ArticlePDF AvailableLiterature Review

Cod Liver Oil, Vitamin A Toxicity, Frequent Respiratory Infections, and the Vitamin D Deficiency Epidemic

Authors:
  • Vitamin D Council, Inc.
COMMENTARY
Cod Liver Oil, Vitamin A Toxicity, Frequent Respiratory
Infections, and the Vitamin D Deficiency Epidemic
John J. Cannell, MD; Reinhold Vieth, MS, PhD; Walter Willett, MD, DrPH;
Michael Zasloff, MD, PhD; John N. Hathcock, MSc, PhD; John H. White, PhD;
Sherry A. Tanumihardjo, MSc, PhD; D. Enette Larson-Meyer, PhD;
Heike A. Bischoff-Ferrari, MD, MPH; Christel J. Lamberg-Allardt, PhD;
Joan M. Lappe, PhD, RN; Anthony W. Norman, PhD; Armin Zittermann, PhD;
Susan J. Whiting, MSc, PhD; William B. Grant, PhD; Bruce W. Hollis, PhD;
Edward Giovannucci, MD
In the previous issue of the Annals, Linday et al1 reported a case series of 16 children who underwent
tympanostomy tube placement, of whom they found that 80% had 25-hydroxyvitamin D [25(OH)D] levels of
less than 30 ng/mL (reference range, 30 to 100 ng/mL in most American laboratories). Although interesting,
especially in light of recent recommendations that the lower level of adequate 25(OH)D levels may be as high
as 50 ng/mL2-4 (levels none of their children achieved), the implications of the work of Linday et al1 are best
appreciated when one reviews their 2 previous publications5,6 in this journal and puts their important work in
a larger historical context.
In 2004, Linday et al,5 using a medical record control group, reported that 600 to 700 IU of vitamin D and
3,500 IU of vitamin A, given as cod liver oil and a multivitamin, slightly reduced (p = 0.04) the mean number
of upper respiratory tract visits over time when given to 47 young children. However, the total number of vis-
its for upper respiratory tract infections was slightly higher in the treatment group (68 versus 61). In an earlier
pilot study, they found that a similar regimen reduced antibiotic use by 12% in 8 children.6 However, all but
1 of the treated children had an upper respiratory tract infection during the study period. In contrast, 2 larger,
controlled studies in the 1930s found more robust results: the first found that cod liver oil given to 185 adults
for 4 months reduced the incidence of colds by 50%,7 and the second study found that cod liver oil given to
1,561 adults reduced the incidence of respiratory infections by 30%.8 We suggest that the much higher vitamin
D content in 1930s cod liver oil may explain the different results.
Vitamin D alone, whether from ultraviolet lamps, the sun, or from supplements, reduces the incidence of
respiratory infections. In 1926, Smiley, who first discovered the strong inverse association between sun ex-
posure and upper respiratory tract infections, also first theorized that such seasonality was caused by “disor-
dered vitamine metabolism in the human. . . directly due to a lack of solar radiation during the dark months of
winter.”9(p626) This explains why Dutch children with the least sun exposure were twice as likely to develop a
cough, and 3 times as likely to have a runny nose, as the children with the most sun exposure.10
Furthermore, sub-erythemal courses of vitamin D–producing ultraviolet radiation administered twice a
week for 3 years to 410 teenage Russian athletes, compared to 446 non-irradiated athletes, resulted in 50%
fewer respiratory viral infections and 300% fewer days of absences.11 Wayse et al12 compared 80 non-rachitic
children with lower respiratory tract infections to healthy controls and found that the children with the low-
est 25(OH)D levels were 11 times more likely to become infected. Sixty thousand international units (IU) of
vitamin D per week administered for 6 weeks to 27 children with frequent respiratory infections resulted in a
complete disappearance of such infections for the following 6 months.13
More recently, some of us presented extensive epidemiological evidence that the seasonality of vita-
min D deficiency may explain the seasonality of influenza epidemics.14,15 We concluded that physiological
doses of vitamin D would reduce the incidence of influenza, but theorized as well — on the basis of vita-
Annals of Otology, Rhinology & Laryngology 117(11):864-870.
© 2008 Annals Publishing Company. All rights reserved.
864
min D’s mechanism of action that pharmacologic
doses might effectively treat cases of influenza. Aloia
and Li-Ng16 then published the most rigorous evidence
to date supporting the prevention theory. In a post hoc
analysis of their original 3-year randomized controlled
interventional trial, they discovered that 104 African
American women given vitamin D were 3 times less
likely to report cold and flu symptoms than were 104
placebo control subjects (p < 0.002). A low dose (800
IU/d) abolished the seasonality of reported colds and
flu, and even a sub-physiological dose of 2,000 IU/d
(40% of treated women still had serum 25(OH)D lev-
els of less than 32 ng/mL after 1 year) virtually eradi-
cated all reports of upper respiratory tract infections
(see Figure16).
Although Linday et al1 mention vitamin D’s anti-
microbial mechanism of action, a more detailed expla-
865 Commentary 865
Incidence of reported cold and influenza symptoms ac-
cording to season. Subjects (n = 104) in placebo group
(light shading) reported cold and flu symptoms year-
round, with most symptoms in winter. While on 800 IU/d
(intermediate shading), 104 test subjects were as likely
to get sick in summer as in winter. Only 1 of 104 test
subjects had cold and/or influenza symptoms during fi-
nal year of trial, when they took 2,000 IU/d of vitamin D
(dark shading). (Modified with permission.16)
nation would remind readers that the pathology of respiratory infections involves a complex interaction among
the microbe, adaptive immunity, and innate immunity. Whereas adaptive immunity requires prior exposure to
an antigen, innate immunity is that branch of host defense that is “hard-wired” to respond rapidly to antigens
by using effectors that are genetically coded for activation before they ever encounter that antigen. Of the ef-
fectors, the best studied are the antimicrobial peptides (AMPs).17
These endogenous antimicrobials exhibit broad-spectrum microbicidal activity against bacteria, fungi,
and viruses. In general, they rapidly damage the lipoprotein membranes of microbial targets, including envel-
oped viruses such as influenza. Both the epithelium, in which they form a protective shield in mucus, and pro-
fessional phagocytes, in which they provide microbicidal activity within the phagolysosome, produce AMPs.
