symptoms which include diabetes , CTS , paraproteinaemia important to note that neurological manifestations of B12 deficiency may happen despite normal haematological indices

Malabsorption –steatorrhoea ( pale stools )
this can happen due to pancreatic disease , coeliac disease bowel movements at night abdominal pain mouth or perianal ulceration ? pancreatitis due to alcohol excess h/o gastrectomy , bariatric surgery or small bowel resection ( may happen as part of a hemicolectomy )

Other causes-Drug history ? PPIs , Metformin , oral contraceptive pills Pregnancy- 3rd trimester low cobalamin levels may be physiological Elderly -low folate/b12 may reflect poor general

Full Blood Count- Anaemia ( low Hb and low haematocrit ) Peripheral blood film -
○ hypersegmented neutrophils
○ oval macrocytes
○ circulating megaloblasts Leucopenia and thrmbocytopenia ( also common ) Folate can be normal or high

These are typical features of cobalamin deficiency , however an elevated MCV is not a specific indicator of cobalamin deficiency and the possibility of underlying myelodysplastic syndrome should be considered

It is also important to take into account that neurological impairment can occur with a normal MCV in 25 % cases 


Serum B12 and Folate –Easily available and a familiar test Limited diagnostic accuracy – unreliable as a standalone marker No well-defined cut-offs for deficiency BMJ best practice suggests that generally B12 values can be broken down into 3 categories

○ < 148 probable Vit B12 deficiency
○ 148-258 possible B12 deficiency
○ > 258 deficiency unlikely

This seems to be the the most practical parameter to follow. 

Also take into account that serum B12 may be artificially elevated in patients with alcoholism , liver disease or cancer ( decreased hepatic clearance of transport proteins and resultant

Other tests if diagnosis remains unclear-Plasma homocysteine
○ sensitive biomarker of cobalamin deficiency
○ B12 deficiency leads to elevation of plasma homocyteine
○ not specific to cobalamin deficiency as levels as conc also elevated in folate deficiency , B6 deficiency , renal failire , hypothyroidism and certain genetic polymorphisms MMA ( plasma methylmalonic acid )
○ a more direct measure if Vit B12 phsyiologic activity
○ raised in B12 deficiency
○ expensive and not widely available
○ can be also elevated with folate deficiency , renal failure Holotranscobalamin ( hTC )
○ transcobalamin bound to VitB12 and can be a measure of the true functional serum B12 level
○ this is still being studied to evaluate the clinical utility Reticulocyte count – helps differentiate B12 deficiency from haemolytic anaemia

Tests for pernicious anaemia –Anti-intrinsic factor antibody ( anti-IFAB ) if positive the test has a high positive predictive value ( 95 % ) for presence of pernicious anaemia with a concurrent low false + ve rate ie a high specificity
○ a negative IFAB test does not r/o pernicious anaemia
○ positivity ↑↑ es with age and in certain racial groups 
○ patients with negative IFAB with no other cause of deficiency can be treated as IFAB negative pernicious anaemia
○ BCSH guideline states that testing for IFAB should be advised in patients with strong clinical features of deficiency as megaloblastic anaemia or SACD despite a normal serum cobalamin level Gastric anti-parietal cell antibody
○ can be helpful in conjunction with other tests if the cause is pernicious anaemia
○ have a low specificity for the presence of pernicious anaemia as despite being + ve in 80 % of PA subjects they are also + ve in 10 % of normal individuals Testing for malabsorption as coeliac disease , bone profile , Vit D , folate , ferriitn Gastrin ( fasting ) – rises in achlorhydria and can signify PA

Treatment –Treatment of B12 deficiency is with hydroxocobalamin in the intramuscular form as outlined in BNF ( see under links ) in the UK Patients with irrversible causes are treated indefinitely Cyanocobalamin – is available as IM / SC/ oral / sub-lingual or intranasal Oral forms can be used if the cause is dietary oral cyanocobalamin 50-150 mcgms between meals
If the cause is unclear oral preparations may not be absorbed as expected if a malabsorbtive condition is present How to manage patients with asymptomatic B12 deficiency remains unclear- you may follow the British Committee for Standards in Haematology guidance on this. This will be under section – Low cobalamin without anaemia or other significant objective parameters ( low cobalamin of uncertain significane ) Folate replacement – it may be useful to add folic acid 5 mg od x 4 months for patients with anaemia due to B12 deficiency ( this avoids the possibility of inducing folate deficiency consequent upon the 
↑ ed normoblastic red cell production that should follow after providing a source of the previously deficient Vit B12 )

