Pernicious Anaemia diagnosis

PA is an autoimmune condition[1] characterised by extreme fatigue, inability to absorb goodness from food (irritable bowel, incontinence, diarrhoea), and progressive degeneration of the nervous system including ‘the fogs’ (a feeling of detachment from the world), confusion (inability to make sense of what’s going on), gloves and socks (numbness and/or pins and needles in hands and feet, progressing up arms and legs), insomnia as well as waking up tired and wanting to sleep all day.

Traditional Addisonian diagnostic criteria are (all of):

• Low haemoglobin
• Macrocytosis (large immature red blood cells, usually volume greater than 98µl)
• Low blood serum B₁₂ (once below 150ng/l, now more usually in UK and USA <200ng/l)
• Schilling test (tests for ability to absorb using radioactive tracer attached to vitamin B₁₂) positive
• Intrinsic Factor (IF) antibodies positive

Many of these are symptoms or tests for conditions peripheral to B₁₂ deficiency.  For example:

• Low haemoglobin is commonly treated with iron and may be caused by lack of iron, bleeding, etc;
• Macrocytosis is caused also by folic acid deficiency: flour is routinely dosed with folic acid to prevent problems in pregnancy in USA, Australia/New Zealand, and in UK since 2007; this will mask/ prevent macrocytosis.  Since December 2008 the laboratory thresholds for B₁₂ and Folic acid in the blood have been moved in our local laboratory to lower the threshold for a diagnosis of folic acid deficiency and raise the threshold for a diagnosis of B₁₂ deficiency, which would exacerbate this problem.  We the patient group can see no reason for this and are concerned that it will delay treatment further and mask blood diagnostic criteria during the critical window of opportunity when the damage can be reversed; we also observe that the practice of adding folic acid to food is now being questioned because high levels of folic acid in the blood are known to cause other problems[1]
• the threshold blood serum B₁₂ for deficiency varies from laboratory to laboratory and no country has issued guidance (see table below);
• people may suffer from ‘subtle’ cobalamin (or B₁₂) deficiency [2-3], which is characterised by many or all of the symptoms of B₁₂ deficiency but with normal (300-1000ng/L) serum B₁₂[4-8]. This may be because of the tissue’s insensitivity to or inability to absorb B₁₂ from the blood because of the form of the B₁₂ molecule, though it may be because of genetic damage to the transporter molecules Trans-Cobalamin (of which the one carrying B₁₂ in the blood is TC-II)[7]
• the Schilling test is for the ability to absorb B₁₂ with or without added Intrinsic Factor, and is now very expensive and difficult due to the difficulty of obtaining radioactive B₁₂.
• Tests for IF antibodies (or parietal cell antibodies) diagnose onset of autoimmune disease: B₁₂ deficiency may be caused by other factors.

‘Normal’ Levels of serum B₁₂ recognised in different countries:

 We recommend that vitamin B₁₂ deficiency (or cobalamin deficiency) is diagnosed using criteria based on signs and symptoms which are listed on the Vitamin B₁₂ deficiency diagnosis page.

Citations

1.            Smith, A.D., Y.I. Kim, and H. Refsum, Is folic acid good for everyone? Am J Clin Nutr, 2008. 87(3): p. 517-33.

2.            Baboir, B.M. and H.F. Bunn, Pernicious Anaemia, in Harrison's Principles of Internal Medicine. 2005. p. 601-607.

3.            Turner, M.R. and K. Talbot, Functional vitamin B12 deficiency. Pract Neurol, 2009. 9(1): p. 37-41.

4.            Devalia, V., Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay. BMJ, 2006. 333(7564): p. 385-6.

5.            Goodkin, D.E., et al., Serum cobalamin deficiency is uncommon in multiple sclerosis. Arch Neurol, 1994. 51(11): p. 1110-4.

6.            Matchar, D.B., et al., Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci, 1994. 308(5): p. 276-83.

7.            Wickramasinghe, S.N. and I.D. Ratnayaka, Limited value of serum holo-transcobalamin II measurements in the differential diagnosis of macrocytosis. J Clin Pathol, 1996. 49(9): p. 755-8.

8.            Hamilton, M.S., S. Blackmore, and A. Lee, Possible cause of false normal B-12 assays. BMJ, 2006. 333(7569): p. 654-5.

9.            WHO, Updating IS 03/178, E.C.o.B. Standardisation, Editor. 2006, World Health Organisation: Geneva.

10.          McBride, J. B12 Deficiency May Be More Widespread Than Thought. Agricultural Research Service  2000 2 Aug [cited 2009 2 Oct]; Available from: http://www.ars.usda.gov/is/pr/2000/000802.htm.

11.          Mitsuyama, Y. and H. Kogoh, Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment--preliminary study. Jpn J Psychiatry Neurol, 1988. 42(1): p. 65-71.