Archiv der Kategorie: Vitamins

Forget about plasma vitamin D measurements

I have written in my recent editorial about the nonsense of plasma vitamin D measurements. A recent case history of a patient with a deleted vitamin D carrier molecule GC now confirms the free-hormone hypothesis. The patient’s plasma 25(OH)D levels was only 0.4% of those in the unaffected sibling.

Despite a lifelong deficiency of vitamin D binding protein, limited sun exposure (for religious reasons), and a diet that was probably lacking sufficient vitamin D, our patient did not have rickets or osteomalacia but rather osteopenia and fragility fractures that occurred in the fifth decade of life.

Another carrier sibling had only two third of the plasma 25(OH)D level compared to the unaffected sibling but showed “no appreciable clinical manifestations”.
So why measure 25(OH)D?

Single vitamin D bolus and HLA accessible chromatin

We have already recently seen that gene methylation in newborns can be changed by maternal vitamin D supplementation.
This is now confirmed in a single individual who was exposed to an oral bolus of 2000  μg of vitamin D3. Even within one day, effects could be observed.

Consistently accessible chromatin was detected at 5,205 genomic loci, the 853 most prominent of which a self-organizing map algorithm classified into early, delayed and non-responding genomic regions: 70 loci showed already after one day and 361 sites after two days significant (p < 0.0001) chromatin opening or closing. Interestingly, more than half of these genomic regions overlap with transcription start sites, but the change of chromatin accessibility at these sites has no direct effect on the transcriptome.

Early responses are described for SUN1 (funny in this context :-), FBF1 and WRAP73. Overall the genomic region around the human leukocyte antigen (HLA) cluster in chromosome 6 showed the highest normalized density of accessible chromatin explaining the immunosuppressive effect of sunshine.

Allergy and vitamin D supplements only in domesticated animals

This is an argument that I found only recently in the excellent review  by Hellman 2017

Both humans and rodents living under laboratory conditions are generally free from worm infections, which are known to be potent inducers of IgE production. By contrast, most wild animal populations have massive amounts of intestinal worm parasites … To our knowledge, allergies have not been described in wild animals. One potential factor could be a genetic drift due to strong selection for phenotypic characteristics like coat color, long or short noses, running fast, or wanted social behaviors. Such strong selections are seen in the breeding programs for dogs, horses, and cats, but a questionable cause for human allergies. However, it is possible that we constantly need to be selecting against hypersensitivities, which may occur due to minor shift in immune functions caused by spontaneous point mutations. A strong such selection process most likely exists in wild animals under tough environmental conditions but not in domestic animals and in humans.

I agree on the observation – allergy is found only in humans and domesticated animals – while the explanation is implausible as it cannot be generalized to humans. As vitamin D supplements are both used for humans, cats, dogs, horses and lab mice, it is a more likely explanation in particular as we have now have 4 randomized trials in humans confirming the hypothesis.

Vitamin D and farming

We published already in 2004 that farmers use less vitamin D supplements as they spend so much time outdoors

and give their babies more raw milk avoiding supplemented milk. Just for the notes.


Viel hilft viel

Immer wieder wird Deutschland ein flächendeckender Vitamin-D-Mangel attestiert. So schrieb beispielsweise die Deutsche Gesellschaft für Ernährung in ihrem Bericht, den sie im Sommer veröffentlichte, rund 30 Prozent der Erwachsenen seien nicht ausreichend mit Vitamin D versorgt. Wobei Ältere als Risikogruppe gelten und bei Seniorinnen der Mangel aber ausgeprägter ist als bei Männern. Für Personen mit hohem Risiko für einen Vitamin-D-Mangel erachtet es die DGE für notwendig, ein Vitamin-D-Präparat einzunehmen, um den Bedarf zu decken. Evidenz für eine generelle Substitution gibt es zwar nicht. Aber anscheinend führen solche Berichte und das zugehörige Medien-Echo dazu, dass eigenmächtig ohne Rücksprache mit Arzt oder Apotheker Vitamin D eingenommen wird – und zwar nach dem Motto: „viel hilft viel“

Wer glaubt schon der Deutsche Gesellschaft für Ernährung? Immerhin doch Einige: Die Deutschen Apothekerzeitung berichtet aktuell über zwei Fälle von akuten Nierenversagen bei ausgeprägter Hyperkalzämie,.

