Diagnosis and management of vitamin D deficiency
BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.b5664 (Published 11 January 2010) Cite this as: BMJ 2010;340:b5664All rapid responses
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Pearce and Cheetham’s review of the diagnosis and management of
vitamin D deficiency (BMJ 2010;340:b5664) is welcome in bringing to
attention this important topic, though it barely scratches the surface of
the diverse range of health problems associated with vitamin D deficiency.
A more comprehensive list (based on a thorough review of the published
scientific literature published over the past few years) is presented
below:
• Increased inflammation (elevated CRP)
• Muscle weakness and pain (hypovitaminosis D myopathy)
• Rotator cuff muscle degeneration
• Poor physical performance
• Loss of muscle mass with ageing (sarcopenia)
• Falls in the elderly
• Aches and pains, non-specific musculoskeletal pain
• Fibromyalgia (vitamin D deficiency is often misdiagnosed as
fibromyalgia)
• Fatigue
• Chronic low back pain
• Osteomalacia; bone pain; tenderness on pressing sternum, shinbone,
or forearm bone
• Rickets
• Osteopaenia, osteoporosis
• Osteoarthritis
• ‘Hurting hair’ during childhood (pain in the scalp when hair is
brushed or combed)
• Easily tired legs in children
• ‘Growing pains’ in childhood
• Sensitive, aching or ‘throbbing’ teeth
• Periodontal disease, gingivitis
• Dental caries
• Anxiety
• Depression
• Seasonal affective disorder
• Bipolar disorder
• Schizophrenia
• Insulin resistance
• Insulin deficiency
• Impaired glucose tolerance
• Diabetes (type 1 and type 2)
• Diabetic retinopathy
• Obesity
• Polycystic ovary syndrome
• Premenstrual syndrome
• Infertility (in men and women)
• Pre-eclampsia
• Low-birth weight
• Seizures in newborns
• Hypocalcaemia
• Auto-immune diseases, including multiple sclerosis, type 1
diabetes, rheumatoid arthritis, Sjogren’s syndrome, lupus, Graves’
disease, Hashimoto’s disease, Crohn’s disease, autoimmune prostatitis
• Increased susceptibility to infection (including influenza)
• HIV disease progression
• Psoriasis
• Rosacea
• Atopic dermatitis
• Alopecia
• Hypertension
• Peripheral arterial disease
• Myocardial infarction
• Left ventricular hypertrophy
• Congestive heart failure
• Cardiomyopathy
• Stroke
• Asthma
• Chronic obstructive pulmonary disease
• Cystic fibrosis
• Renal disease
• Multiple sclerosis
• Parkinson’s disease
• Impaired cognitive function in elderly
• Alzheimer’s disease
• Motor neurone disease
• Migraine
• Tension headache
• Retinitis pigmentosa, cataracts, myopia, keratoconus
• Age-related macular degeneration
• Hearing loss, otosclerosis, cochlear deafness
• Increased risk of 17 types of cancer, including breast, prostate,
colon, ovarian, endometrial, oesophageal, Hodgkin’s and non-Hodgkin’s
lymphoma, bladder, gallbladder, gastric, pancreatic, rectal, renal,
testicular, vulvar and skin cancers
Vitamin D deficiency is endemic (even in sunny climes such as
Australia, where sun avoidance and excessive use of sun screens is the
order of the day), and it would thus be prudent for clinicians to maintain
a high level of awareness of the likelihood that their patients may be
vitamin D deficient, and that this will have adverse consequences on their
health. Ideally, it is suggested that all patients should have their
vitamin D levels routinely checked at least once or twice a year.