The innate immune system not only provides direct antimicrobial defense for these “front lines,” but it also
signals and primes the adaptive immune system to produce antigen-specific T lymphocytes and immunoglob-
ulins. In addition, AMPs — such as the potent antimicrobial cathelicidin — trigger tissue repair through acti-
vation of epithelial growth and angiogenesis.18
Antimicrobial peptides protect mucosal epithelial surfaces by creating a hostile antimicrobial barricade.
The epithelia secrete them constitutively into the thin layer of fluid that lies above the apical surface of the
epithelium but below the viscous mucous layer. To effectively access the epithelium, a microbe must first in-
filtrate the mucous barrier and then survive assault by the AMPs present in this fluid. Should microbes breach
this constitutive cordon, their binding to the epithelium rapidly mobilizes the expression of high concentra-
tions of specific inducible AMPs such as human β-defensin 2 and cathelicidin, which provide a “backup” an-
timicrobial shield.
Vitamin D’s pivotal role in innate immunity has become evident only recently.19 First White’s group at
McGill University,20 then 2 independent groups at the University of California–Los Angeles,21,22 showed that
activated vitamin D [1,25(OH)2D] dramatically up-regulates genetic expression of AMPs in immune cells.
(For details of the mechanism of action, see White’s23 review.) Both epithelial cells and macrophages increase
expression of the antimicrobial cathelicidin upon exposure to microbes — an expression that is dependent
upon the presence of vitamin D. Pathogenic microbes, much like the commensals that inhabit the upper air-
way, stimulate the production of a hydroxylase that converts 25(OH)D to 1,25(OH)2D, a seco-steroid hor-
mone. In turn, this activates a suite of genes involved in defense.
In the macrophage, the presence of vitamin D also suppresses the pro-inflammatory cytokines interferon
γ, tumor necrosis factor α, and interleukin-12 and down-regulates the cellular expression of several pathogen-
associated molecular pattern (PAMP) receptors. In the epidermis, vitamin D induces additional PAMP recep-
tors, enabling keratinocytes to recognize and respond to microbes.24 Thus, vitamin D both enhances the local
capacity of the epithelium to rapidly produce endogenous antibiotics and, at the same time, dampens certain
arms of adaptive immunity, especially those responsible for the signs and symptoms of acute inflammation.
The work of Liu et al22 is of particular interest. Plasma levels of vitamin 25(OH)D in African Americans,
known to be about one half those of light-skinned individuals, are inadequate to fully stimulate the vitamin D–
dependent antimicrobial circuits that are operative within the innate immune system. However, the addition of
25(OH)D restores the dependent circuits and the expression of cathelicidin. High concentrations of melanin
in dark-skinned individuals shield the keratinocytes from the ultraviolet radiation required to generate vitamin
D in skin.25 Therefore, relative — but easily correctable — deficiencies in innate immunity probably exist in
many children during the dark days of winter, with dark-skinned children at highest risk. Black children con-
tinue to have twice the rate of mortality from pneumonia of white children, despite modern antibiotics.26
Furthermore, during any season, for any skin type, and at any latitude, a percentage of the population is
vitamin D–deficient, although the percentage is highest in the winter and in dark-skinned individuals, and in-
creases the further poleward the population. For example, seasonal variation of vitamin D levels even occurs
in equatorial Hong Kong,27 and widespread vitamin D deficiency occurs at such latitudes,28 probably because
of sun avoidance,29 rainy seasons,30 and air pollution.31 A study of Hong Kong infants showed that about half
had 25(OH)D levels of less than 20 ng/mL in the winter.32 None of the infants had levels higher than 40 ng/
mL, even in the summer. Thus, a substantial percentage of all children will have impaired innate immunity at
any given time, although the impairment is greatest during the dark days of the cold and flu season.
Our main concern with the previous work of Linday et al5,6 is the cod liver oil. They gave their children
approximately 3,500 to 5,000 IU/d of preformed retinol, although none of their children had low serum retinol
levels. However, they only administered 700 IU/d of vitamin D. (International units of vitamin D and vitamin
A are not comparable.) We believe, first, that the ratio of the vitamins should be reversed and, second, that the
dose of each vitamin should be lowered. Detrimental amounts of vitamin A may explain why their earlier work
on prevention of upper respiratory tract infection was less than robust.
Although activated vitamin D and vitamin A signal through common cofactors, they compete for each
other’s function. Retinoic acid antagonizes the action of vitamin D and its active metabolite.33,34 In humans,
even the vitamin A in a single serving of liver impairs vitamin D’s rapid intestinal calcium response.35 In a di-
etary intake study, Oh et al36 found that a high retinol intake completely thwarted vitamin D’s otherwise pro-
tective effect on distal colorectal adenoma, and they found a clear relationship between vitamin D and vitamin
A intakes, as the women in the highest quintile of vitamin D intake ingested around 10,000 IU/d of retinol.