Did we trade rickets with allergy?

I have written on that before but find it striking again when reading another historical perspective.

The first insight into the possible relationship between the industrialization of Northern Europe and rickets was made by Sniadecki in 1822 when he concluded that children who lived in the inner city of Warsaw had a high incidence of rickets because of their lack of sun exposure. This was based on his clinical observations that children living in rural areas outside of Warsaw did not suffer from rickets while children born and raised in Warsaw were plagued with the disease.

Now we are supplementing vitamin D to nearly all inner city children who have a high allergy prevalence but not so much in rural areas where we see less allergy – everywhere, not only in Warsaw.

Did we trade rickets with allergy?

I can see you with my eyes closed

Today I cam across extraocular photoreceptors which make up a fascinating story, explained by Wikipedia

A third class of mammalian photoreceptor cell was discovered during the 1990s: the photosensitive ganglion cells. These cells do not contribute to sight directly, but are thought to support circadian rhythms and pupillary reflex.

A paper (“seeing without eyes”) at has the details

“extraocular photoreceptors” are usually found in the central nervous system or in the skin, but also frequently in internal organs. … All the visual cells identified in animals detect light using a single family of proteins, called the opsins. These proteins grab a light-sensitive molecule – derived from vitamin A – that changes its structure when exposed to light. The opsin in turn changes its own shape and turns on signaling pathways in photoreceptor cells … The skin is where we see most other light receptors, particularly in active color-changing cells or skin organs called chromatophores.

I tried but could not find any link between chromatophores, vitamin D production and skin tanning in humans although such a link would make a lot of sense. While changing the search strategy to opsin expression in the skin, I found something interesting

Here we show that four opsins—OPN1‐SW, OPN2, OPN3 and OPN5—are expressed in the two major human epidermal cell types, melanocytes and keratinocytes, and the mRNA expression profile of these opsins does not change in response to physiological UVR doses. … Notably, OPN2 and OPN3 mRNA were significantly more abundant than other opsins and encoded full‐length proteins. Our results demonstrate that opsins are expressed in epidermal skin cells and suggest that they might initiate light–induced signaling pathways, possibly contributing to UVR phototransduction.

It seems that the effect is mainly  by OPN5

Human OPN5 also had an absorption maximum at 380 nm with spectral properties similar to mouse OPN5, revealing that OPN5 is the first and hitherto unknown human opsin with peak sensitivity in the UV region. OPN5 was capable of activating heterotrimeric G protein Gi in a UV-dependent manner.

which came into life by just a single mutation. As far as I understand it, UVR exposure is not leading to any opsin expression. Maybe it is just a very low threshold trigger for TYR et al ?

We investigated the effects of UV on human skin of various races before and at different times after a single 1 minimal erythemal dose UV exposure. … The expression of melanocyte-specific proteins (including TYR (tyrosinase), TYRP1 (tyrosinase-related protein 1), DCT (tyrosinase-related protein 2), MART1 (melanoma antigens recognized by T-cells) gp100 (Pmel17/silver), and MITF (micropthalmia transcription factor)) increased from 0 to 7 d after UV exposure, but the melanin content of the skin increased only slightly. The most significant change, however, was a change in the distribution of melanin from the lower layer upwards to the middle layer of the skin

A recent review in Current Biology pointed out that vitamin A-based chromophores were initially used in harvesting light energy, but have then become the most widely used light sensor.

Unfortunately many research questions have not been answered yet. We can only speculate about the function of extraocular photoreceptors in humans. In the mammalian retina it is probably part of a self-defense mechanism of the eye to avoid UVR induced destruction. There could be similar functions in the human skin including circadian entrainment, DNA protection and repair. Vitamin D production in the skin after UVR exposure is an independent process as ergosterol itself can efficiently absorb UVB radiation.

Finally here is a speculation about the pathophysiology: Extraocular photoreceptors could be key structures in photophobia, phototoxic and photo allergic reactions.