As a practical guide to diagnosis and management, I would suggest the
following (25OHD levels in nmol/L):
• <100 = Deficient
• 100-200 = Optimal
• 135-225 = Normal in sunny countries
• 500+ = Potentially toxic (this would require a sustained daily
intake >/= 40,000 IU)
[Note: To convert to nmol/L to ng/ml, divide by 2.5]
As far as treatment is concerned, a good rule of thumb (based on my
personal experience of treating 100’s of vitamin D deficient patients) is
that a dose of 1,000 IU of cholecalciferol (vitamin D3) will raise 25OHD
levels by approximately 10 nmol/L over 3 months (I would not agree with
the quoted 1,000 IU raising 25OHD by 25 nmol/L). Thus, an appropriate
individualised dosage can be easily calculated. Therefore, for a patient
with an initial blood level of 50 nmol/L, a daily dose of 10,000 IU/day
would be required to raise their 25OHD level to about 150 nmol/L (i.e. the
middle of the optimal range) over 3 months. Note that ergocalciferol
(vitamin D2) is not normally found in humans, and is less effective than
cholecalciferol in raising 25OHD levels.
The maintenance dose of 1,000-2,000 IU daily that Pearce and Cheetham
suggest is likely to be inadequate for most individuals. It is my
experience that an ongoing dosage of 5,000-10,000 IU of cholecalciferol
daily may frequently be required to maintain optimal 25OHD levels,
especially in obese, elderly and darker skinned patients.
In Australia, whilst cholecalciferol 1,000 IU supplements are readily
available over the counter, we are fortunate in that there are an
increasing number of compounding chemists that can make up capsules of any
strength that a doctor wishes to prescribe.
Competing interests:
None declared
Competing interests: No competing interests
Vitamin D deficiency is very common and questions are arising about
the relation of Vitamin D and the influence on the innate immune system
and the development of diseases. Since it has been shown that melatonin
and its circadian rhythm induces the vagus nerve, and the vagus as a major
component of the autonomic nervous system is able to suppress inflammation
by the inhibition of the activation of macrophages and the release of
various cytokines we are wondering if there is a connection between the
melatonin year-over rhythm and the year-over rhythm of vitamin D
production. Vitamin D is produced after sun exposure; Melatonin release
increases when it’s dark and further induces the vagal activity, thus
inversely correlated. This communication is at least bi-directional and
represents highly complex systems. So could it be that lower Vitamin D levels during winter time are a normal adaption to environmental challenges and Vitamin D substitution during that time could be seen critically?
Tracey KJ. The inflammatory reflex. Nature 2002; 20(6917):853-9.
Mutoh T et al. Melatonin modulates the light-induced
sympathoexcitation and vagal suppression with participation of the
suprachiasmatic nucleus in mice. J Physiol 2003; 547(1):317–332.
Competing interests:
None declared
Competing interests: No competing interests
Amanda Da Costa rightly points out the unavailability of
Ergocalciferol 10,000 and 50,000 IU tablets (formerly available via UCB
Pharma). These are no longer being imported into the UK due to the higher
price they command in the North American market.
She is also correct in pointing out the very poor bioavailability of
intramuscular Ergocalciferol, compared with the same quantity given orally
(1). In much of the Middle East, where photosynthetic Vitamin D deficiency
is rife for multifactorial reasons, IM Ergocalciferol 300,000 and 600,000
IU ampoules for injection are unfortunately the only available
preparations. Cognisant of this, many Arab Physicians wisely advise their
patients to simply drink the contents of the ampoule, rather than having
it injected (Dr. E.S. Al-Ozairi -personal communication).
However, Ms Da Costa is inaccurate in describing the situation in the UK
in respect of Vitamin D product availability as being like the Third
World, because in fact, licensed, pharmaceutical-strength Vitamin D
preparations are readily available in many Third World countries;
Colecalciferol 60,000 IU sachets (brand name Calcirol) can be purchased
from most pharmacies in India for the modest fixed price of Rp24 (around
35p).
The UK situation is unlikely to improve unless Public Health Physicians
become better informed in relation to the published scientific data
(worryingly exemplified in the error-strewn response by Nagaraj &
Howe). Indeed, there is a danger that we might in fact be going backwards
due to ongoing evolution of the "modern" lifestyle towards progressively
less UVB light exposure. The NHANES III study indentified a 20% fall in
mean serum 25OHD levels over a period of just 16 years in a US population
(2).
