Facts and Information sheet – Treatment of Pernicious Anaemia

Treatment

Treatment of established cobalamin deficiency should follow the schedules in the BNF 1

For people with neurological involvement
Initially administer hydroxocobalamin 1 mg intramuscularly on alternate days until there is no further improvement, then administer hydroxocobalamin 1 mg intramuscularly every 2 months.
For people with no neurological involvement
Initially administer hydroxocobalamin 1 mg intramuscularly three times a week for 2 weeks. The maintenance dose : hydroxocobalamin 1 mg intramuscularly every 2–3 months for life. 2

Testing during Treatment

Serum B12

Maintenance treatment for patients presenting without neurological deficit is with hydroxocobalamin 1000 lg i.m. every 2-3 months. Those with initial neurological deficit should receive hydroxocobalamin 1000 lg i.m. every 2 months.
No further testing for cobalamin levels is required. 1

Measuring cobalamin levels is unhelpful as levels increase with treatment regardless of how effective it is, and retesting is not usually required. 2

Cobalamin and holo-transcobalamin II levels are uninformative because they rise with cobalamin influx regardless of therapeutic effectiveness. 3

Intrinsic Factor Antibodies

The Intrinsic Factor Antibody Test is notoriously insensitive as it only comes back positive in around 50% of patients with PA. If the test comes back positive for the IF antibodies then the patient will have Pernicious Anaemia. However, if the patient tests negative for the antibodies he or she can still have Pernicious Anaemia. A negative test-result can not rule out PA. Retesting patients who have previously tested positive is not needed.

  • Patients suspected of having Pernicious Anaemia should be tested for IFAB.
  • Patients found to be positive should have lifelong therapy with cobalamin.
  • Patients negative for IFAB, with no other causes of deficiency, may still have Pernicious Anaemia and should be treated as anti-IFAB-negative pernicious anaemia. Lifelong therapy should be continued in the presence of an objective clinical response. 1

It has been advised to administer 1000 μg hydroxocobalamin IM twice weekly for a period of 5 weeks, and thereafter the dose is reduced to 1000 μg IM every 2 months. In case of neurologic symptoms or abnormalities, it is suggested to administer hydroxocobalamin 1000 μg, once or twice weekly for a period of up to 2 years, and the package insert for hydroxocobalamin has included these particular instructions for several decades. However, it is ill defined which neurologic symptoms or abnormalities require such intensive treatment. Clinical practice has shown that in a substantial number of patients seen in a tertiary care setting, injection frequency cannot be reduced after the initial loading regimen. This topic has gained much interest recently, and studies evaluating this phenomenon are ongoing 4

Treatment of pernicious anemia is lifelong. In patients in whom vitamin B12 supplementation is discontinued after clinical recovery, neurologic symptoms recur within as short a period as 6 months 7

Tablets vs injections

Injections are the preferred method of treatment. Initial treatment with oral cobalamin may not be appropriate in Pernicious Anaemia, but may be considered in maintenance or correction of suboptimal levels in asymptomatic patients. 1

There is no proof in large prospective, double-blind studies that oral supplementation is as effective in reducing symptoms associated with vitamin B12 deficiency as parenteral treatment. 4

No trial reported on clinical signs and symptoms of vitamin B12 deficiency, health‐related quality of life, or acceptability of the treatment scheme. 5

Low quality evidence shows oral and IM vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels, but oral treatment costs less. We found very low‐quality evidence that oral vitamin B12 appears as safe as IM vitamin B12. Further trials should conduct better randomisation and blinding procedures, recruit more participants, and provide adequate reporting. Future trials should also measure important outcomes such as the clinical signs and symptoms of vitamin B12 deficiency, health related‐quality of life, socioeconomic effects, and report adverse events adequately, preferably in a primary care setting. 5

Other alternative delivery methods for B12 such as sub-lingual sprays, sub-lingual tablets, ointments, skin patches have not been evaluated
to determine how effective they are in treating Pernicious Anaemia and they may contain ‘analogues’ of B12 rather than ‘true’ B12 which
means the patients serum B12 will show adequate amounts of the vitamin but it will not be biologically active.

B12 storage

There is the erroneous belief that patients with Pernicious Anaemia can ‘store’ B12 in the liver for up to two years and consequently
stopping injections for a longer period of time could be possible. However, although the liver will have levels of B12 this is not biologically
available to PA patients.

  • Patients with true Pernicious Anaemia, lacking intrinsic factor, are unable to reabsorb the B12 lost in bile, which varies from 3 to 9 μg daily. To maintain tissue stores, between 100 and 300 μg of B12 should therefore be retained monthly 6
  • About 10% of the injected dose (100 of 1000 μg) is retained.7
  • Vitamin B12 excreted in the bile is effectively reabsorbed through enterohepatic circulation. The amount of B12 excreted in bile varies
    from 1 to 10 lg/d. Biliary B12 is reabsorbed across the ileal enterocytes and requires IF, in the absence of which nearly all cobalamin is excreted. 8
  • Vitamin B12 is not stored in the liver for a year or more. Indeed, many Patients experience symptoms even before the end of their normal treatment intervals and are therefore being under-treated. Livers of patients treated for Pernicious Anaemia contain substantially less B12 than those of healthy individuals.9 Moreover, the amount of B12 in the liver reflects its metabolic requirements, not storage.10
References
  1. Devalia V, Hamilton M, Molloy A; Guidelines for the Diagnosis and Treatment of Cobalamin and Folate Disorders; British Journal of Haematology, 2014, 166, 496-513
  2. NICE Clinical Knowledge Summaries Anaemia – B12 and folate deficiency
  3. How I treat cobalamin (vitamin B12) deficiency, R. Carmel; Blood. 2008 Sep 15; 112(6): 2214–2221. doi: 10.1182/blood-2008-03-040253
  4. Wolffenbuttel, Bruce H R et al. “The Many Faces of Cobalamin (Vitamin B12) Deficiency.” Mayo Clinic proceedings. Innovations, quality & outcomes vol. 3,2 200-214. 27 May. 2019, doi:10.1016/j.mayocpiqo.2019.03.002
  5. Wang, Haiyan et al. “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.” The Cochrane database of systematic reviews vol. 3,3 CD004655. 15 Mar. 2018, Doi:10.1002/14651858.CD004655.pub3
  6. Green, R., Allen, L., Bjørke-Monsen, AL. et al. Vitamin B12 deficiency. Nat Rev Dis Primers 3, 17040 (2017). https://doi.org/10.1038/nrdp.2017.40
  7. Sally P. Stabler, M.D. “Vitamin B12 Deficiency”N Engl J Med 2013;368:149-60. DOI: 10.1056/NEJMcp1113996
  8. Agata Sobczyńska-Malefora, Edgard Delvin, Andrew McCaddon, Kourosh R. Ahmadi & Dominic J. Harrington (2021): Vitamin B12 status in health and disease: a critical review. Diagnosis of deficiency and insufficiency – clinical and laboratory pitfalls , Critical Reviews in Clinical Laboratory Sciences, DOI: 10.1080/10408363.2021.1885339
  9. Bozian RC, Ferguson JL et al. Evidence Concerning the Human Requirement for Vitamin B12. Use of the Whole Body Counter for Determination of
    Absorption of Vitamin B12. AJCN. 11963 Feb;12:117-29. doi: 10.1093/ajcn/12.2.117.
  10. Nexø, E. Conference communication. 11th International Conference on Homocysteine & One-Carbon Metabolism. 2017; Aarhus, Denmark.

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