Concerning: In response to the new NHG Position regarding vitamin B12 deficiency (NHG-Standpunt Diagnostiek van vitamine B12-deficiëntie), published September 3, 2014

We have read with great interest and appreciation the recently published NHG Position regarding vitamin B12 deficiency diagnostics. We want to react in substance to the key messages, since we do not recognize our views in all of its aspects and believe that it does not do justice to a number of our patients, by depriving them of simple treatment.

Diagnosis

It is indeed true that up till now there is “no test which can with any certainty eliminate or establish vitamin B12 deficiency as the cause  of symptoms. “(“geen test waarmee vitamine B12-tekort als oorzaak van klachten met zekerheid kan worden aangetoond of uitgesloten”) Very often a patient has clinical symptoms before the biochemistry follows (Herrmann & Obeid, 2008; Kuzminski, 1998). Moreover, vitamin B12 measurements by different laboratories show discrepancies (Oberley, 2013).

Considering the progressive nature, the severity of the disease and the irreversibility of the clinical symptoms we believe that in case of doubt or with vitamin B12 related complaints, patients should receive treatment immediately.

This also applies to subclinical vitamin B12 values and recently introduced laboratory tests, such as the methylmalonic acid (MMA) test (Bailey et al., 2011) and active – B12 (Graaf, 2010). With all tests ‘grayscale levels’ must be taken into account. Early diagnosis is of utter importance (Glaser et al., 2014; Healton et al., 1991; John Lindenbaum et al., 1988; Reynolds, 2006).

Prevalence and vitamin B12 deficiency

We cannot agree with this NHG statement: ´B12 deficiency prevalence in the western world is only a few percent”.(“De prevalentie van B12 tekort in westerse landen bedraagt enkele procenten.”). The words ‘a few percent’ present an underestimation of the problem.

Despite increased attention for B12 deficiency in Dutch healthcare there are still no national statistics on incidence and prevalence of vitamin B12 deficiency. Van Asselt did demonstrate prevalence among the elderly (Van Asselt et al., 1998).

Outside the Netherlands more research has been done into the scale of this problem. In 2008 WHO asserted that this might be a worldwide healthcare problem (McLean, 2008). These foreign studies unanimously have established that vitamin B12 deficiency prevalence is higher than is generally thought.

The Framingham Offspring B12 Study into vitamin B12 deficiency prevalence (Tucker et al., 2000) shows a plasma level of <185 pmol/L among 17 % of the population. 39% of the population has a level of <258 pmol/L and 9 % has a level of < 148 pmol/L. These statistics are confirmed by a recent English NHS research (Hunt, Harrington, & Robinson, 2014). These studies show that vitamin B12 deficiency is not only prevalent among the elderly but also affects a younger population.

A recent study carried out under the auspices of Prof. Dr. J. H. Richardus, professor of infectious diseases and public health at Erasmus MC, and Dr. S. de Lathouder, clinical chemist at STAR-MDC, demonstrates that in 2013 45 percent of the over 70,000 people who had their B12 levels measured had a value less than 200 pmol/L, regardless of age or gender. See Table 1, data in progress.

Table 1

Vitamin B12 category 2009 2010 2011 2012 2013
B12 < 130 2688 (17,3%) 5951 (16,6%) 7192 (14,1%) 7705 (12,6%) 9261 (13,1%)
           
B12 < 150 4225 (27,2%) 9298 (25,9%) 11501 (22,5%) 12711 (20,8%) 15108 (21,4%)
           
B12 < 200 8087 (52,1%) 17999 (50,1%) 23331 (45,6%) 27109 (44,3%) 31505 (44,6%)
           
Subclinical 5310 (34,2%) 12029 (33,5%) 16426 (32,1%) 19970 (32,6%) 22760 (32,3%)

Statistics in this table suggest that a higher prevalence can be expected.

These statistics are confirmed by other research (J Lindenbaum, Rosenberg, Wilson, Stabler, & Allen, 1994; Pennypacker et al., 1992; Strachan & Henderson, 1965; Tucker et al., 2000; Van Asselt et al., 2000).

The Rotterdam study is currently being widened to the region of Utrecht (SALTRO, Dr. T. Njo) and the region of Amsterdam-Flevopolder (CKCL, OLVG, Dr. M. Elissen).

When the Tucker study data (2000) are extrapolated to the Dutch population (9% of the population serum B12 < 148 pmol/L), this would, according to a cautious estimate, give a prevalence of 1.530.000 patients!