1. Romagnoli E, Mascia ML, Cipriani C, Fassino V, Mazzei F, D'Erasmo
E, Carnevale V, Scillitani A, Minisola S. Short and long-term variations
in serum calciotropic hormones after a single very large dose of
ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the
elderly. J Clin Endocrinol Metab. 2008; 93: 3015-3020.
2. Ginde AA, Liu MC, Carmargo CA, Jr. Demographic differences and
trends of Vitamin D insufficiency in the US population, 1988-2004. Arch
Intern Med. 2009; 626-632.
Competing interests:
None declared
Competing interests: No competing interests
Agree with the sentiment of other responses. It's not about GP
awareness.
For years our local lab would simply refuse to process samples for
vitamin D levels. Instead they would write back saying that low vitamin D
levels are common in this area and replacement is safe.
This has changed in the last few months.
We have also had difficulties with availability of vitamin D
preparations.
Competing interests:
None declared
Competing interests: No competing interests
In the last few years we have been confronted with a huge wave of
published research articles regarding the role of Vitamin D in
immunological disorders. The problem of our time now is to find out how to
implement these findings into daily clinical work and to act in the sense
of the public health. In northern countries such as Norway Vitamin D
deficiency seems to be common and they have faced this problem for hundreds of
years. In these regions it is widespread to take cod liver oil during
winter time. Cod liver oil contains Vitamin A, Vitamin D and omega-3 fatty
acids. In immunological studies it has been shown that the complex
relationship of Vitamins A and D posses powerful immunological properties,
including the proliferation of macrophages, production of cathelecidin,
production of IL-10 by dendritic cells, inhibition of IL-2, IL-17 and
stimulation of regulatory T cells. The substitution of Vitamin D alone in
healthy individuals with low Vitamin D levels should be critically seen
due to the fact that there are no data existing concerning the effects and
long term outcomes of a single Vitamin D substitution for the general
population. Perhaps the potential is far beyond our understanding now and
will be again evaluated to get access into daily clinical practice.
Moro JR, Iwata M, von Andriano UH. Vitamin effects on the immune
system: vitamins A and D take centre stage. Nat Rev Immunol 2008;8(9):685-
98.
Ebbing M et al. Cancer incidence and mortality after treatment with folic
acid and vitamin B12. JAMA 2009;18;302(19):2119-26.
Competing interests:
None declared
Competing interests: No competing interests
We all should expect that whenever any symptom can be found to have any correlation with any measurable parameter that the following questions should be asked and researched:
1)Is this parameter just a correlation?
2) Is it a cause?
3) Is it a consequence?
I cannot find any hint that these questions have been discussed at all. It is just taken as fact that a found low vit D level is the cause of all those diseases it has been found to be correlated with.
You may know the story that storks bring babies? The 'proof' was given statistically: Since the number of storks had decreased fewer (human) babies were born. Fact!
Even if you just remember that vit D is a secosteroid, a kind of 'half cortison' many people not having studied medicine can imagine that it may eventually cause (as it it proven for cortison) diabetes, obesity, osteoporosis etc etc over the time. Now as the era of vit D deficiency is propagated it should be remembered that for at least 20 years vit D is given to babies, food is fortified with vit D, people enjoy more sun than all the times before.
Sure, for at least 20 years there are increased numbers of sufferes from obesity, diabetes, osteoporosis and other chronic diseases in those 'developed' countries fortifying nearly any food with vit D like USA. How can there be more diseases caused by vit D deficiency when there is more vit D eaten than all times before? So, might a measured low vit D level just be a correlation or eventually be a consequence of these diseases?
Meanwhile it should be known to all scientists publishing about vit D that it is a secosteroid and that there is a vitamin D nuclear receptor which affects transcription of at least 913 genes. This VDR is regulated differently by different vit D metabolites.