Furthermore, the consumption of preformed retinol — even in amounts consumed by many Americans in
both multivitamins and cod liver oil — may cause bone toxicity in individuals with inadequate vitamin D sta-
tus.37 Women in the highest quintile of total vitamin A intake have a 1.5-times elevated risk of hip fracture.38
Indeed, a recent Cochrane Review found that vitamin A supplements increased the total mortality rate by
16%,39 perhaps through antagonism of vitamin D. Another recent Cochrane Review concluded that although
vitamin A significantly reduced the incidence of acute lower respiratory tract infections in children with low
intake of retinol, as occurs in the Third World, it appears to increase the risk and/or worsen the clinical course
in normal children.40 As early as 1933, Alfred Hess, who discovered that sunlight both prevented and cured
rickets — writing in JAMAwarned about vitamin A consumption, concluding, “...as to a requirement of
thousands of units of vitamin A daily, the unquestionable answer is that this constitutes therapeutic absurdity,
which, happily, will prove to be only a passing fad.”41(p662)
Unfortunately, Hess’s41 prophecy of the fad’s passing proved premature. Americans continue to consume
multivitamins and/or cod liver oil containing disproportionately small amounts of vitamin D but detrimental
quantities of vitamin A. Until quite recently, when most manufacturers willingly changed their product com-
position, nearly all multivitamins had small amounts of vitamin D (200 to 400 IU) but high amounts of pre-
formed retinol (5,000 IU). This pales in comparison to a tablespoon of modern cod liver oil, most of which
contains sub-physiological amounts of vitamin D (400 to 1,200 IU) but supra-physiological amounts of com-
pletely preformed retinol (4,000 to 10,000 IU or, in some cases, 30,000 IU).
As Linday et al1 point out, clinical lore holds that vitamin A is an “anti-infective.” We suggest that lore
exists because of old cod liver oil studies and newer studies in developing countries in which endemic vitamin
A deficiency leads to a variety of adverse health outcomes.42,43 Semba44 reviewed the early literature on vita-
min A, finding cod liver oil was a successful “anti-infective.” For reasons that are not entirely clear, the cod
liver oil of the time contained higher amounts of vitamin D then does modern cod liver oil, perhaps because
modern deodorization removes the vitamin D, which processors then replace at lower doses. However, for un-
clear reasons, the amount of vitamin D in modern cod liver appears to be falling over time. For example, one
manufacturer sells cod liver oil with only “naturally occurring vitamins A and D.” It contains only 3 to 60 IU
866 Commentary 866
of vitamin D per tablespoon, but between 3,000 and 6,000 IU of vitamin A.45
A meta-analysis concluded that vitamin A, when given alone, slightly increased the incidence of respira-
tory tract infections.46 If vitamin A increases the risk of respiratory infections by antagonizing the action of
vitamin D, its high content in modern cod liver oils will mask the benefit of adequate vitamin D nutrition. As
the prevalence of vitamin A deficiency in the United States — but not in the Third World — is much lower
than the prevalence of subclinical vitamin A toxicity,47 we cannot recommend cod liver oil or even multivita-
mins with preformed retinol (retinyl palmitate and retinyl acetate) for either adults or children. (We exclude
fish body oil from our warning, as it contains no vitamin A — or vitamin D — but is a very important source
of omega-3 fatty acids.)
In a recent assessment of serum retinyl esters in a group of obese Wisconsin adults, 4% had levels of more
than 10% of total retinol, which usually indicates hypervitaminosis A.48 A diet rich in carrots, sweet potatoes,
cantaloupe, and other colorful fruits and vegetables will supply all the carotenoids the body needs to make
retinol without the potential for hypervitaminosis A from preformed retinol, especially when preformed retinol
exists in other foods in the United States.49 Manufacturers should properly balance vitamin D with vitamin A
in fortified foods and dietary supplements, although at this time it is unclear what that ratio should be.
We wish that our diets were as rich in vitamin D as they are in vitamin A. With the exception of infants
on formula or toddlers drinking large amounts of milk or vitamin D–fortified juice, adequate amounts of vita-
min D are virtually impossible to obtain from diet. Unlike vitamin A deficiency, vitamin D deficiency in child-
hood is now epidemic in Western populations, probably because of the advent of sun exposure protection in
the 1980s. Recently, Gordon et al50 at Boston Children’s Hospital found that 40% of 365 healthy infants and
toddlers had 25(OH)D levels of less than 30 ng/mL, and it appears from our extrapolation of their data that
more than 85% had levels below 40 ng/mL. Thus, unlike the rare occurrence of vitamin A deficiency in the
developed world, childhood vitamin D deficiency is the rule, not the exception.
As Holick’s51 New England Journal of Medicine review stressed, the litany of vitamin D deficiency dis-
eases is now legion. Evidence even suggests that vitamin D is involved in the triple current childhood epi-
demics of autism,52 asthma,53 and autoimmune diabetes.54 Not only do tenable mechanisms of action exist to
explain vitamin D’s role in all three, but epidemiological evidence suggesting a vitamin D connection to these
devastating diseases is growing. For example, in May 2008, a group at the US National Institutes of Health
discovered that boys with autism have unexplained decreased metacarpal bone cortical thickness.55 Whatever
the connections are, all 3 epidemics appear to have blossomed after wide dissemination of sun avoidance ad-
vice in the 1980s.52,56,57
What should practicing health-care providers do? Certainly, we need more science and better public
health measures, but what do we do while we are waiting? The conclusion of the 334 scientists from 23 coun-
tries at the recent 13th Vitamin D Workshop was that although the problem of insufficient vitamin D is widely
recognized and reported, diet will not solve the problem.58
The first thing to remember is that the current Adequate Intakes (AI) and Upper Intake Levels (UL) of
vitamin D for children, set by the US Institute of Medicine’s Food and Nutrition Board (FNB) in 1997, are
intended for non–medically supervised intake and do not — and never did — apply to medically supervised
treatment. Astonishingly, the FNB says that the AI for vitamin D is the same for the largest pregnant woman
as for the smallest premature infant (200 IU/d) — frightening advice for pregnant women, in light of animal
studies that showed that gestational vitamin D deficiency causes both neuronal injury and autistic-like gross
morphological changes in the brains of offspring.59 Furthermore, the FNB’s ULs for a 1-year-old, 9-kg (20
lb) child and a 30-year-old, 135-kg (300 lb) adult are also the same — 2,000 IU/d — and are based on their
selective focus on 1 flawed study; ample new data from well-conducted clinical trials support raising the UL
to 10,000 IU.60 The 1997 FNB recommendations offend the most basic principles of pharmacology and toxi-
cology, leading us to conclude that the current official guidelines and limitations for vitamin D intakes are
scientifically indefensible.