Medical symptoms

NHG: “The main point of discussion has been on the question whether a low vitamin B12 level can be associated with atypical complaints, such as dizziness, fatigue and loss of memory or concentration.“

(“Er is vooral veel discussie over de vraag of een lage vitamine B12-spiegel geassocieerd zou kunnen zijn met atypische klachten zoals duizeligheid, vermoeidheid en vermindering van het geheugen of concentratievermogen.”).

“[…] about 50% shows clinical signs of myelopathy, neuropathy or cognitive dysfunction, but these signs do not indicate vitamin B12 deficiency”.

“[…] circa 50% klinische tekenen heeft van myelopathie, neuropathie of cognitieve disfunctie, maar dat deze afwijkingen niet kenmerkend zijn voor een vitamine-B12-tekort.”

The complaints mentioned here actually do fit the B12 deficiency picture, and have been described as early as 1849 by Thomas Addison (Addison, 1849) and even earlier than that, in 1822 by James Scarth Combe (Combe, 1822). We quote Addison:

“the lips, gums, and tongue seem bloodless… extreme languor and faintness supervene, breathlessness and palpitations being produced by the most trifling exertion or emotion.”.

Michael Anton Biermer (Biermer, 1872) was the first person who called this pattern of symptoms Progressive Pernicious Anemia and from then on the deadly disease was described in numerous academic publications (Cole, 1924; Skoog, 1926; etc).

“The mental symptoms are extremely variable and include mild disorders of mood, mental slowness, memory defect which may be gross, confusion, severe agitation and depression, delusions and paranoid behaviour, visual and auditory hallucinations, urinary and faecal incontinence in the sence of overt spinal lesions, dysphasia, violent maniacal behaviour and epilepsy.” (MacDonald Holmes, 1956).

However, Hooper recently defined a vitamin B12 – related symptomatology (Hooper et al., 2014). In a survey with a respons of about 1000 patients in England, published in The British Journal of Nursing, all patients with confirmed B12 deficiency showed a large variety of complaints. Most common: 96% of all patients suffer general fatigue, 87% wake up tired, 34% have glossitis, 30% hair loss, etc. As far as neurological complaints are concerned: 78% suffer memory loss, 75% reduced concentration, 59% dizziness, 66% clumsiness/ataxia, 50% aphasia, 73% are short of breath and 56% have cardiac arrythmia.

These medical symptoms are found in a survey by B12 Tekort Foundation as well, which is also mentioned by NHG (Visser et al., 2013). Over 1500 persons participated in this survey (data still in progress), and provides clear information on clinical symptoms, delay in identification and treatment. Foundation B12 tekort has a trustworthy website, with relevant professional  literature references.

Both surveys show a clear overlap between fibromyalgia, ME/CVS and MUPS (medically unexplained physical symptoms). Present cut-off points may result in misdiagnosis (Carmel, 2011; Iqtidar, 2012).

Our experience is that medical symptoms can also occur with subclinical vitamin B12 deficiency (Van Asselt et al., 2000) (see also all references under ‘clinical limits values’). In case of insufficient or delayed treatment these are irreversible and may do permanent damage (Graber, et al., 2010). A different year-long study (Abyad, 2002) among elderly with dementia and vitamin B12 deficiency symptoms showed significant improvement after treatment with parenteral suppletation.  

That is why we do not understand what the grounds are for NHG to state: “Fatigue, dizziness, loss of memory and concentration are usually not caused by low levels of vitamin B12.”.(“Moeheid, duizeligheid, geheugen- en concentratieproblemen komen meestal niet door een te laag vitamine B12.”).

Clinical limit values

NHG:“The limit value for low vitamin B12 blood levels (distinguishable from vitamin B12 deficiency which has complaints as well) is a serum concentration of 148 pmol/L. At this limit value 95 – 97% of the patients with complaints as a result of B12 deficiency can be detected”.

These patients, however, do not necessarily have abnormal biochemistry, like when they have macroscopic blood count or anemia. Those values, however, do need to be considered adequately, since delayed or under-treatment can lead to irreversible neurological damage (Carmel, 2008; Pedersen & Mosbech, 1969; Reynolds, 2006; Lawrence R. Solomon, 2007; S. P. Stabler, 2013; Tucker et al., 2000; Wickramasinghe, 2006).