For a short period of time higher vit D intake will indeed
palliate pain, weakness (less effective) similar to cortison as described in the given studies but in the long run I can imagine it to be one curse of the 21st century with more and more chronic ill people.
For a better in depth knowledge and understanding of the vit D regulatory loops I recommend the following internet site where references for this rapid-answer are given:
http://mpkb.org/doku.php/home:pathogenesis:vitamind
Competing interests:
I have been suffering from chronic progredient sarcoidosis. Since I avoid Vit D and are treated via the Marshall Protocol my health has improved.
Competing interests: No competing interests
As a GP in a multiethnic indoor inner city part of London, I welcome the thorough review of vitamin D by Pearce and Cheetham in this week’s BMJ. Now that testing is easy, we are overwhelmed by evidence of low levels. A quick search tonight reveals that in the last two years 10% (1085) of our patients have had vitamin D levels measured in the practice, of whom only a third were above treatment threshold in the review. (Table1) Most of those tested were young and middle aged adults, some with vague aches and pains, some just pregnant. We now find white male bankers as well as those with darker skins or covered for religious reasons among the unrecordably low. We wonder should we be screening more widely? Meanwhile vitamin D replacement has already become a high expenditure area in the local drugs budget.
Table 1: first measurement in 2008 -2009 Serum 25ohD3 Nmol/l Patient nos. under 18 171 19-24 145 25-49 419 50-75 252 over 75 98
A number of issues arise in relation to vitamin D supplements.
While those taking their replacement usually have levels which rise rapidly on 800iu (two of the commonly available calcium and vitamin D or vitamin A and D oral combinations) daily we find concordance very low. Many people hate taking gritty large chewable or soluble calcium and vitamin D tablets. In addition, we have been unable to find acceptable gelatine free products and the source of the gelatine is difficult to identify. Some is porcine. More than half of those needing supplements are Muslim and their views vary about what to do when there are haram (proscribed)ingredients in a needed medicine, but some will not take it and all would prefer a gelatine free product.
Meanwhile high dose supplements by injection or tablet costly and became unobtainable locally once the assay revealed demand. If concordance could be improved through understanding and better products they would rarely have a role. There is an urgent need for small, palatable, gelatine free vitamin D 1000IU tablets for maintenance, when calcium is not needed if we are to treat this public health problem appropriately and equitably.
Finally Healthy Start vitamins are not getting to mothers and children entitled to them because they aren't routinely available from pharmacies. This needs national resolution to reduce childhood deficiency.
Competing interests:
None declared
Competing interests: Table 1: first measurement in 2008 -2009Serum 25ohD3Nmol/l Patient nos.under 18 17119-24 14525-49 41950-75 252over 75 98
Like Ms Da Costa, I was struck by the listed 'available' calciferol
in the UK. Our local pharmacists have had tremendous difficulty sourcing
these for us and, as a practice with a high proportion of first, second
and third generation Asian patients, this is not an obscure problem.
The article, whilst interesting, makes a common assumption; that GPs lack
the knowledge to manage these patients. This is not always the case, often
we - like our patients - lack access to the correct resources. Which no
amount of knowledge can address.
Competing interests:
None declared
Competing interests: No competing interests
We read with interest, the clinical review on vitamin D deficiency
and were reminded of the pressures we face from our local clinicians and
sometimes members of the public demanding a universal approach, especially
because our borough has a high ethnic mix. While we agree with the authors
regarding the clinical management of vitamin D deficiency, we cannot agree
with the authors’ recommendation that the public health approach needs to
be a universal supplementation (here universal means all pregnant women,
children and the elderly) or fortification of foods with vitamin D .
Authors state that vitamin D deficiency is common in the UK. However,
there is no national data at population level to support this and most
prevalence studies are based on hospital data or on small samples.
Similarly the data on at risk groups such as the Asian population comes
from hospital based studies in areas with higher ethnic mix such as
Bradford and Birmingham.
