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.
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
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-
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 JAMA — warned 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
The diagnosis of vitamin D deficiency in children rests solely on the practitioner’s 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
Reinhold Vieth, MS, PhD
Department of Laboratory Medicine
University of Toronto
Walter Willett, MD, DrPH
Departments of Nutrition and Epidemiology
Harvard School of Public Health
Michael Zasloff, MD, PhD
Departments of Surgery and Pediatrics
John N. Hathcock, MSc, PhD
Scientific and International Affairs
Council for Responsible Nutrition
John H. White, PhD
Departments of Physiology and Medicine
Sherry A. Tanumihardjo, MSc, PhD
Department of Nutritional Sciences
University of Wisconsin–Madison
D. Enette Larson-Meyer, PhD
Department of Family and Consumer Sciences
University of Wyoming
Heike A. Bischoff-Ferrari, MD, MPH
Department of Rheumatology
University Hospital Zurich
Christel J. Lamberg-Allardt, PhD
Department of Applied Chemistry
University of Helsinki
Joan M. Lappe, PhD, RN
Department of Medicine and Nursing
Anthony W. Norman, PhD
Departments of Biochemistry and
University of California at Riverside
Armin Zittermann, PhD
Department of Cardiothoracic Surgery
Ruhr University Bochum
Bad Oeynhausen, Germany
Susan J. Whiting, MSc, PhD
Division of Nutrition and Dietetics
University of Saskatchewan
William B. Grant, PhD
Sunlight, Nutrition, and Health Research Center
San Francisco, California
Bruce W. Hollis, PhD
Department of Pediatrics, Biochemistry
and Molecular Biology
Medical University of South Carolina
Charleston, South Carolina
Edward Giovannucci, MD
Departments of Nutrition and Epidemiology
Harvard School of Public Health
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.