Category Archives: Vitamins

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 are 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). Continue reading Genetics of vitamin D

The end of the vitamin D deficiency debate? 8 facts

Most recently, a NEJM paper “Vitamin D Deficiency — Is There Really a Pandemic?” by Manson, Brannon, Rosen, and Taylor explains the big misunderstandings that let some authors conclude that whole populations are being vitamin D deficient. Just to recall, the IOM recommended in 2010 serum concentrations of vitamin D (i.e., 25-hydroxyvitamin D [25(OH)D]) above 20 ng per milliliter (or 50 nmol per liter) as appropriate level and supplementation with 600 to 800 IU per day as Recommended Dietary Allowance (RDA). And here are the 8 facts: Continue reading The end of the vitamin D deficiency debate? 8 facts

Vitamin D responder: Check CD14 methylation

A clinical study in 2015 already showed, how to recognize vitamin D responders using a preselected gene set based on VDR chip seq data.

Vitamin D3 is a pleiotropic signaling molecule that has via activation of the transcription factor vitamin D receptor (VDR) a direct effect on the expression of more than 100 genes. The aim of this study was to find transcriptomic and clinical biomarkers that are most suited to identify vitamin D3 responders within 71 pre-diabetic subjects during a 5-month intervention study (VitDmet). In hematopoietic cells, the genes ASAP2, CAMP, CD14, CD97, DUSP10, G0S2, IL8, LRRC8A, NINJ1, NRIP1, SLC37A2 and THBD are known as primary vitamin D targets […] only 39-44 (55-62%) of the study subjects showed a highly significant response to vitamin D3, i.e., we considered them as “responders” … genes were expressed but in a wide range that differed up to 327-fold between the most prominently (CD14) and the lowest expressed candidate (CAMP)

y-axis end/start CD15 serum, x-axis end/start 25-OH-D3 

In new editorial, the same authors argue that the vitamin D response index is an epigenetic property of an individual that may not change at all. Indeed, changes in the epigenome, such as methylation of genomic DNA is an essential prerequisite for initiating gene transcription. The concept of an individual vitamin D response therefore has a lot of merits and is able to resolve a long controversy which serum vitamin D levels are sufficient.

CD14 is a particular interesting gene. As we have learned in allergy research, however, methylation status is not stable over time, it increases slightly over the first decade, possibly as vitamin D sensitivity decreases??

The average increase in CD14 methylation from 2 to 10 yr (n = 153) was 1.3% (from 5.5% to 6.8%, p = 0.001)

This difference isn’t really huge while also the time spent outdoors seem to be relevant. CD 14 methylation may even influence SNP association results

rs2569191, rs5744455, and rs2569190 were associated with sCD14 levels at birth and 2 years, but only rs5744455 was associated with sCD14 levels at 10 years. CD14 methylation increased significantly from age 2 to 10 years.

So CD14 methylation looks like an interesting indicator and may even have biological relevance itself as CD14+ monocytes can differentiate into a host of different cells.

Death of a newborn following vitamin D drops

aerzteblatt.de, thejournal.ie, bbc.com, reuters.com, lemon.fr (with video) report that

France has moved to suspend sales of a vitamin D medication following the death of a baby who suffocated after being given the liquid supplement, health authorities said today. France’s ANSM agency that oversees the safety of medicines and health products said it had taken the measure “as a precaution” after investigations showed “a probable link between the death and the administration of Uvesterol D”.

Indeed vitamin D is used as a rodenticide with high toxicity. The death of the baby was probably not a direct effect of vitamin D but induced by the kind of application. In any case, I would avoid any oral application of an immunosuppressive hormone to a healthy newborn.

Rat race

While working on a review about vitamin D and the microbiome, I came across an interesting article Immune-Microbiota Interactions: Dysbiosis as a Global Health Issue

Recent research, however, demonstrated that a number of specific interventions can lead to (partial) primary prevention of allergy, especially of atopic dermatitis (AD) and food allergy (FA). Three types of primary prevention strategies have been successfully studied: early administration of bacterial products (most studies are on probiotics), early moisturizing in infants at risk for AD and early exposure to allergenic foods (peanut and egg).