Patients with subnormal blood counts, e.g. between 148 and 221 pmol/L can also suffer medical symptoms:

  1. In the meantime it has been proven that such counts can definitely indicate deficiency on the tissue level (Hunt et al., 2014; Russcher, 2012; Savage & Lindenbaum, 1995; A. D. M. Smith, 1960; S. Stabler, Allen, Savage, & Lindenbaum, 1990; S. P. Stabler, 2013; Van Asselt et al., 2000).
  2. Besides the new English ‘Vitamin B12 and Folate Guidelines’ (British Society for Haematology, 2014), uptodate.com (Schrier, 2014) also warns against the risks of subclinical B12 deficiency. They also point out that such results should be interpreted as borderline/possible vitamin B12 deficiency.
  3. Van Tiggelen, Matthews & Linell, Kallstroum & Nylof warned before that they were not settling for subclinical vitamin B12 values (Matthews, 1979), (Kaullstroum & Nylouf, 1669), based on comparisons between vitamin B12 levels and CSF B12 values. (Van Tiggelen et al. 1983).
  4. Michael Fenech concludes that when serum B12 levels are higher than 300 pmol/L, damage on a cellular level is minimized: “Intervention studies in humans show that […] micronucleus formation is minimised when plasma concentration of vitamin B12 is greater than 300pmol/L and plasma homocysteine is less than 7.5μmol/L.” (Fenech, 2012; Ferguson & Fenech, 2012).
  5. Lindenbaum concludes that in his study 5% of the patients with clinical symptoms of B12 deficiency had a serum B12 value between 150 and 350 pmol/L (J Lindenbaum et al., 1994). That is why they said: “We chose a serum Cbl concentration of 258 pmol/L (350 pg/mL) as a cutoff point for suspecting Cbl deficiency.”
  6. A recent two-year Oxford University study also proves that vitamin B12 indeed has a neurological impact in case of subclinical limit values. It found a clear impact on the brains of 90 patients with early onset Alzheimer, after treatment with a combination of B vitamins (a combination of B12, B6 and folic acid). Strikingly, these patients had a ‘normal’ serum B12 count of 350 pmol/L (Douaud et al., 2013; A. Smith, 2008).

It is with good reason that Lindemans recommends listening to patients’ complaints and not just pay attention to laboratory values (Graaf, 2010). Fortunately the authors conclude:

NHG: “In case of a vitamin B12 count between 148 pmol/L and 250 pmol/L B12 deficiency cannot be excluded”. (“Bij een vitamine-B12-spiegel tussen de 148 pmol/l en de 250 pmol/L een tekort niet wordt uitgesloten.”)

A statement we would like to have read in the key message and a condition that certainly is not ‘improbable’.

Normal ranges vitamin B12

As far as we know, normal ranges in a healthy reference population have not been established in the Netherlands. Therefore hematology levels have been linked to absence of symptoms. In Japan a healthy population has an average serum B12 level of 450 pmol/L (Mitsuyama & Kogoh, 1988). Patients with lower levels and showing B12 deficiency related symptoms are given B12 supplements.

Treatment

As far as treatment is concerned we would like to make the following comments. The new guideline advises:

NHG: “A vitamin B12 count below 148 pmol/L and clinical symptoms are treated with 1000 mg oral vitamin B12 a day”. (“Bij een vitamine-B12-spiegel lager dan 148 pmol/l en klinische verschijnselen bestaat de behandeling uit 1000 mg vitamine B12 oraal per dag.”)

This suggests that oral treatment is just as effective as parenteral treatment and that if a quick reaction is wished for, parenteral treatment may be considered.

Parenteral administering was introduced in the late 1940s (Rundles, 1946). Since then it is the preferred administration route.

Recent studies, however, have shown that oral administration can also produce biochemistry restoration. These studies do acknowledge their restrictions, which are:

