B₁₂ deficiency

Case Scenario 

Romika, in her mid-20s, asks your advice about ongoing fatigue and pins and needles which she has had for several months. You recognise that her strict vegan diet increases her risk of vitamin B12 deficiency and that her symptoms are consistent with this. You refer her to her GP for blood tests. There is macrocytosis and her serum B12 level is equivocal. Her HoloTC levels are found to be 35 nmol/L, indicating likely B12 deficiency.

Learning Objectives  After reading this article, pharmacists should be able to:  Describe the causes of vitamin B12 deficiency  Discuss how vitamin B12 deficiency is diagnosed  Describe the treatments for vitamin B12 deficiency  Discuss when pharmacist administration of intramuscular vitamin B12 is appropriate.  Competency (2016) standards addressed: 1.1, 1.4, 1.5, 2.2, 3.1, 3.2, 3.5

 

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Introduction 

Vitamin B12 (cobalamin) is an essential water-soluble vitamin that humans obtain from their diet.^1-6 Deficiency can cause serious haematological, neurological and psychiatric problems.^1-6 Early diagnosis and treatment may reverse deficiency and minimise harms.^3,5 Pharmacists can identify and refer patients with possible deficiency, advise on suitable treatments and can administer intramuscular vitamin B12 treatment where there is a therapeutic need and professional obligations are met.

Absorption and importance 

The absorption of B12 is complex. In sequence it is^1-2: 

• ingested protein-bound in food, or free in supplements and fortified food 
• separated from protein by stomach acid and pepsin 
• bound with haptocorrin in the stomach (from salivary glands and parietal cells) 
• separated from haptocorrin in the duodenum by pancreatic enzymes 
• bound with intrinsic factor (IF – from parietal cells) in the duodenum 
• absorbed into ileal enterocytes, separated from IF and exported into the portal circulation 
• bound as holo-transcobalamin (holoTC) which is transported around the body and absorbed by cells, or it is bound as holo-haptocorrin (holoHC) which is not biologically active and is unavailable for cellular uptake. HoloHC is then transported to the liver for storage, undergoing enterohepatic recirculation.

B12 is involved in two biochemical pathways^1,2,4-8,11: 

1. As a cofactor for L-methylmalonylCoA mutase: deficiency causes accumulation of methylmalonic acid (MMA) and a de cit of succinyl-CoA, disrupting myelin synthesis. 
2. As a cofactor for methionine synthase: B12 and folate de ciency both cause accumulation of homocysteine and de cit of S-adenosyl methionine (SAMe), disrupting synthesis of myelin, neurotransmitters and membrane components and the generation of thymidine for DNA.

Signs and symptoms 

Hepatic stores of B12 may delay symptom onset for years.^2,4

General 

Symptoms include^2-4,6,12: 

• anorexia 
• glossitis 
• infertility 
• stomatitis. 

Haematological 

Deficiency can cause macrocytic megaloblastic anaemia and pancytopenia. 

Symptoms include^1-6: 

• dyspnoea 
• fatigue 
• palpitations 
• pallor. 

Neurological 

Deficiency can cause progressive demyelination of neurons. Symptoms include^1-6,10: 

• autonomic dysfunction 
• developmental delay in children 
• motor/gait disturbance 
• paraesthesia 
• peripheral neuropathy 
• subacute combined degeneration of the spinal cord. 

Psychiatric 

As well as nerve damage, deficiency disrupts production of neurotransmitters. 

Symptoms include^1-6,11: 

• cognitive impairment 
• dementia 
• depression 
• irritability 
• memory loss 
• personality change. 

Cardiovascular 

High homocysteine levels have been associated epidemiologically with increased risk of myocardial infarction and stroke.^1-6,13

Causes and risk factors 

B12 deficiency can occur in people who have low dietary intake, increased requirements, or impaired absorption, or any combination of these.^1-6

Nutritional deficiency 

B12 is obtained from eating animal products. Some soy products, yeast spreads and meat alternatives are fortified with B12.^1-6,10

Deficiency can occur in^1,3,4,10: 

• people who do not eat any, or insufficient, animal products or fortified foods 
• people with malnutrition 
• newborn or exclusively breastfed children of B12-deficient mothers.