The diagnosis of vitamin D deficiency in children rests solely on the practitioners willingness to obtain a
serum 25(OH)D level. Sadly, some practitioners still obtain serum 1,25-dihydroxyvitamin D levels, which are
often high, not low, in vitamin D deficiency. Just as disappointing, practitioners still advise mothers to “give
a multivitamin if you’re concerned,” without recommending a particular product with an appropriate balance
of vitamins A and D, thus delivering inadequate amounts of vitamin D and potentially adverse amounts of vi-
867 Commentary 867
868 Commentary 868
tamin A. (According to our review of the Table of Linday et al,1 children taking a multivitamin with vitamin
D actually had slightly lower mean 25(OH)D levels than did children not taking multivitamins.) Very recent
evidence indicates that ideal levels may be above 50 ng/mL. The parent compound (cholecalciferol) does not
begin to be routinely stored in fat and muscle tissue until the 25(OH)D levels reach 50 ng/mL.3,4 At lower
levels, the initial 25-hydroxylation in the liver often follows first-order mass action kinetics, and the reaction
is not saturable. That is, at levels below 50 ng/mL, much of the ingested or sun-derived vitamin D is immedi-
ately diverted to metabolic needs, indicating chronic substrate starvation. Only a tiny fraction of our children
now achieve levels of 50 ng/mL.
Until we have better information on doses of vitamin D that will reliably provide adequate blood levels of
25(OH)D without toxicity, treatment of vitamin D deficiency in otherwise healthy children should be individ-
ualized according to the numerous factors that affect 25(OH)D levels, such as body weight, percent body fat,
skin melanin, latitude, season of the year, and sun exposure.2 The doses of sunshine or oral vitamin D3 used
in healthy children should be designed to maintain 25(OH)D levels above 50 ng/mL. As a rule, in the absence
of significant sun exposure, we believe that most healthy children need about 1,000 IU of vitamin D3 daily
per 11 kg (25 lb) of body weight to obtain levels greater than 50 ng/mL. Some will need more, and others less.
In our opinion, children with chronic illnesses such as autism, diabetes, and/or frequent infections should be
supplemented with higher doses of sunshine or vitamin D3, doses adequate to maintain their 25(OH)D levels
in the mid-normal of the reference range (65 ng/mL) — and should be so supplemented year round. Otolaryn-
gologists treating children are in a good position to both diagnose and treat vitamin D deficiency.
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870 Commentary 870
John J. Cannell, MD
Department of Psychiatry
Atascadero State Hospital
Atascadero, California
jcannell@ash.dmh.ca.gov
Reinhold Vieth, MS, PhD
Department of Laboratory Medicine
and Pathobiology
University of Toronto
Toronto, Canada
rvieth@mtsinai.on.ca
Walter Willett, MD, DrPH
Departments of Nutrition and Epidemiology
Harvard School of Public Health
Boston, Massachusetts
wwillett@hsph.harvard.edu
Michael Zasloff, MD, PhD
Departments of Surgery and Pediatrics
Georgetown University
Washington, DC
maz5@georgetown.edu
John N. Hathcock, MSc, PhD
Scientific and International Affairs
Council for Responsible Nutrition
Washington, DC
jhathcock@crnusa.org
John H. White, PhD
Departments of Physiology and Medicine
McGill University
Montreal, Canada
john.white@mcgill.ca
Sherry A. Tanumihardjo, MSc, PhD
Department of Nutritional Sciences
University of Wisconsin–Madison
Madison, Wisconsin
sherry@nutrisci.wisc.edu
D. Enette Larson-Meyer, PhD
Department of Family and Consumer Sciences
University of Wyoming
Laramie, Wyoming
Enette@uwyo.edu
Heike A. Bischoff-Ferrari, MD, MPH
Department of Rheumatology
University Hospital Zurich
Zurich, Switzerland
hbischof@hsph.Harvard.edu
Heike.Bischoff@usz.ch
Christel J. Lamberg-Allardt, PhD
Department of Applied Chemistry
and Microbiology
University of Helsinki
Helsinki, Finland
christel.lamberg-allardt@helsinki.fi
Joan M. Lappe, PhD, RN
Department of Medicine and Nursing
Creighton University
Omaha, Nebraska
Joanlappe@creighton.edu
Anthony W. Norman, PhD
Departments of Biochemistry and
Biomedical Sciences
University of California at Riverside
Riverside, California
anthony.norman@ucr.edu
Armin Zittermann, PhD
Department of Cardiothoracic Surgery
Ruhr University Bochum
Bad Oeynhausen, Germany
azittermann@hdz-nrw.de
Susan J. Whiting, MSc, PhD
Division of Nutrition and Dietetics
University of Saskatchewan
Saskatoon, Canada
Susan.Whiting@usask.ca
William B. Grant, PhD
Sunlight, Nutrition, and Health Research Center
San Francisco, California
wbgrant@infionline.net
Bruce W. Hollis, PhD
Department of Pediatrics, Biochemistry
and Molecular Biology
Medical University of South Carolina
Charleston, South Carolina
Hollisb@musc.edu
Edward Giovannucci, MD
Departments of Nutrition and Epidemiology
Harvard School of Public Health
Boston, Massachusetts
edward.giovannucci@channing.harvard.edu
Competing Interests: Dr Cannell heads the nonprofit educational group The Vitamin D Council and consults
for DiaSorin Corporation, which makes vitamin D testing equipment. Dr Vieth is a consultant to the D Drops
Company, a vitamin D supplement manufacturer. Dr Grant receives funding from the UV Foundation, the
Vitamin D Society, and the European Sunlight Association. Dr Hollis consults for DiaSorin Corporation. Dr
Hathcock is an employee of the Council for Responsible Nutrition, a trade association representing manufac-
turers of dietary supplement ingredients and products.