  1. None of these studies draw a relationship between biochemistry and clinical symptoms.
  2. Nearly all studies were carried out among the elderly and cannot be translated automatically to a ‘young’ population and other (elderly) patients with varying vitamin B12 deficiency causes (L. R. Solomon, 2006).
  3. Most studies ran for only one to three months. One was carried out during four months. That is far too little to get a good picture of patient recovery. If complaints, not diagnosed as B12 deficiency, existed before, they are usually irreversible and/or take much longer to recover. (Dobrozsi, Flood, Panepinto, Scott, & Brandow, 2014; Reynolds, 2006; Lawrence R. Solomon, 2007).
  4. Most cited studies relate to small patient cohorts. (Andres, 2010; R. Malouf & Areosa, 2003; Troilo et al., 2010). In one of the meta analyses that are cited, a systematic review of the Cochrane database, out of 108 test persons only seven remain with pernicious anemia and seven with atrophic pastritis. (Vidal-Alaball et al., 2005).
  5. One misunderstanding is that oral supplements are less expensive (Duyvendak, 2009; Vidal-Alaball et al., 2005). Producing vitamin B12 injection-ampoules turns out to be cheaper than producing B12 tablets (Elia, 1998). However, if  patients (or next-of-kin) learn to inject themselves, as do diabetes patients with diabetes, the costs of injection are a lot lower. (Carmel, 2008).
  6. Oral supplementation is insufficiently effective with patients with isolated ‘methylation disorders’, such as MTHFR deficiency. (Schiff et al., 2011).
  7. Another misunderstanding is that patients seem to prefer oral supplements. Adherence to daily intake of oral supplements appears to be more difficult than a monthly parenteral maintenance dose. (Carmel, 2008). Patients with swallowing difficulties, nausea or diarrhea prefer parenteral supplementation as well. (Duyvendak, 2009).
  8. Regarding the literature cited by you, on which your positions are based:
    • The article by Stabler (S. P. Stabler, 2013) states that injections are to be preferred in case of clear neurological complaints, because insufficient or undertreatment may lead to irreversibility of the complaints
    • In his article ( Andres et al., 2010) which involved only 31 patients, Andres mentions that his research focused on hematological levels only, and that further research should be carried out on patients with severe deficiencies. Moreover, he writes that only 30% of the patients showed signs of clinical recovery after treatment, and 70% showed no recovery at all.

Doets (Doets & van Wijngaarden et al., 2012) also clearly indicates that : “Current evidence on the relation between vitamin B12 intake or status and cognitive function is not sufficient for consideration in the development of vitamin B12 Further studies should consider the selection of sensitive markers of vitamin B12 status.” 

    • The article you cited to prove that there is no relationship between B12 supplements and cognitive enhancement, deals with oral supplements, a small cohort and a short duration (M. Malouf, Grimley et al., 2003). Malouf also states that his study does not provide sufficient evidence and further enquiries are necessary.
  2. There are also studies claiming that oral supplements are ineffective (Favrat et al., 2011), is highly debatable and without evidence (Chevalier, 2007; L. R. Solomon, 2006; Lawrence R. Solomon, 2007). The effect of cyanocobalamine (synthetic form of B12, prescribed by NHG in the new Standaard Anemie (Anemia Standards) is not beyond all doubts, either. Hydroxycobalamine is an evident cyanide antagonist removing toxins at the same time, which cyanocobalamine cannot do. (A. Freeman et al., 1978; A. G. Freeman, 1999; Merck Santé, 2014).

Furthermore, lack of understanding in this area just brings about a proliferation of supplementation and supplements for sale on the internet. (L. R. R. Solomon, 2004).

Uncontrolled intake of vitamin B12 prevents proper diagnosis, partly because of the false high levels patients will visit their GP with (Graaf, 2010). It will also prevent serious examination of the causes and underlying conditions. If treatment is ineffective, patients will see a broad range of specialists, unjustly overburdening primary and secondary health care, plus all additional costs involved.

Nevertheless, there is some evidence that oral supplements can be effective for elderly patients, but this requires further investigation, for a longer period (six – twelve months at least) in particular, including a direct correlation with the symptoms. (Lawrence R. Solomon, 2007).

For the time being, we will continue following the treatment guidelines described in the Pharmacotherapeutic Compass:

“Dosage:

Profylaxis and treatment of vitamin B12 defciency: I.m. or deep s.c.: starting dose 10 injections of 1000 mcg at intervals of  at least three days; maintenance dose once every two months or 300 mcg once a month.

In case of  evident neurological disorders: 1000 mcg once or twice a week for two years, e.g.

Vitamin B12 checks during treatment

NHG: “Checks during treatment are generally considered of little use”. (“Controle tijdens de behandeling wordt over het algemeen als weinig zinvol beschouwd.”).

We agree on this point, since biochemistry is quickly restored. Clinical symptoms, however, often lag behind (cf thyroid treatment), resulting in the early abortion of a simple and relatively harmless treatment because of alleged “elevated serum B12 values”. No upper intake level has been established for B12 by The Health Council of the Netherlands (2003), since fear of overdosage is unfounded. If the cause of B12 deficiency has not been removed, treatment should not be stopped. (Russcher, 2012; Reynolds, 2006; S. P. Stabler, 2013).

