B12 deficiency and anaemia

One of the major misconceptions about a B12 deficiency is that it is always accompanied by anaemia, or that without anaemia a deficiency is nothing serious. Many patients are being missed because physicians only test B12 when anaemia is present, and, even when a deficiency is obvious by a low blood value, patients are not being treated, because the deficiency is not being taken seriously without the presence of anaemia.

Dutch GP Guidelines

In the Dutch General Practitioners guidelines1 vitamin B12 is only mentioned, briefly, in the guidelines for Delirium in the elderly and Dementia. Only in the guideline for Anaemia, B12 is mentioned as a possible cause for the anaemia. When macrocytic anaemia is found during blood tests, meaning a low value of haemoglobin and a high value for ‘mean corpuscular volume’, the guideline Anaemia recommends: test reticulocytes, WBC, platelets, vitamin B12, folate and LDH. In normocytic anaemia of microcytic anaemia: just test ferritin. Many patients are being missed because vitamin B12 is only tested (according to the guidelines) in cases of macrocytic anaemia. Normocytic anaemia can occur in patients who have both iron and B12 deficiency (and/or folate deficiency). Patients with anaemia, but without macrocytosis run the risk of being treated with iron alone, with potentially serious consequences. This is not the only group of patients that is being missed. The guidelines suggest that vitamin B12 is only relevant when anaemia is present. However, many B12 deficiency patients do not have anaemia and/or macrocytosis. For these patients there is no guideline available.

There is a footnote (nr.12) in the Anaemia Guideline that says: “In a (B12) deficiency muscle weakness, smooth tongue and neurological symptoms (tingling and numbness is hands and feet; symptoms of combined degeneration of the spinal cord) can occur. These can precede the (presence of) anaemia. “The severeness of the anaemia does not correspond with the severeness of these symptoms”. But this footnote is often overlooked.

The Dutch National Health Council published “Voedingsnormen: vitamine B6, foliumzuur en vitamine B12” 2 in 2003 in which it states: Hematologic indicators like hemoglobin, red blood cell volume and reticulocytes are of limited value in the diagnosis because of insufficient specificity and sensitivity. There are indications of an inversed relationship between the occurrence of neurological symptoms and the occurrence of hematologic symptoms.


Research from Lindenbaum et al 3 had already shown that the neurological symptoms of a B12 deficiency can occur without hematologic abnormalities and even with a low-normal serum B12.
In 1990 the same Lindenbaum et al published: “Clinical spectrum and diagnosis of cobalamin deficiency” 4 in which they showed that 44% of the patients with a B12 deficiency in their study did not have anaemia, 36% did not have macrocytosis and 43% did not have an elevated LDH value.
And in 1992 from the same authors5: “We have shown that the clinical spectrum of Cbl deficiency is much broader and varied than previously believed and that neuropsychiatric abnormalities occur frequently in the absence of the classic hematologic abnormalities.”


However, this problem in the diagnosis of a B12 deficiency is not new.
In 1905 (!) Langdon6 wrote in The Journal of the American Medical Association about a group of patients in which the occurrence of mental and neurological symptoms preceded anaemia and he described a large variety of neurotic and psychic symptoms.
In 1929 McAlpine7 wrote in his article in The Lancet: “Mental changes occur not uncommonly in pernicious anaemia. They range from states of depression accompanied by loss of mental energy to definite psychoses. They, like the nervous symptoms, may precede the characteristic changes in the blood by many months. It must be emphasized that the cerebral symptoms, like those due to lesions in the spinal cord, may precede the appearance of anaemia for long periods, sometimes for years, and that they may occur in the presence of a completely normal blood picture and bone marrow and even in the absence of spinal lesions.”
In 1933 Greenfield and O’Flynn8 stated that 14% of patients with combined degeneration of the spinal cord have normal blood values.