... In tal senso, saranno necessari studi meccanicistici per valutare le eventuali variazioni in termini di espressione genica e di risposta citochinica che si verificano in soggetti con ipovitaminosi D successivamente alla supplementazione di vitamina D [43] . Diversi studi clinici osservazionali hanno dimostrato come bassi livelli sierici di vitamina D siano significativamente associati ad un'aumentata frequenza di infezioni acute del tratto respiratorio [49][50][51] , inclusa l'influenza stagionale [52] . Questi dati suggeriscono che bassi livelli circolanti di vitamina D potrebbero incrementare il rischio di infezioni virali dell'apparato respiratorio. ...
Article
Full-text available
LRIOG - La Rivista Italiana di Ostetrica e Ginecologia. Volume 2021, Issue 4 (December 1, 2021): 51-59. p-ISSN: 1724-6776. e-ISSN: 1824-0283. DOI: 10.53146/lriog1202148 [Article in Italian]. Abstract: Since March 2020, the coronavirus disease 2019 (COVID-19) pandemic caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has been posing a serious threat to global public health. Significant efforts have been made by the scientific community to develop different types of vaccines against SARS-CoV-2, such as inactivated whole-virion vaccines, viral vector-based vaccines, mRNA vaccines, DNA vaccines and protein subunit vaccines. To date, nationwide and global vaccination campaigns represent critical tools to reach the so-called “herd imunity” aimed at controlling and eventually ending the COVID-19 pandemic. Due to the continuous emergence and spread of novel SARS-CoV-2 viral variants, complementary strategies aimed at improving the immunity of the general population and frail individuals may contribute to increase the effectiveness of COVID-19 vaccines. Therefore, the scientific community is also focused on factors able to determine an effective immune response against the virus after vaccination against COVID-19. Currently, vitamin D deficiency also represents a global pandemic afflicting more than one billion individuals across all age groups. Several observational studies have demonstrated that serum levels of vitamin D are significantly and inversely correlated with the incidence and severity of COVID-19. In addition, intervention studies have shown that vitamin D supplementation may have a role in mitigating the clinical progression of COVID-19 in light of the anti-infective, anti-inflammatory and immunomodulatory properties exerted by this vitamin. Nevertheless, it remains unclear whether vitamin D supplementation (particularly in subjects with vitamin D deficiency) plays a relevant role in enhancing the effectiveness of different COVID-19 vaccines. Thus, future prospective studies are needed to address this unanswered question. In this Report article, we discuss the relationship between hypovitaminosis D and COVID-19 pathophysiology, as well as the potential mechanisms behind the role of vitamin D as as an immunologic adjuvant for COVID-19 vaccines.
... 1 Some studies have also linked vitamin D insufficiency to respiratory tract infections including epidemic influenza and one meta-analysis showed those with low serum vitamin D levels had 64% more risk of developing community acquired infections. [5][6][7][8] We aimed to further understand the relationship between vitamin D deficiency and COVID-19 outcomes. ...
Article
Full-text available
Introduction: The COVID-19 pandemic has prompted the medical world to look at factors that may influence outcomes. There have been connections made between vitamin D and COVID-19, as vitamin D has previously been shown to play a role in the maintenance of immune homeostasis. Materials and methods: We performed a prospective cohort study on 103 patients at Wigan Wrightington and Leigh NHS Foundation Trust looking at serum vitamin D levels of patients with positive COVID-19 swabs. Results were collated and correlations were made to compare vitamin D levels with age; severity of illness; hospital outcomes; and frailty. Comparisons were also made between frailty and outcome. Results: The results showed that there was a significant statistical difference between vitamin D levels and severity of infection: those who were treated in the intensive care units (ICU) (severe symptoms) had lower vitamin D levels than those treated on the ward (p=0.0446). There was also a correlation between vitamin D levels and frailty: those who were more frail had higher vitamin D levels than fitter patients (P=0.005). Vitamin D and frailty had no effect on hospital outcomes of COVID-19 infection. Conclusion: Ultimately, we concluded that low vitamin D can increase susceptibility of contracting COVID-19, increase severity of infection but does not affect mortality.
... Consumed animal products such as salmon, tuna, sardines, fish liver oils, beef liver, cheese, egg yolks contain vitamin D 15 . Some foods such as milk, soy or rice beverage, yogurt and cheese are fortified with vitamin D 16 . Skin derived synthesis of vitamin D depends on pigmentation, latitude, season, clothing, age, sunscreen use and local weather conditions 17 . ...
Article
Background : Vitamin D is an essential nutrient and deficiency of it leads to devastating disorders. This study aimed to find out the associated factors with selected variables of low vitamin D among adult females of Chattogram. Materials and methods : Cross-sectional observational study was conducted from September 2019 to February 2020 at a diagnostic complex of Chattogram. Participants were adult females of Chattogram. All participants gave oral informed consent and answered a questionnaire that included 16 questions covering demographic information, monthly income, educational status, occupation, body weight, duration of sun exposure, dress pattern (Using hijab or burkha, regular dress-up) drug and disease history. Blood samples were collected by cautious aseptic procedure. Serum vitamin D levels were measured by using immunoassay method. Adult females of Chattogram with no religious restrictions, n= 150,aged 31 to 70 years. Results: Overall, 88% had low vitamin D levels with deficient 60.66% and insufficient 27.34%. Sufficient level of vitamin D was found only among 12%. The prevalence of vitamin D deficiency was much higher in females with house-wife status 73.33% (p value of 0.0001) wearing hijab 46.66% (p value of 0.001). It could be due to interference with UVB radiation into skin, short duration of sun exposure, use of sunblock cream or less supplementary intake. Conclusion : Vitamin D deficiency is an emerging but neglected health issue in modern time, particularly more vulnerable are female population. Ironically, abundant sunlight of Bangladesh seems failed to protect the self-imposed concrete prisoner, classically known as home-makers, and practitioner of indoor life style that leads to avoidance of sun light. However, large sample size is mandatory to boost-up the findings of current study. Chatt Maa Shi Hosp Med Coll J; Vol.20 (2); July 2021; Page 74-78
... Дополнительно витамин D участвует в регуляции иммунитета путем модуляции уровней цитокинов и регулирует деление лимфоцитов Т-хелперов и дифференцировку В-лимфоцитов [19], а также стимулирует выработку факторов естественного иммунитета -кателецидина и ␤-дефензинов [20][21][22]. Взаимосвязь уровня витамина D и эффективности иммунной защиты была продемонстрирована как в наблюдательных исследованиях, где дефицит витамина D ассоциировался с повышением заболеваемости респираторными инфекциями [23][24][25][26][27], так и в интервенционных исследованиях, которые продемонстрировали снижение риска заболевания острыми респираторными инфекциями на фоне дотации витамина D [28,29]. ...