Increased requirements

More B12 is required during periods of growth, pregnancy and lactation, and in diseases that increase blood cell turnover.^1,2,6

Impaired absorption 

Absorption can be impaired in people who have^1-6,14: 

• autoantibodies against parietal cells or IF (pernicious anaemia) 
• reduced parietal cell mass from atrophic gastritis 
• reduced pepsin from aging 
• reduced stomach acid and IF from ongoing proton pump inhibitor or histamine type 2 receptor antagonist use 
• reduced ileal absorption from ongoing metformin use 
• surgery or defects affecting gastrointestinal tract (GIT) structures 
• inherited conditions affecting IF 
• malabsorption syndromes 
• pancreatic insufficiency. 

Diagnosis 

Diagnosis is made by a medical practitioner with blood tests, with consideration of a patient’s risk factors and any signs and symptoms suggesting deficiency. Patients may have neuropsychiatric symptoms without haematological changes2,6 and damage may be irreversible if neuronal death occurs.^2-4,6,11 Conversely, haematological findings of deficiency do not always manifest symptoms.¹

Pharmacists should refer all patients with suspected deficiency to a medical practitioner for investigation including pathology.^2,3

The haematological effects of B12 and folate deficiency are identical.¹ Folate supplementation may mask B12 deficiency, allowing neurological damage to progress.⁵ Screening healthy populations for B12 deficiency is not necessary but may be warranted in people with risk factors.^1,4

Blood tests

Full blood count (FBC) 

A FBC showing macrocytosis suggests B12 deficiency.^1-4,15 However, this is a late manifestation and may not occur^3,5,11,15 or can be masked by iron deficiency.² 

Serum B12 

Serum B12 testing measures combined holoTC and holoHC and therefore does not clearly indicate the amount of biologically active B12. Generally, it should be measured after a FBC has shown signs of deficiency, in the presence of symptoms or in people with risk factors. Results may not correlate with symptoms however, and relying on serum B12 may underestimate true deficiency.^1-3,6

The values used for B12 deficiency can vary significantly between laboratories. A common measure of deficiency is serum B12 <80 nmol/L, with deficiency considered unlikely >340 nmol/L.^20,21 Many patients experience symptoms above a level where deficiency is considered likely, with up to 30% of patients with a serum B12 measuring in the range 200–340 nmol/L having low levels of HoloTC.^12,21

If symptoms exist and/or serum B12 measurement is equivocal, measurement of a metabolic marker of vitamin B12 reserves will improve diagnostic accuracy.^1,4,5 The active form of B12 (HoloTC) is considered the best indicator of a patient’s B12 levels.²¹

Metabolites 

HoloTC 

Lowered serum HoloTC is the earliest marker for B12 deficiency, falling before serum B12.^1,2,4 <38 nmol/L indicates deficiency,20,21 however it has an intermediate range where deficiency is uncertain and may be associated with neurological symptoms.^2,21

Methylmalonic acid (MMA)

MMA may also be elevated in renal impairment. It rises before haematological changes occur. 1–6 – >260 nmol/L indicates deficiency.¹

Homocysteine 

Homocysteine accumulates in both B12 and folate deficiency and may also be elevated in renal impairment. It rises before haematological changes occur.^4,5,6

– >9 micromol/L suggests emerging deficiency.¹

– >12 micromol/L indicates low B12 status.¹

– >15 micromol/L indicates depleted B12 stores.¹

Treatment

Treatment involves initial replacement then ongoing maintenance therapy, or preventive therapy for patients with risk factors.^2-4,16

Treatment with B12 supplements is generally well tolerated and relatively inexpensive.^1,2,3,6 Increased dietary intake may be sufficient in some cases.^3,4

B12 is administered either orally or intramuscularly.^2,5,6 There is debate about the relative effectiveness of oral and intramuscular administration. Overall, high-oral dose treatment (>1,000 micrograms) is as effective as intramuscular treatment, even if GIT absorption is impaired.^2,3,5,6

However, the intramuscular route is recommended for initial treatment by the Therapeutic Guidelines and as maintenance therapy in patients with severe anaemia or neurological symptoms.¹⁶ It is also recommended in other cases where a rapid response is required (e.g. severe anaemia or severe symptoms).^2,4

Intramuscular 

Supplements available for intramuscular injection include cyanocobalamin and hydroxocobalamin.^14,16