A serious backslash

It is a serious backslash to the pro vitamin D lobby that has been published in the Lancet Diabetes & Endocrinology last week.

Our findings suggest that vitamin D supplementation does not prevent fractures or falls, or have clinically meaningful effects on bone mineral density. There were no differences between the effects of higher and lower doses of vitamin D. There is little justification to use vitamin D supplements to maintain or improve musculoskeletal health.

Odds ratio 1.00. There is nothing to add.

Unspezifische Impfeffekte als Allergieprävention?

Unspezifische Impfeffekte  wird es wohl  geben, so der neue SPON Artikel von heute

Allerdings wird in Industrienationen daran geforscht, wie die unspezifischen Effekte früher Impfungen möglicherweise ein Leben nachwirken. Zurzeit läuft zum Beispiel eine große Studie in Australien zur Frage, ob eine frühe BCG-Impfung (gegen Tuberkulose) das Allergierisiko senkt.
Vielleicht hängt der Anstieg von Allergien ja damit zusammen, dass wir aufgehört haben, gegen Pocken und BCG zu impfen”, vermutet Aaby. Er fragt sich sogar, ob das Einstellen der Pocken-Impfung nicht auch Schaden angerichtet haben könnte, weil nun das Immuntraining durch diese Impfung ausfalle.

Der Bezug zu den Allergien ist allerdings sehr unwahrscheinlich, siehe Arnoldusson

We identified 767 articles, of which 17 satisfied our inclusion criteria; there was only 1 randomized controlled trial, with the remaining studies being epidemiologic investigations. Meta-analyses did not show any protective effect of vaccination against the risk of sensitization, as judged by specific IgE tests or skin prick testing …BCG vaccination is unlikely to be associated with protection against the risk of allergic sensitization and disease.

Es ist mir also ziemlich schleierhaft, warum das Murdoch Childrens Research Institute dazu eine Studie macht. Aber das Research Institute hat schon ganz andere Flops produziert…

Auch die Pockenimpfung schützt nicht, das ist eigentlich längst abgehakt

We found no association between having been vaccinated against smallpox in childhood and risk of atopy or allergic rhinitis. Smallpox vaccination was associated with a slightly decreased risk of asthma. There was no association between age at smallpox vaccination and risk of atopy, allergic rhinitis, or asthma. Adjusting for birth cohort, sibship size, age of the woman’s mother at birth, and social class in childhood did not change these results.

Es geht hier auch nicht so sehr um eine neue wissenschaftliche Diskussion, sondern um die journalistische Aufarbeitung eines “Dokumentarfilms”.

Nach  Masernimpfung hat im übrigen Seif Shaheen in Guinea-Bissau mehr(!) Allergien gefunden, was aber wohl auch fraglich ist, da hier nicht nur die Impfung, sondern die medizinische Betreuung generell (“iatrogen”) zur Debatte steht. Interessanterweise wird in Guinea-Bissau auch Vitamin D zur Tbc Prophylaxe gegeben wobei Vitamin D selbst ein Allergierisikofaktor ist.

Gene methylation in newborns is changed by maternal vitamin D supplementation

A randomized controlled study of pregnant women examined 400 IU vitamin D3 vs 3,800 IU from the second trimester through 4-6 weeks postpartum by genome-wide DNA methylation in leukocytes.

At birth, intervention group mothers showed DNA methylation gain and loss at 76 and 89 cytosine- guanine (CpG) dinucleotides, respectively, compared to controls. Postpartum, methylation gain was noted at 200 and loss at 102 CpGs. Associated gene clusters showed strongest biologic relevance for cell migration/ motility and cellular membrane function at birth and cadherin signaling and immune function at postpartum.

It seems that D3 supplementation is generating epigenetic effects in the offspring, something that we predicted already in 2012 as programming of vitamin D sensitivity.

When re-annotating the genes above using biocLite(“mygene”) there are at least 2 interesting genes for gain of methylation are getting to the surface: ZMIZ1  T cell differentiation) and CYP7B1 (first reaction in the cholesterol catabolic pathway of extrahepatic tissues, which converts cholesterol to bile acids). But also methylation loss is interesting with HLA-A (antigen processing).