Article
Совместная позиция Российской ассоциации эндокринологов, Союза педиатров России и Российской ассоциации по остеопорозу.
... Cross-sectional clinical studies found that lower serum vitamin D levels are significantly associated with respiratory tract infections [25][26][27] and epidemic influenza 28 . These findings suggest that low vitamin D levels may increase the risk of viral respiratory infections and prompted researchers to better investigate the role of vitamin D deficiency in these conditions in children, adolescents and adults, as well as the influence of vitamin D on immune response to influenza vaccine and other vaccines against infectious diseases. ...
... There are three ways by which vitamin D decreases the risks of infections. First is by controlling physical barriers, secondly by cellular natural immunity and thirdly by adaptive immunity [9]. ...
Article
Full-text available
Background As the pandemic COVID-19 affected developing and developed countries, there is no proven treatment options available yet. The anti-inflammatory, antiviral and immune modulator effect of Vitamin D could be beneficial to COVID-19. Aim To find out the possible association between Vitamin D and COVID-19. Methods The present case-control study was conducted at tertiary care hospital, AIIMS, Patna, Bihar, India. Total 156 cases and 204 controls were enrolled in the study after obtaining informed consent. Categorization of the patients were done based on clinical severity and level of Vitamin D. The association between these categories with different variables were analyzed using regression analysis and other statistical tests. Results The status of Vitamin D (optimal, mild to moderate deficiency and severe deficiency) differed significantly among cases and controls. Diabetes and hypertension were most prevalent comorbidities among cases. On regression analysis, the difference in Vitamin D level was significant (aOR, 3.295; 95%CI, 1.25–8.685). The association between Vitamin D status and clinical severity group was statistically significant among cases. Among all variables, age, diabetes, hypertension and clinical severity were associated with worst outcome. Conclusion Vitamin D status appears to be strongly associated with COVID-19 clinical severity. After COVID-19 confirmation, Vitamin D level should be measured in all patients and curative plus preventive therapy should be initiated.
... 76 Moreover, it was suggested that VAD can increase the host susceptibility to influenza viral infection. [77][78][79] It should be noticed that infection with influenza virus, the novel coronavirus, and SARS-CoV have been more abundant in winter, when the circulating level of VitD is the lowest. 77,80,81 Angiotensin (Ang) II-converting enzyme (ACE2) molecule was reported to be the main host cell receptor of COVID-19 and plays a critical role in the entry of virus into the cell to trigger the final infection. ...
Article
Full-text available
Background: The novel coronavirus (COVID-19) is considered as the most life-threatening pandemic disease during the last decade. The individual nutritional status, though usually ignored in the management of COVID-19, plays a critical role in the immune function and pathogenesis of infection. Accordingly, the present review article aimed to report the effects of nutrients and nutraceuticals on respiratory viral infections including COVID-19, with a focus on their mechanisms of action. Methods: Studies were identified via systematic searches of the databases including PubMed/ MEDLINE, ScienceDirect, Scopus, and Google Scholar from 2000 until April 2020, using keywords. All relevant clinical and experimental studies published in English were included. Results: Protein-energy malnutrition (PEM) is common in severe respiratory infections and should be considered in the management of COVID-19 patients. On the other hand, obesity can be accompanied by decreasing the host immunity. Therefore, increasing physical activity at home and a slight caloric restriction with adequate intake of micronutrients and nutraceuticals are simple aids to boost host immunity and decrease the clinical manifestations of COVID-19. Conclusion: The most important nutrients which can be considered for COVID-19 management are vitamin D, vitamin C, vitamin A, folate, zinc, and probiotics. Their adequacy should be provided through dietary intake or appropriate supplementation. Moreover, adequate intake of some other dietary agents including vitamin E, magnesium, selenium, alpha linolenic acid and phytochemicals are required to maintain the host immunity.
... 39 Nevertheless, excess retinol intake via supplementation can compete with vitamin D receptors and enhance the risk of fracture in children. 40 Furthermore, excess retinol intake may increase the incidence of respiratory infections. Thus, it is pivotal to correctly identify children with vitamin A deficiency who need for vitamin A supplementation, to avoid vitamin A toxicity due to equivocal supplementation. ...
Article
Context Blood cutoff values for vitamin A deficiency in children aged 3–10 years have not been addressed in the literature. Objective To identify blood retinol concentrations for determining severe vitamin A deficiency in children aged 3–10 years. Data Sources The MEDLINE, Web of Science, Embase, and Scopus databases were searched. Data Extraction Two reviewers independently extracted article data and assessed quality. Data Analysis The hierarchical summary receiver operating characteristic models were applied for the diagnostic accuracy meta-analysis. This review is registered at PROSPERO (identifier: CRD42020149367). Results A total of 15 articles met the eligibility criteria, and 9 were included in the diagnostic accuracy meta-analysis. The summary estimates (95%CI) were: Sensitivity, 0.39 (0.20–0.62); specificity, 0.79 (0.65–0.88); positive likelihood ratio, 1.85 (1.33–2.57); and negative likelihood ratio, 0.77 (0.60–0.99). The area under the curve of the overall analysis was 0.68 (95%CI 0.63–0.72). Conclusions Blood retinol concentrations have low diagnostic accuracy for severe vitamin A deficiency in children aged 3–10 years. Therefore, there is unclear evidence about the preferable cutoff point for determining severe vitamin A deficiency in children in this age group.