MMA regulation

NHG: “ With symptoms indicating B12 deficiency and subnormal B12 levels an additional methyl/methylmalonic acid test may be carried out or a test dose of 1000 mcg vitamin B12 orally may be prescribed.”(“Bij klachten suggestief voor vitamine-B12-tekort en een laag-normale B12 spiegel kan een additionele methylmalonzuurbepaling worden gedaan of een proefbehandeling met vitamine B12 1dd 1000 mgr oraal worden ingenomen.”

As suggested in your article, the diagnostic value of methylmalonic acid (MMA), as well as the value of homocysteine, do insufficiently prove deficiency, considering the large number of pitfalls of these diagnostics and the lack of associations with the clinical symptoms. (J. Lindenbaum et al., 1994). Therefore we wonder why they are recommended here. We prefer relying on the symptoms themselves instead of on pure laboratory results (Graaf, 2010).

Anemia

The latest NHG-Position Diagnostics vitamin B12 deficiency uses only few words abandoning the 2003 standard Anemia Values regarding B12 deficiency. This standard has failed to enter B12 deficiency as an isolated entity, it only occurs as a cause for anemia, resulting in the persistent misunderstanding that patients are considered B12 deficient only after having been diagnosed with anemia (and elevated MCV). The misunderstanding even caused the publication in “Huisarts & Wetenschap” magazine of October 2012 (Meijer de, 2012) of an article which seriously asked the question whether vitamin B12 deficiency without anemia should be treated. The argumentation was: if there is a deficiency with symptoms but no anemia, the deficiency will not be treated.

Plenty of literature indicates absence of anemia in B12 deficiency cases. NHG itself alleges that in 20 – 30% of the cases there is no anemia, and uptodate.com mentions a number of even over 70%. (Schrier, 2014). From 1905 onwards (Langdon, 1905) a lot of academic literature has been published endorsing this. Classical hematology is preceded by a long series of complaints (McAlpine, 1929; Nieweg, 1953; de Natale, 1941; MacDonald Holmes, 1956; A. D. M. Smith, 1960; S. Stabler et al., 1990; Velde, 1967; Lee et al., 2005).

Recent unpublished studies among Rotterdam residents prove that in only 6% of the cases  B12 deficiency in combination of elevated MCV (Table 2) is found. In 2013 20,6 of the men and 15,6% of the women appeared to have B12 deficiency (serum B12 < 148 pmol) in combination with low HB levels (Table 3). These numbers correspond to the once found by uptodate.com. (Schier, 2014).

Table 2

MCV All MCV conditions Conditions where B12 < 130 Conditions where B12 < 148 Conditions waarbij B12 < 150 Bepalingen where B12 < 200
MCV < 80 6661 | 4,8% 1109 | 5% 1619 | 4,8% 1673 | 4,8% 3098 | 4,5%
MCV 80-100 126565 | 91,4% 19925 | 89,1% 30184 | 90,0% 31400 | 90,0% 62051 | 91,1%
MCV > 100 5253 | 3,8% 1328 | 5,9% 1768 | 5,2% 1835 | 5,2% 2972 | 4,4%
Total period 2010-2013 138.479 22.362 33.517 34.908 68.121

Conclusion

In conclusion we can say that there are still a large number of unanswered questions regarding “symptomatic’ B12 deficiency, and that, considering the great impact this problem entails (B12-tekort Foundation has 6000 forum members and Henk de Jong’s site (Jong, 1996 – 2014) has 20,000 unique monthly hits and receives 1200 letters every year) there is sufficient reason to conduct additional research.

Vitamin B12 deficiency is not just a simple vitamin problem, it is a malabsorption disorder with a complicated underlying metabolism and atypical symptoms.

A lot of research has to be done, but dismissing patients with a pill the effect of which is based on very weak evidence, and referring them to medically unexplained symptoms clinics after three months (under the guise of ‘there is no evidence yet, so it’s all in your head), we think is a scientifically incorrect approach. Regrettable and wrong, considering the severe consequences patients have to deal with. A proper differential diagnosis with (evident) neurological and neuro-psychiatric symptoms doesn’t seem an unnecessary luxury. (Berryet al., 2003; Burns, 1998; Dommisse, 1991; Erol, Alehan, & Gümüs, 2007; Evans, 1983; Hemmer et al., 1998; Jewesbury, 1954; Sahoo, Avasthi, & Singh, 2011; Silver, 2000).

Vitamin B12 deficiency is a seriously underestimated and forgotten disease.