Authors also state that 90% of vitamin D comes from sunlight and the
at risk population (dark skinned) needs up to a 10 fold increase in
exposure to sunlight compared to the light skinned population. If this is
entirely true, given the amount of sunlight exposure in South Asian
countries, one would expect the prevalence of vitamin D deficiency to be
considerably lower. But studies have shown that the prevalence of vitamin
D deficiency in South Asian counties is higher than in the UK at 50% and
above. Often this problem has been attributed to poor dietary intake and
calcium deficiency .
Some might attribute this to the practice of South Asian population
covering themselves fully. However, a study in India where 75% are Hindus
and 4% Christians who do not cover themselves and with sunscreen creams
not in common use showed that the prevalence in pregnant women was >80%
.
The authors have discussed the DH’s guidance but have not discussed
the most recent NICE guidance on maternal and child nutrition which
supersedes the DH’s guidance . NICE has looked into the evidence and has
recommended the issue of the healthy start vitamins to children aged 6
months to 4 years and pregnant women who are eligible for income support.
It also recommends that all the frontline professionals should aim to
promote the benefits of vitamin D to all the pregnant women and children
who are not eligible for healthy start vitamins.
Supplementation of vitamin D without assessing the dietary intake (a
person may be identified as being ‘at risk’ because of his or her skin
colour, but may be taking plenty of fish and supermarket cereals which has
100% of the RDA) means that individuals are asked to take unnecessary
levels of vitamin D. Even though toxicity is known only at huge doses of
vitamin D intake, the risk of chronic toxicity has also been documented
.
We would also like to quote the most recent systematic review
published in August 2009 . This review included 165 studies and 11
systematic reviews and concluded that the majority of the findings
concerning vitamin D, calcium, or a combination of both nutrients on the
different health outcomes were inconsistent. It also acknowledged that
synthesising a dose-response relationship between intake of either vitamin
D, calcium, or both nutrients and health outcomes in this heterogeneous
body of literature was challenging. It concluded that studies on the
association between either serum 25(OH)D concentration or calcium intake
and other forms of cancer (colorectal, pancreas, prostate, all-cause),
incidence of hypertension or specific cardiovascular disease events,
immunologic disorders and pregnancy-related outcomes including
preeclampsia were either few in number or reported inconsistent findings.
While vitamin D deficiency is unacceptable and should be treated
promptly, the evidence available so far and the magnitude of the problem
in the UK does not justify universal vitamin d supplementation or
fortification for the following reasons:
1. Apart from hospital based data and few small scale studies, there
is no national level data to show that vitamin D deficiency is increasing
at levels that makes it a public health priority.
2. While vitamin D deficiency in the high risk population has been
attributed to lack of sunlight in the UK, the even higher prevalence in
countries with excessive sunlight (and where people do not cover
themselves fully), has been attributed to poor dietary intake.
3. The evidence linking the different health problems and vitamin D
as an independent risk factor is inconclusive.
We strongly believe that the best strategy for the UK in the current
situation is that every front line health professionals provide
information on the benefits and sources of vitamin D and empower the
individuals to decide. After all, it is freely available to purchase in
the UK.
Competing interests:
None declared
Competing interests: No competing interests
Why universal vitamin d supplementation or fortification is not the best Public health strategy for vitamin D deficiency in the UK
(We are re submitting this with the references)
We read with interest, the clinical review on vitamin D deficiency
and were reminded of the pressures we face from our local clinicians and
sometimes members of the public demanding a universal approach, especially
because our borough has a high ethnic mix. While we agree with the authors
regarding the clinical management of vitamin D deficiency, we cannot agree
with the authors’ recommendation that the public health approach needs to
be a universal supplementation (here universal means all pregnant women,
children and the elderly) or fortification of foods with vitamin D (Simon
H S Pearce, Tim d Cheetham. Diagnosis and management of vitamin D
deficiency. BMJ 2009;340:142-47).
Authors state that vitamin D deficiency is common in the UK. However,
there is no national data at population level to support this and most
prevalence studies are based on hospital data or on small samples.