Article
oxidative stress is caused by an abundant generation of reactive oxygen species, associated to a diminished capacity of the endogenous systems of the organism to counteract them. Activation of pro-oxidative pathways and boosting of inflammatory cytokines are always encountered in viral infections, including SARS-CoV-2. So, the importance of counteracting cytokine storm in COVID-19 pathology is highly important, to hamper the immunogenic damage of the endothelium and alveolar membranes. Antioxidants prevent oxidative processes, by impeding radical species generation. It has been proved that vitamin intake lowers oxidative stress markers, alleviates cytokine storm and has a potential role in reducing disease severity, by lowering pro-inflammatory cytokines, hampering hyperinflammation and organ failure. For the approached compounds, direct antiviral roles are also discussed in this review, as these activities encompass secretion of antiviral peptides, modulation of angiotensin-converting enzyme 2 receptor expression and interaction with spike protein, inactivation of furin protease, or inhibition of pathogen replication by nucleic acid impairment induction. Vitamin administration results in beneficial effects. Nevertheless, timing, dosage and mutual influences of these micronutrients should be carefullly regarded.
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Determining the trace element levels in the human hair is a significant analytical technique, a screening element in the evaluation of possible deficiencies, excesses, and/or biochemical imbalances in all bodies of these microelements. In this work of research, by an inductively coupled plasma– mass spectrometry (ICP-MS) analyzer, the authors have proposed the discovery of toxic trace elements (Al, Pb, Hg) and levels principal mineral elements (Ca, Mg, Cu, Zn) from the human body on healthy individuals with a good nutritional status. The study was performed on a sample of 75 adult women (30-35 years old) from different regions of the country, by taking 100 mg of hair from the base of the scalp with a length of 3 cm, for analysis and evaluation of trace elements. Twelve patients (16%) had high mean values of intracellular Mg (1.2 mmol / L), high Ca values (0.72 mmol / L), but low mean Ca / Mg ratios, (0.58). In addition, six patients (8%) had low mean values of Mg (0.004 mmol / L) and Ca (0.04 mmol / L) but a high Ca / Mg ratio. At the moment of analysis, all individuals did not have acute or severe intoxication signs with heavy metals. The environmental lifestyle of analyzed individuals, from various areas of the country, was observed in their hair cells, by present levels of trace elements. Copyright © 2013 - All Rights Reserved - Pharmacophore
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The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.
Article
Vitamin A deficiency is an endemic nutrition problem throughout much of the developing world, especially affecting the health and survival of infants, young children, and pregnant and lactating women. These age and life-stage groups represent periods when both nutrition stress is high and diet likely to be chronically deficient in vitamin A. Approximately 127 million preschool-aged children and 7 million pregnant women are vitamin A deficient. Health consequences of vitamin A deficiency include mild to severe systemic effects on innate and acquired mechanisms of host resistance to infection and growth, increased burden of infectious morbidity, mild to severe (blinding) stages of xerophthalmia, and increased risk of mortality. These consequences are defined as vitamin A deficiency disorders (VADD). Globally, 4.4 million preschool children have xerophthalmia and 6 million mothers suffer night blindness during pregnancy. Both conditions are associated with increased risk of morbidity and mortality. While reductions of child mortality of 19–54% following vitamin A treatment have been widely reported, more recent work suggests that dosing newborns with vitamin A may, in some settings, lower infant mortality. Among women, one large trial has so far reported a ≥ 40% reduction in mortality related to pregnancy with weekly, low-dose vitamin A supplementation. Epidemiologic data on vitamin A deficiency disorders can be useful in planning, designing, and targeting interventions.
Article
An antagonistic interaction between retinol and calciferol has been established. However, the mechanism by which this antagonism occurs is unclear. One possibility is that retinol affects the metabolism of calciferol. To investigate this hypothesis, retinol- and calciferol-depleted rats were given various amounts of ergocalciferol, cholecalciferol, 1 alpha,25-dihydroxycholecalciferol [1,25(OH)(2)D-3], or 24,24-difluoro-1 alpha,25-dihydroxycholecalciferol [24-F-2-1,25(OH)(2)D-3] in combination with various amounts of retinyl acetate or all-trans retinoic acid (ATRA) in a series of studies. Rats administered 1720 or 3440 mu g retinyl acetate once every 3 d for 33 d in combination with 25.8 ng ergocalciferol or 25 ng cholecalciferol every 3 d had lower serum calcium and greater serum phosphorus concentrations than rats fed 0 or 11.4 mu g retinyl acetate every 3 d. In addition, rats fed 400 jig ATRA/d in combination with 25.8 ng ergocalciferol every 3 d, 25 ng cholecalciferol every 3 d, 2-5 ng 1,25(OH)(2)D-3/d, or 0.5-1 ng 24-F-2-1,25(OH)(2)D-3/d had significantly lower serum calcium and higher serum phosphorus concentrations than rats not given ATRA in the diet. Therefore, both retinyl acetate and ATRA are able to antagonize the action of ergocalciferol and cholecalciferol in vivo. Additionally, ATRA antagonizes the in vivo action of 1,25(OH),D, and an analog, 24-F-2-1,25(OH)(2)D-3, that cannot be 24-hydroxylated. Together, these results suggest that retinol does not antagonize the action of calciferol by altering the metabolism of calciferol or 1,25(OH)(2)D-3, but does so by another mechanism.
