The serum B12 test is often not sufficient to diagnose a deficiency

In 2012 an article (1) was published focusing on the available tests for diagnosing a vitamin B12 deficiency, in this case in patients with bilateral visual loss. Vitamin B12 deficiency is a known cause for bilateral visual loss because of an optic neuropathy. This case study involved seven patients – in only three patients, the serum vitamin B12 level was below the established norm as set by the laboratory.

Current literature recommends measuring MMA and/or homocysteine (HC) whenever vitamin B12 is below 200 or 300 pmol/l. If these recommendations had been followed, three (from the seven) patients with a vitamin B12 deficiency (based on serum values) would have been missed.

1: (48 years) B12: 120 MMA: 553 HC: 24

2: (47 years) B12: 94 MMA: 830 HC: 14

3: (42 years) B12: 392 MMA: 477 HC: 43

4: (46 years) B12: 392 MMA: 473 HC: 11

5: (59 years) B12: 129 MMA: 1029 HC: 21

6: (82 years) B12: 346 MMA: 1025

7: (27 years) B12: 182 MMA: 444 HC: 9

Normal reference values in this research:
Vitamin B12: 145-450 pmol⁄l
MMA: 90-340 nmol⁄l
HC: <10 μmol/l.

In the four patients where MMA and HC were measured again after treatment, the values had normalized indicating that a vitamin B12 deficiency was the cause.
Two of the seven patients had a pathogenic mutation for Leber’s Hereditary Optic Neuropathy (LHON). Patients with Leber’s disease may NOT be treated with cyanocobalamin as this can lead to severe and swift optic atrophy.
Two patients had macrocytosis without anaemia, and five patients had no anaemia and no macrocytosis.

The results of this investigation confirm that if there is a suspicion of a B12 deficiency, MMA and HC should be tested in addition to the serum B12.

Comments:

In many laboratories in the Netherlands a value of less than 200 pmol/l (or even lower) is considered a low normal value. In addition it is very difficult to get MMA and homocysteine tested. Often only homocysteine is tested and not MMA. In many laboratories if values are between 100 and 200 pmol/l, only homocysteine will be tested.

Many patients will then be missed, as illustrated by this article.

Patient 1: on the basis of serum B12 was fairly obvious & confirmed by MMA and HC.

Patient 2: on the basis of serum B12 was obvious but if only HC had been tested, could still have been considered as ‘fine’.

Patient 3: in practice would most likely have been missed because of a normal serum B12.

Patient 4: in practice would most likely have been missed because of a normal serum B12 & would have probably been excluded on the basis of the HC.

Patient 5: on the basis of serum B12 was fairly obvious & confirmed by MMA/HC.

Patient 6: in practice would almost certainly have been missed due to a good serum B12 value.

Patient 7: serum B12 is low normal. In many labs only HC is tested at this low normal level, which would have missed this patient as well.

If all patients were tested according to this standard: “test for homocysteine between a serum B12 level of 100 -200 pmol/l” then only 3 of the patients (or even just two if the HC value had been used to exclude patient no. 2) would have received treatment, with potentially disastrous consequences.

In this article the upper limit for homocysteine was 10 μmol/l, but in virtually all laboratories values below the 15 μmol/l (including the laboratory in the hospital of this research), or even higher, are considered fine and patients get told they do not have a B12 deficiency as based on the homocysteine values.

Two patients had macrocytosis without anemia, and five patients had no anaemia and no macrocytosis. Many physicians still wrongly believe that both macrocytosis and anaemia need to be present for a B12 deficiency and on this basis they will exclude B12 deficiency as a diagnosis. This research, as well as many others, shows that this is incorrect. The fact that a B12 deficiency can occur without anaemia and/or macrocytosis and with serious symptoms, has been described in medical literature for about a century.
The article shows that by basing a diagnosis only on the serum B12 levels, many patients are being missed, with the risk of permanent neurological damage.

MMA (and homocysteine) should always be tested if a B12 deficiency is suspected, even when serum B12 levels appear normal!

References:

1. Methylmalonic acid and homocysteine assessment in the detection of vitamin B12 deficiency in patients with bilateral visual loss. Pott JW, Klein Wassink-Ruiter JS, van Vliet A. Acta Ophthalmol.2012 May;90(3):e252-3.

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