Similarly the data on at risk groups such as the Asian population comes
from hospital based studies in areas with higher ethnic mix such as
Bradford and Birmingham.
Authors also state that 90% of vitamin D comes from sunlight and the
at risk population (dark skinned) needs up to a 10 fold increase in
exposure to sunlight compared to the light skinned population. If this is
entirely true, given the amount of sunlight exposure in South Asian
countries, one would expect the prevalence of vitamin D deficiency to be
considerably lower. But studies have shown that the prevalence of vitamin
D deficiency in South Asian counties is higher than in the UK at 50% and
above. Often this problem has been attributed to poor dietary intake and
calcium deficiency (Masood SH, Iqbal MP. Prevalence of vitamin D
deficiency in South Asia. Pak J Med Sci 2008;24(6): 891-97).
Some might attribute this to the practice of South Asian population
covering themselves fully. However, a study in India where 75% are Hindus
and 4% Christians who do not cover themselves and with sunscreen creams
not in common use showed that the prevalence in pregnant women was >80%
( Sachan A, Gupta R, Das V, Agarwal A, Pradeep K, Awasthi PK, et al. High
prevalence of vitamin D deficiency among pregnant women and their newborns
in northern India. Am J Clin Nutr 2005;81:1060-4)
The authors have discussed the DH’s guidance but have not discussed
the most recent NICE guidance on maternal and child nutrition which
supersedes the DH’s guidance (NICE. Maternal and Child Nutrition.
PH11.2008). NICE has looked into the evidence and has recommended the
issue of the healthy start vitamins to children aged 6 months to 4 years
and pregnant women who are eligible for income support. It also
recommends that all the frontline professionals should aim to promote the
benefits of vitamin D to all the pregnant women and children who are not
eligible for healthy start vitamins.
Supplementation of vitamin D without assessing the dietary intake (a
person may be identified as being ‘at risk’ because of his or her skin
colour, but may be taking plenty of fish and supermarket cereals which has
100% of the RDA) means that individuals are asked to take unnecessary
levels of vitamin D. Even though toxicity is known only at huge doses of
vitamin D intake, the risk of chronic toxicity has also been documented
(Leake CD. Vitamin D Toxicity. Cal West Med. 1936 Mar;44(3):149–150.)
We would also like to quote the most recent systematic review
published in August 2009 (Evidence Report/Technology Assessment Number 183
Vitamin D and Calcium: A Systematic Review of Health Outcomes) This
review included 165 studies and 11 systematic reviews and concluded that
the majority of the findings concerning vitamin D, calcium, or a
combination of both nutrients on the different health outcomes were
inconsistent. It also acknowledged that synthesising a dose-response
relationship between intake of either vitamin D, calcium, or both
nutrients and health outcomes in this heterogeneous body of literature was
challenging. It concluded that studies on the association between either
serum 25(OH)D concentration or calcium intake and other forms of cancer
(colorectal, pancreas, prostate, all-cause), incidence of hypertension or
specific cardiovascular disease events, immunologic disorders and
pregnancy-related outcomes including preeclampsia were either few in
number or reported inconsistent findings.
While vitamin D deficiency is unacceptable and should be treated
promptly, the evidence available so far and the magnitude of the problem
in the UK does not justify universal vitamin d supplementation or
fortification for the following reasons:
1. Apart from hospital based data and few small scale studies, there
is no national level data to show that vitamin D deficiency is increasing
at levels that makes it a public health priority.
2. While vitamin D deficiency in the high risk population has been
attributed to lack of sunlight in the UK, the even higher prevalence in
countries with excessive sunlight (and where people do not cover
themselves fully), has been attributed to poor dietary intake.
3. The evidence linking the different health problems and vitamin D
as an independent risk factor is inconclusive.
We strongly believe that the best strategy for the UK in the current
situation is that every front line health professionals provide
information on the benefits and sources of vitamin D and empower the
individuals to decide. After all, it is freely available to purchase in
the UK.
Competing interests:
None declared
Competing interests: No competing interests