In 1956 the British Medical Journal published ‘Cerebral Manifestations of vitamin B12 deficiency’ 9 from J. MacDonald Holmes. He wrote: “The great difficulty in establishing the diagnosis of vitamin-B12 deficiency with involvement of the nervous system is the lack of correlation between the haematological and neurological manifestations. There is also a similar lack of correlation between the spinal and cerebral symptoms of the syndrome. Early diagnosis is essential if treatment is to be effective, for the reversibility of neurological symptoms is largely dependent on their duration. The brain lesions which form part of the neurological syndrome of vitamin-B12 deficiency, although they have been recognized for more than half a century, are still much less familiar than those which occur in the spinal cord and peripheral nerves, to which by long usage the term “subacute combined degeneration” has been applied. The end result of unrecognized and untreated cerebral lesions may be a severe dementia, even more crippling than the paraplegia produced by the spinal lesions, but early treatment will produce complete remission. The cerebral symptoms preceded the appearance of Addisonian anaemia or of spinal and peripheral nerve involvement by several years in some instances.”

And in 1960 The British Medical Journal published A.D.M Smith’s ‘Megaloblastic Madness’ 10 He wrote: “The occurrence of subacute combined degeneration of the cord prior to the onset of anaemia is well recognized and clinicians are now fully alive to this possibility.” “The time-lag may be considerable and may give rise to diagnostic difficulty unless this situation is constantly borne in mind. Owing to the many tragedies that have resulted from unawareness, with subsequent irreversible cord damage, it is now unusual to come across cases of this nature.” “The necessity for making the correct diagnosis cannot be overstressed, as delay is extremely dangerous and the condition eminently treatable, provided cerebral demyelination has not occurred.”


Apparently this knowledge (and all the aforementioned) was lost over the years, as these days many physicians are not aware of the fact that neurologic and neuropsychiatric symptoms of a B12 deficiency occur without anemia and/or macrocytosis, and that a deficiency can have serious consequences before anemia ever develops. Unfortunately it is not unusual, like Smith reported back then, to come across cases of this nature.
A vitamin B12 deficiency can lead to serious neurological, cognitive and psychiatric symptoms. Delaying treatment can have devastating effects. Physicians should be aware that neurological damage can occur before anemia develops, and consider a vitamin B12 deficiency when neurological and/or neuropsychiatric symptoms are present, with or without the presence of anemia. The cost of testing for a possible B12 deficiency and treating the deficiency when present, are low. The benefits of an early diagnosis are potentially enormous, and not just financially.



1. NHG Standaard ANEMIE M76 (maart 2003)
2. Voedingsnormen: vitamine B6, foliumzuur en vitamine B12 Den Haag: Gezondheidsraad, 2003; publicatie nr 2003/04.
3. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. J Lindenbaum, EB Healton, DG Savage, JC Brust, TJ Garrett, ER Podell, PD Marcell, SP Stabler, and RH Allen NEJM Volume 318:1720-1728
4. Clinical Spectrum and Diagnosis of Cobalamin Deficiency. Sally P. Stabler, Robert H. Allen, David G. Savage, and John Lindenbaum Blood. Vol 76, No 5 (September 1). 1990: pp 871-881
5. New Approaches to the Diagnosis of Cobalamin Deficiency in Neuropsychiatric Disorders R.H. Allen , S.P. Stabler , D.G. Savage and J. Lindenbaum J Nutr Sci Vitaminol (Tokyo). 1992;Spec No:130-3.
6. Langdon, F.W. (1905) J. Amer. med. Ass., 45, 1635.
7. Lancet, 2, 643. (1929) McAlpine, D
8. Lancet, 2, 62 (1933) Greenfield J.G. and O’Flynn, E
9. Cerebral Manifestations of vitamin B12 deficiency. J. MacDonald Holmes, M.D., F.R.C.P. Dec. 15, 1956 British Medical Journal
10. Megaloblastic Madness A. D. M. Smith Br Med J. 1960 December 24; 2(5216): 1840–1845.


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