Hydroxocobalamin has a longer duration of action, allowing less frequent administration.^9,14,16

A typical adult initial replacement regimen is hydroxocobalamin 1,000 microgram every second day for 2 weeks.¹⁶ This regimen may be less intensive in cases without severe anaemia or neurological symptoms.¹⁶

A typical adult preventative or maintenance regimen is hydroxocobalamin 1,000 microgram every 2–3 months.^14,16

Oral 

Supplements include cyanocobalamin tablets and sublingual sprays, and mecobalamin chewable and sublingual tablets.^2,6,14,16 They have similar absorption and efficacy.⁶

Cyanocobalamin 1,000–2,000 microgram orally daily for 1–2 weeks has been used for initial adult B12 replacement treatment.^5,9 As mecobalamin has similar absorption,6 the same regimen using it may be equivalent. A typical adult preventive or maintenance regimen is mecobalamin 1,000 microgram daily.¹⁶ Cyanocobalamin 50–200 microgram daily can be used if gastrointestinal absorption is not impaired.¹⁶

Intramuscular administration by pharmacists 

Intramuscular hydroxocobalamin may be administered by suitably trained pharmacists.¹⁷ PSA’s Guidelines for Pharmacists Administering Medicines by Injection describe the professional requirements that must be met by pharmacists, and PSA’s Administering Medicines by Injection Course upskills trained and authorised pharmacist immunisers to administer medicines by injection, including hydroxocobalamin.^17,18

Patient counselling and follow-up 

Ongoing treatment is required for all patients with irreversible causes of deficiency.^2,4,16 

There are no clear Australian guidelines for frequency of B12 testing;^1,4 however, regular review (i.e. every 1–2 years) is recommended if risk factors exist.^5,16

The Medicare Benefits Schedule funds one serum B12 test a year.19 Some overseas references and guidelines indicate that retesting of vitamin B12 after treatment starts is generally not necessary unless there is no symptom improvement as levels increase with vitamin B12 supplementation regardless of effectiveness of treatment.^2,4

However, the Therapeutic Guidelines recommends rechecking serum B12 3–6 months after starting initial supplementation,¹⁶ and a yearly full blood count and vitamin B12 level is also recommended.^14,17 Patients requiring treatment should confirm their monitoring needs with their medical practitioner, as these may vary depending on their specific therapeutic needs. 

Neurological symptoms may improve in the first week and take 6–12 weeks to resolve. Rehabilitation may speed recovery but there may be permanent symptoms if treatment is delayed.² Patients may feel symptom improvement within 24 hours of starting treatment. Haematological response can take several days to occur and up to 2 months to complete.^2,10

Treatment with B12 is generally well tolerated.^1,3,6 Some rare side effects include itching, nausea and dizziness.² Adverse effects typical of IM injection may occur (e.g. pain and injection site reactions).⁵ B12 is water soluble and excreted in the urine. There is low risk of toxicity from excessive intake.¹

Knowledge to practice 

Pharmacists should consider B12 deficiency in people with typical symptoms or patients with risk factors and refer them to their medical practitioner for assessment. Pharmacists can advise on suitable treatments and can administer intramuscular B12 if there is established therapeutic need, they are suitably trained and they meet all professional requirements. Pharmacists should provide advice on potential adverse effects of treatment and when to expect benefit and resolution of symptoms.

Conclusion 

Vitamin B12 deficiency is common and can cause serious health problems.2 Early detection and treatment is vital in preventing or potentially reversing complications.5 Pharmacists can play a key role in identifying typical symptoms in people at risk, and in recommending and providing treatment.

Case Scenario Continued  Romika’s GP advises Vitamin B12 replacement and lifelong maintenance if necessary. She is prescribed intramuscular hydroxocobalamin 1,000 microgram every second day for 2 weeks, followed by ongoing daily oral B12. She is unable to attend her doctor’s surgery frequently for injections. As therapeutic need has been established, and as you are an authorised pharmacist immuniser and have met all professional requirements, you administer her course of intramuscular injections in your pharmacy. Afterwards, you advise her to take chewable mecobalamin 1,000 microgram daily. Romika’s fatigue improves in the first week of treatment, and her pins and needles reduce after several months.

