nutrients

Review
Infections and Autoimmunity—The Immune System and
Vitamin D: A Systematic Review
Sunil J. Wimalawansa

Medicine, Endocrinology & Nutrition, Cardiometabolic & Endocrine Institute, North Brunswick, NJ 08902, USA;
[email protected] or [email protected]

Abstract: Both 25-autoimmunity and(25(OH)D: calcifediol) and its active form, 1,25-dihydroxyvitamin
D (1,25(OH)2 D: calcitriol), play critical roles in protecting humans from invasive pathogens, reducing
risks of autoimmunity, and maintaining health. Conversely, low 25(OH)D status increases suscep-
tibility to infections and developing autoimmunity. This systematic review examines vitamin D’s
mechanisms and effects on enhancing innate and acquired immunity against microbes and preventing
autoimmunity. The study evaluated the quality of evidence regarding biology, physiology, and as-
pects of human health on vitamin D related to infections and autoimmunity in peer-reviewed journal
articles published in English. The search and analyses followed PRISMA guidelines. Data strongly
suggested that maintaining serum 25(OH)D concentrations of more than 50 ng/mL is associated
with significant risk reduction from viral and bacterial infections, sepsis, and autoimmunity. Most
adequately powered, well-designed, randomized controlled trials with sufficient duration supported
substantial benefits of vitamin D. Virtually all studies that failed to conclude benefits or were am-
biguous had major study design errors. Treatment of vitamin D deficiency costs less than 0.01% of
the cost of investigation of worsening comorbidities associated with hypovitaminosis D. Despite
cost-benefits, the prevalence of vitamin D deficiency remains high worldwide. This was clear among
those who died from COVID-19 in 2020/21—most had severe vitamin D deficiency. Yet, the lack of
direction from health agencies and insurance companies on using vitamin D as an adjunct therapy
is astonishing. Data confirmed that keeping an individual’s serum 25(OH)D concentrations above
50 ng/mL (125 nmol/L) (and above 40 ng/mL in the population) reduces risks from community
outbreaks, sepsis, and autoimmune disorders. Maintaining such concentrations in 97.5% of people is
Citation: Wimalawansa, S.J.
achievable through daily safe sun exposure (except in countries far from the equator during winter)
Infections and Autoimmunity—The
Immune System and Vitamin D: A
or taking between 5000 and 8000 IU vitamin D supplements daily (average dose, for non-obese adults,
Systematic Review. Nutrients 2023, 15, ~70 to 90 IU/kg body weight). Those with gastrointestinal malabsorption, obesity, or on medications
3842. https://doi.org/10.3390/ that increase the catabolism of vitamin D and a few other specific disorders require much higher
nu15173842 intake. This systematic review evaluates non-classical actions of vitamin D, with particular emphasis
on infection and autoimmunity related to the immune system.
Academic Editor: Dimitris
Tsoukalas
Keywords: 25(OH)D; epidemiology; morbidity; mortality; prevention; treatment; public health
Received: 29 July 2023
Revised: 24 August 2023
Accepted: 29 August 2023
Published: 2 September 2023 1. Introduction
In humans, most of the vitamin D requirement is expected to be generated by summer-
like sunlight, with at least a third of the upper body exposed to direct sunlight [1]. The
Copyright: © 2023 by the author.
best time for sun exposure is between 10.30 a.m. and 1.30 p.m. (when one’s shadow is
Licensee MDPI, Basel, Switzerland. shorter than the height), when the sun’s ultraviolet B rays (UVB) come at a narrow (zenith)
This article is an open access article angle, allowing better skin penetration [2,3]. Since most vitamin D should be derived
distributed under the terms and from UVB rays from the sun, insufficient exposure is the most typical cause of vitamin D
conditions of the Creative Commons deficiency [4–7]. Nevertheless, most people have inherent sun avoidance behavior, making
Attribution (CC BY) license (https:// it worse. While 40% of citizens in Western countries take supplements (mostly insufficient
creativecommons.org/licenses/by/ doses), less than 5% do so in developing countries. Over 50% of the world’s population has
4.0/). suboptimal vitamin D concentrations at a given time [8,9].