Referral / Follow up-Be guided by likely aetiology Consider haematological referral if
○ cause of B12 and folate deficiency remains unclear
○ a serious underlying cause is suspected for e.g haematological malignancy or other blood disorders
○ response to treatment is not as expected
○ MCV is persistently greater than 105
○ neurological symptoms
○ pregnancy Gastroenterological referral
○ suspected malabsorption or inflammatory bowel disease 
○ pernicious anaemia diagnosed and GI symptoms particularly if gastric cancer is suspected ( for e.g co-existing iron deficiency ) Dietitian referral
if B12 or folate deficiency is dietary in origin
 Check FBC and reticulocyte count within 7-10 days of treatment
○ a rise in Hb and ↑ in reticulocyte ct above normal range is 
indicative of a positive response
○ after 8 weeks of treatment ( MCV should have normalised )
○ check B12 1-2 months after Rx if there is no response
○ check folate if no response or not tested earlier


LINKS AND RESOURCES

PATIENT RESOURCES 

Impressive work from NHS Inform – a complete educational resource for the patient with 6 sections https://www.nhsinform.scot/illnesses-and-conditions/nutritional/vitamin-b12-or-folate-deficiency-anaemia

Information from NHS UK https://www.nhs.uk/conditions/vitamin-b12-or-folate-deficiency-anaemia/

Another very useful educational tool for the patient from Health Service Executive Ireland https://www.hse.ie/eng/health/az/b/b12-deficiency/

A section on B12 deficiency from Oregon State University– should be an essential read for patients and clinicians alike who deal with this condition. This may confuse the patient a bit and please read first before recommending to patients https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12

Hydroxocobalamin Patient information leaflet from Medicine Compendium https://www.medicines.org.uk/emc/files/pil.5038.pdf

FOR HEALTH CARE PROFESSIONALS

A simple to understand plain language article from National Institute of Health https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/

BNF dosage for hydroxocobalamin https://bnf.nice.org.uk/drug/hydroxocobalamin.html

The management of B12 deficiency can be challenging and confusing – several trusts have tried to produce a guideline for GPs to help the situation.

From Bury Clinical Commissioning Group https://www.buryccg.nhs.uk/download/document_library/your-local-nhs/plans_policies_and_reports/medicines_optimisation/Treatment-vitB12-deficiency.pdf

Mid-Essex Clinical Commissioning Group https://midessexccg.nhs.uk/about-us/the-library/medicines-management/clinical-pathways-and-medication-guidelines-1/chapter-9-nutrition-and-blood-2/3002-vitamin-b12-deficiency-in-adults-september-2018-new/file

Royal United Hospital Bath https://www.ruh.nhs.uk/For_Clinicians/departments_ruh/Pathology/documents/haematology/B12_-_advice_on_investigation_management.pdf

Hull and East Rising Prescribing Committee https://www.hey.nhs.uk/wp/wp-content/uploads/2016/03/vitaminB12FolateDeficiency.pdf

Guideline on B12 Deficiency Management from the British Committee for Standards in Haematology ( open access ) https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12959

Can we prescribe oral cyanocobalamin ? Read further https://westessexccg.nhs.uk/your-health/medicines-optimisation-and-pharmacy/clinical-guidelines-and-prescribing-formularies/09-nutrition-and-blood/vitamins/3194-cyanocobalamin-decision-document/file

Another paper on oral cyanocobalamin from Frontiers in Medicine https://www.frontiersin.org/articles/10.3389/fmed.2016.00038/full

 

 

 

References

  1. Anaemia and B12 deficiency CKS NHS July 2015
  2. Vitamin B12 deficiency BMJ Clinical Review BMJ 2014;349:g5226
  3. Guideline for the diagnosis and treatment of cobalamin and folate disorders Vinod Devalia et al British Journal of Haematology June 2014
  4. Manchester anaemia guide- accessed via https://www.cmft.nhs.uk/media/499600/manchester%20anaemia%20guide.pdf
  5. Essential Haematology AV Hoffbrand , PAH Moss John Wiley and Sons Inc
  6. Medscape Pernicious Anaemia Paul Schick , MD et al Sep 2015
  7. Oxford Handbook of Clinical Haematology Drew Provan et al Oxford University Press
  8. Medicines complete- drugs used in megaloblastic anaemias Kumar and Clark’s Clinical Medicine -Edited by Parveen Kumar , Michael Clark
  9. Vitamin B12 Deficiency Alex Ankar , Anil Kumar StatPearls Bookshelf January 2019
  10. BMJ Best Practice Vit B12 deficiency
  11. Vitamin B12 deficiency : Recognition and Management Robert C Langan et al Am Fam Physician . 2017 Sep 15;96 (6) : 384-389

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