Der Vitamin D Lobbyist Achim Zittermann und seine erfundene Heidi Geschichte

Es ist schon kurios, was das Web manchmal zu Tage fördert.
Zum Beispiel ein Vortrag des Vitamin D Experten Dr. oec. troph. Achim Zittermann ( Bad Oeynhausen ), der Clara Sesemann aus dem Heidi Roman eine Rachitis andichtet.



Im Original bei Johanna Spyri kann man aber nachlesen, dass Clara regelmässig “Fischthran” bekommt, also hochdosiert Vitamin  D (und A).



Wenn Claras Symptome also wirklich auf eine endokrine Störung zurückzuführen wären, dann müsste es sich um eine Vitamin-D resistente Rachitis Typ I oder II sein. Beide Formen reagieren aber nicht auf zusätzliche Sonneneinstrahlung in den Bergen.

Die Heidi Geschichte des Vitamin D Experten ist also genauso Unsinn wie seine 18300 Toten durch Vitamin D Mangel.

Refutation of the vitamin D hypothesis?

A new epidemiological study arguments against vitamin D inducing later allergy (Parr et al., Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother and Child Cohort, Am J Clin Nutr 2018;107:789-798). Table 5 in the most recent paper shows no effect when correlating first year of life supplementation and later asthma.


But why did they authors not even cite our study from 2004 (Hyppönen et al. Infant Vitamin D Supplementation and Allergic Conditions in Adulthood Northern Finland Birth Cohort 1966.  Ann. N.Y. Acad. Sci. 1037: 84-95) ??


Although our interest was more with allergy there have been clear effects on asthma  that have been confirmed now two dozen times.  Why did the authors miss that effect?

  • The cohort consists of 115,000 children but only 55,000 are analyzed. So selection bias is omnipresent.
  • A key issue is the definition of “asthma” as “having ≥2 pharmacy dispensations of asthma medication within a 12-month interval, which is more a “last resort” option than a correct diagnosis. “We cannot rule out some misclassication in our asthma outcome“. I agree.
  • Another issue is the unrecorded vitamin supply by standard baby food in the range of 500-1000 IU/daily. Does it make any sense to test for excess supplements in a population that is already heavily exposed to >90%? “A limitation of this study is that we did not have data on nutrient intake from supplements in infant“. I agree, it makes the study worthless.
  •  The supplementation with cod liver oil, vitamin D and multivitamins is chaotic as been shown in the last row of table 5. In real life or just in this paper? Numbers are contradicting “Vitamin D only, sometimes” and “daily” do not add to the number given for “vitamin D only” in the “combined use” section.
  • Supplementation at  month 6 is even a late event if we believe that the first allergen contact under vitamin D exposure is  being important.

So, still not need to drop the vitamin D hypothesis.

Vitamin D trials in newborns

Vitamin D was introduced into clinical medicine in 2 large waves basically in the 1930ies and 1960ies. Although we were interested in the relationship to allergy since 1999 none of our proposed vitamin D trials were funded.

2005: “Vitamin D and Induction of Allergies”
2013: “Vitamin D and allergy (VIT-AL)”
2017: “Biomarker Screening of Vitamin D response in Newborns (VITAPRIME)”
2017: “Immunological effects of vitamin D supplementation in newborns in Ghana (IMVITAD-GHA)”

All published clinical studies so far missed the point except one as they were looking only at pregnancy and not at newborn supplements (VDAART, COPSAC and Grant/NZ).

But there are good news now, as studies are going on in Australia and Finland that are sufficiently powered and examining exposure in the newborn period: VIDI and VITALITY. The only problem there will be the inevitable co-exposure by vitamin D supplemented baby food.

Genetics of vitamin D

A new GWAS of vitamin D serum level reports two new loci as sample size could be increased from 16K to 79K. While the previous GWAS hits had a reasonable biological function (GC transport protein,  DHCR7 converting to cholesterol, CYP2R1  to calcidiol and CYP24A1 degradation)  the new loci look more like statistical artifacts.
The authors tried some kind of dose effect estimates

where SNP effects on serum level became slightly weaker (which makes sense as diet is a clear environmental factor). Genetics of vitamin D weiterlesen