I am not so much convinced of any successful probiotics research that prevents all kind of allergy (ref, ref, just to name two). The interesting point, however, is the new recommendation to early exposure of allergenic foods. Does earlier exposure mean less exposure under vitamin D suppression that shouldn’t start before week 6?

Low serum vitamin D – reverse causation or true risk factor?

Even with thousands of studies, one of the most basic questions in vitamin D research is being unanswered. Low serum 25(OH)D3 – is it reverse causation or a true risk factor? As plasma 25(OH)D3 can be easily determined, it became the standard measurement for vitamin D supply. Unfortunately numerous other factors – season, genetics, sex, age, race – all influence serum 25(OH)D3 levels.

Then in 2011 David Reid et al. published a paper of 25(OH)Dfollowing up changes during acute inflammatory response after knee surgery. In essence, plasma concentrations of 25(OH)D decreased after an inflammatory insult and are not a reliable measure of 25(OH)D status in subjects with a significant systemic inflammatory response. This observation is being confirmed in the meantime by 2 further studies (Barker 2012 and Waldron 2013). I think this is a clear result now.

I have never been convinced that Mendelian randomization will help here at all – as done in earlier studies. These are clearly situations where Mendelian randomization does not work as shown  by Smith and Ebrahim back in 2004

—failure to establish reliable genotype (seldom)
—intermediate phenotype genotype—disease associations (frequent)
—confounding of genotype—intermediate phenotype—disease associations (unclear)
—pleiotropy and multi-functional genes (frequent)
—canalization and developmental compensation (unclear, but expected to be frequent)
—Lack of suitable polymorphisms for studying modifiable exposures of interest (no more a problem)

So, 25(OH)D3 is more an acute phase indicator where low levels in inflammatory diseases is effect not a cause. It is, however, still unclear if low 25(OH)D levels are due to an increased demand (as the vitamin D lobby already argues), a shift in free/bioavailable metabolite (by hemodilution, binding protein capacity what I expected) or just other unknown factors.

Vitamin D Vergiftung bei Weidetieren

Auch Kühe können erhöhte Vitamin D Werte haben, wenn sie Goldhafer fressen, der ab 500m im alpinen Raum auftritt.

Trisetum flavescens ist zwar kein bevorzugtes Futter und wird nur gefressen, wenn das Angebot von anderen Gräsern knapp ist, enthält aber Goldhafer Calcitriol, das aktive Vitamin D Hormon. (Ansonsten ist Vitamin D in der Nahrungskette nur als Ergocalciferol in sonnenbestrahlten Steinpilzen, Pfifferling, Spinat, einigen Kohlarten und Hefe (bis 3 µg/100 g) zu finden. Lebensmittel mit hohem Gehalt tierischen Ursprungs sind Hühnereier, fettreiche Fische wie Lachs, Forelle, Thunfisch).

Sensationell ist jedenfalls der direkte Hormongehalt des Hafers, den es sonst in keinem Lebensmittel gibt. Denn in der Milch der Kühe kommen natürlich erhöhte Vitamin D-Metabolite gemessen werden.  Das bayrische Landesamt für Umwelt 2007 weiss auch, wo besonders viel Goldhafer in Bayern zu finden ist – südlich des Chiemsees

Einziger Fundort [von Trisetum flavescens ssp. purpurascens (Goldhafer)] im Landkreis am Sagberg bei Frasdorf in Goldhaferwiesen bei 820 m, an den rotbraunen, kräftigen Fruchtständen und kräftigeren Blattspreiten gut kenntliche Unterart des Goldhafers, bisher nur bekannt und zahlreich nachgewiesen aus höheren Lagen der Allgäuer Alpen. Außerhalb davon nur noch drei Meldungen aus tieferen Lagen im Rahmen der ABK (außer diesem sonst nur noch Einzelnach- weise aus den Landkreisen Lindau und Garmisch-Partenkirchen).

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Why allergy and vitamin D trials failed so far

The following figure highlights the exposure scheme in the three published vitamin D / allergy clinical trials so far: Grant 2016, Litonjua 2016 and Chawes 2016.

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None of them found anything important, maybe due to the design flaw in all these studies? All three studies have been designed with the assumption of a beneficial vitamin D effect. They are dose finding studies that do not allow to prove or disprove any vitamin D effect.