Article
In the last fifteen years, a large series of controlled clinical trials showed that vitamin A supplementation reduces morbidity and mortality of children in developing countries. It is less well known that vitamin A underwent two decades of intense clinical investigation prior to World War II. In the 1920s, a theory emerged that vitamin A could be used in “anti-infective” therapy. This idea, largely championed by Edward Mellanby, led to a series of at least 30 trials to determine whether vitamin A—usually supplied in the form of cod-liver oil—could reduce the morbidity and mortality of respiratory disease, measles, puerperal sepsis, and other infections. The early studies generally lacked such innovations known to the modern controlled clinical trial such as randomization, masking, sample size and power calculations, and placebo controls. Results of the early trials were mixed, but the pharmaceutical industry emphasized the positive results in their advertising to the public. With the advent of the sulfa antibiotics for treatment of infections, scientific interest in vitamin A as “anti-infective” therapy waned. Recent controlled clinical trials of vitamin A from the last 15 y follow a tradition of investigation that began largely in the 1920s.
Article
Context Ingestion of toxic amounts of vitamin A affects bone remodeling and can have adverse skeletal effects in animals. The possibility has been raised that long-term high vitamin A intake could contribute to fracture risk in humans.Objective To assess the relationship between high vitamin A intake from foods and supplements and risk of hip fracture among postmenopausal women.Design Prospective analysis begun in 1980 with 18 years of follow-up within the Nurses' Health Study.Setting General community of registered nurses within 11 US states.Participants A total of 72 337 postmenopausal women aged 34 to 77 years.Main Outcome Measures Incident hip fractures resulting from low or moderate trauma, analyzed by quintiles of vitamin A intake and by use of multivitamins and vitamin A supplements, assessed at baseline and updated during follow-up.Results From 1980 to 1998, 603 incident hip fractures resulting from low or moderate trauma were identified. After controlling for confounding factors, women in the highest quintile of total vitamin A intake (≥3000 µg/d of retinol equivalents [RE]) had a significantly elevated relative risk (RR) of hip fracture (RR, 1.48; 95% confidence interval [CI], 1.05-2.07; P for trend = .003) compared with women in the lowest quintile of intake (<1250 µg/d of RE). This increased risk was attributable primarily to retinol (RR, 1.89; 95% CI, 1.33-2.68; P for trend <.001 comparing ≥2000 µg/d vs <500 µg/d). The association of high retinol intake with hip fracture was attenuated among women using postmenopausal estrogens. Beta carotene did not contribute significantly to fracture risk (RR, 1.22; 95% CI, 0.90-1.66; P for trend = .10 comparing ≥6300 µg/d vs <2550 µg/d). Women currently taking a specific vitamin A supplement had a nonsignificant 40% increased risk of hip fracture (RR, 1.40; 95% CI, 0.99-1.99) compared with those not taking that supplement, and, among women not taking supplemental vitamin A, retinol from food was significantly associated with fracture risk (RR, 1.69; 95% CI, 1.05-2.74; P for trend = .05 comparing ≥1000 µg/d vs <400 µg/d).Conclusions Long-term intake of a diet high in retinol may promote the development of osteoporotic hip fractures in women. The amounts of retinol in fortified foods and vitamin supplements may need to be reassessed.
Article
Background To study the epidemiology of childhood-onset type 1 insulin-dependent diabetes in Europe, the EURODIAB collaborative group established in 1988 prospective geographically-defined registers of new cases diagnosed under 15 years of age. This report is based on 16 362 cases registered during the period 1989—94 by 44 centres representing most European countries and Israel and covering a population of about 28 million children. Methods Multiple sources of ascertainment were used in most centres to validate the completeness of registration by the capture-recapture method. Trends in incidence during the period were analysed by Poisson regression, the data from centres within each country being pooled. Findings The standardised average annual incidence rate during the period 1989—94 ranged from 3.2 cases per 100 000 per year in the Former Yugoslav Republic of Macedonia to 40.2 cases per 100 000 per year in two regions of Finland. By pooling over centres, the annual rate of increase in incidence was 3.4% (95% Cl 2.5—4.4%), but in some central European countries it was more rapid than this. Pooled over centres and sexes, the rates of increase were 6.3% (4.1—8.5%) for children aged 0—4 years, 3.1% (1.5—4.8%) for 5—9 years, and 2.4% (1.0—3.8%) for 10—14 years. Interpretation The results confirm a very wide range of incidence rates within Europe and show that the increase in incidence during the period varied from country to country. The rapid rate of increase in children aged under 5 years is of particular concern.
Article
Unlabelled: Any theory of autism's etiology must take into account its strong genetic basis while explaining its striking epidemiology. The apparent increase in the prevalence of autism over the last 20 years corresponds with increasing medical advice to avoid the sun, advice that has probably lowered vitamin D levels and would theoretically greatly lower activated vitamin D (calcitriol) levels in developing brains. Animal data has repeatedly shown that severe vitamin D deficiency during gestation dysregulates dozens of proteins involved in brain development and leads to rat pups with increased brain size and enlarged ventricles, abnormalities similar to those found in autistic children. Children with the Williams Syndrome, who can have greatly elevated calcitriol levels in early infancy, usually have phenotypes that are the opposite of autism. Children with vitamin D deficient rickets have several autistic markers that apparently disappear with high-dose vitamin D treatment. Estrogen and testosterone have very different effects on calcitriol's metabolism, differences that may explain the striking male/female sex ratios in autism. Calcitriol down-regulates production of inflammatory cytokines in the brain, cytokines that have been associated with autism. Consumption of vitamin D containing fish during pregnancy reduces autistic symptoms in offspring. Autism is more common in areas of impaired UVB penetration such as poleward latitudes, urban areas, areas with high air pollution, and areas of high precipitation. Autism is more common in dark-skinned persons and severe maternal vitamin D deficiency is exceptionally common the dark-skinned. Conclusion: simple Gaussian distributions of the enzyme that activates neural calcitriol combined with widespread gestational and/or early childhood vitamin D deficiency may explain both the genetics and epidemiology of autism. If so, much of the disease is iatrogenic, brought on by medical advice to avoid the sun. Several types of studies could easily test the theory.