 

Key Points 

Vitamin B12 deficiency: 

• can cause serious health consequences affecting haematologic, neurologic, cardiovascular and psychiatric function. 
• must be diagnosed with blood tests and assessment by a medical practitioner. 
• can be readily treated with oral and/ or parenteral treatment. Pharmacists can administer intramuscular vitamin B12 where there is a therapeutic need, if suitably trained to do so and they meet all professional requirements. 
• requires lifelong treatment if risk factors are irreversible.

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References 

1. Australian Government Department of Health and Aged Care. MBS Reviews – Vitamin B12 – Report. 2014. At: www1.health.gov.au/internet/main/publishing.nsf/Content/VitaminB12testing
2. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ 2014;349:g5226.
3. Benson J, Maldari T, Turnbull T. Vitamin B12 deficiency – Why refugee patients are at high risk. Aust Fam Physician 2010;9(4):215–7.

4. Langan R, Goodbred A. Vitamin B12 deficiency: recognition and management. Am Fam Physician 2017;96(6):384–9.

5. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003;67(5):979–86.
6. National Institutes of Health. Vitamin B12 – Fact sheet for health professionals. 2022. At: https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/

7. Miller J. Proton pump inhibitors, H2-receptor antagonists, metformin, and vitamin B-12 deficiency: clinical implications. Adv Nutr 2018;511S–518S.

8. Shane B. Folate and vitamin B12 metabolism: overview and interaction with riboflavin, vitamin B6, and polymorphisms. Food Nutr Bull 2008;29(2):S5–S16.
9. Wang H, Li L, Qin LL, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database of Systematic Reviews 2018, Issue 3.

10. National Health and Medical Research Council. Vitamin B12. In: Nutrient reference values for Australia and New Zealand including recommended dietary intakes. NHMRC; 2006. At: www.eatforhealth.gov.au/sites/default/files/2022-04/n35-vitaminb12_0.pdf
11. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database of Systematic Reviews 2003, Issue 3.
12. Sansom LN, ed. Vitamin B12. Australian pharmaceutical formulary and handbook online. Pharmaceutical Society of Australia; 2022. At: https://apf.psa.org.au/monitoring/normal-physiological-values/vitamins
13. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews 2017, Issue 8.
14. Rossi S, ed. Vitamin B12. Australian medicines handbook online. Adelaide: Australian Medicines Handbook; 2022. At: https://amhonline.amh.net.au/chapters/blood- electrolytes/drugs-anaemias/other-drugs-anaemias/vitamin-b12
15. Rumsey S, Hokin B, Magin P, et al. Macrocytosis – an Australian general practice perspective. Aust Fam Physician 2007;36(7):571–2.
16. Vitamin B12 supplementation in adults. In: Therapeutic Guidelines. Melbourne. Therapeutic Guidelines Ltd; 2022. At: https://tgldcdp.tg.org.au/viewTopic?etgAccess=true&amp;guidelinePage=Gastrointestinal&amp;topicfile=c_GIG_Gastro-oesophageal-reflux-in-adultstopic_1&amp;guidelinename=Gastrointestinal&amp;sectionId=c_GIG_Water-soluble-vitamin-deficienciestopic_2#c_GIG_Water-soluble-vitamin-deficienciestopic_2
17. Pharmaceutical Society of Australia. Administering medicines by injection. 2022. At: www.psa.org.au/programs/administering-medicines-by-injection/
18. Pharmaceutical Society of Australia. Guidelines for pharmacists administering medicines by injection. Canberra: PSA; 2020.
19. Australian Government Department of Health and Aged Care. MBS Online. At: www.mbsonline.gov.au/internet/mbsonline/publishing.nsf/Content/Home
20. Pharmaceutical Society of Australia. Hydroxocobalamin (vitamin B12) injection quick guide. Canberra: PSA; 2022. At: https://my.psa.org.au/s/training-plan/a110o00000IMSVBAA5/hydroxocobalamin-vitamin-b12-quick-guide-only
21. Melbourne Pathology. Information for Doctors – Vitamin B12 (Cobalamin), Insight October 2022. 2022.At: https://www.mps.com.au/media/jx5b2omr/17353_mp_insight_vitamin-b12_2021-v2.pdfmp_insight_vitamin-b12_2021-v2.pdf (mps.com.au)