Nutrients 2023, 15, 3842. https://doi.org/10.3390/nu15173842 https://www.mdpi.com/journal/nutrients

Nutrients 2023, 15, 3842 2 of 33

Therefore, globally, vitamin D deficiency is a significant public health problem—a

pandemic—that has overtaken iron deficiency as the most common nutritional deficiency
in the world. As described below, vitamin D deficiency is associated with many chronic dis-
eases and significantly increases the risk of infections [10–13]. Despite these, no government
or medical insurance companies address this vital public health issue—hypovitaminosis
D. It increases chronic ill-health, absenteeism, and healthcare costs. Nevertheless, with
proper public health guidance related to safe sun exposure and supplements, vitamin D
deficiency can be eliminated cost-effectively, thus reducing morbidities, premature deaths,
and healthcare costs.
25(OH)D is further hydroxylated into a multifunctional seco-steroidal hormone in renal
tubular cells. This is essential for musculoskeletal and parathyroid functions [14–17]. The
prevalence of vitamin D deficiency and its associated complications have been escalating over
the past three decades and affecting globally. This study was undertaken in part to address
this issue. This systematic review focuses on infections and autoimmune disorders related to
hypovitaminosis D.

1.1. Systematic Review Process

PubMed, Medline, Google Scholar, and EMBASE databases were searched for random-
ized controlled clinical trials (RTCs), prospective clinical studies, and original and review
articles related to vitamin D, infections, autoimmunity, and the immune system. The study
was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) statement [18,19], the Equator Network (www.equator-network.org/
(accessed on 5 March 2023), the PRISMA statement [20], and the PRISMA-P guidelines and
checklist [18,21]. Search terms used include the controlled words vitamin D, cholecalciferol,
25(OH)D, 25-hydroxyvitamin D, 25-hydroxycholecalciferol, calcitriol, calcifediol, and cal-
cidiol, in conjunction with infections, autoimmunity, and the immune system. These were
selected from the EMTREE thesaurus, Medical Subject Headings terms [22]. Keywords were
used in combinations of two to reduce the number of manuscripts to a workable number.

1.2. Protocol and Manuscript Selection

A protocol was developed to track pertinent areas and publications. The manuscript
selection included groups covering RCTs, observational, ecological, and epidemiological
studies, and supporting laboratory and animal studies [19]. Following the literature search,
the quality and relevance of studies on the topic were assessed, and a catalog was developed
with manuscripts [18]. Articles published between 1 January 2000 and May 2023 in English
were searched. After removing duplicates, the screening produced 2586 manuscripts from
combined databases. The removal of 1504 and further 789 later records due to duplicates
and lack of direct relevance led to 263 qualified articles for the SR—an additional 26 articles
were included after the search till the end of July 2023. Two hundred eighty-nine articles
were included in the final manuscript using EndNote 20.6 reference manager programs
(Figure 1).

1.3. Search, Data Abstraction, Synthesis, and Scope

Rationale, eligibility, and exclusion criteria for the evidence-based PICO process (pa-
tient problems, intervention, comparison or control, and outcome elements) were observed,
and potential bias in individual studies and design failures were noted for exclusion [18,21].
The strength of the evidence concerning the biology and physiology of vitamin D related
to human health, specifically immunity, autoimmunity, and combatting infections, was
assessed. Synthesized results were included as narrative conclusions [18].
In addition to the association between vitamin D and the musculoskeletal system,
evidence is growing regarding the broader benefits of vitamin D. However, recently pub-
lished larger RCTs, many with poor study designs, have muddled the field of vitamin D,
referencing relationships and causation. This is mainly attributable to the study design
failures [23–27] and some bias. PubMed searches with keywords and analysis revealed
Nutrients 2023, 15, 3842 3 of 33

that the publications over the past 15 years related to non-classic vitamin D actions had far
exceeded the classical action in the musculoskeletal system. In addition, nine out of ten
non-classic vitamin D studies reported positive outcomes.
This study confirmed a strong association between vitamin D status (deficiency) with
the initiation of autoimmunity and failures to combat infections, particularly viral and intra-
cellular bacterial infections. The study also identified (a) the importance of higher-quality
RCTs with proper clinical study designs to test hypotheses regarding health outcomes
attributable to the nutrient vitamin D [1] and (b) the need for eliminating poorly designed
studies from meta-analyses. Positive vs. negative outcomes were predictable based on the
quality or errors of study designs. Whereas almost all well-designed, statistically powered
RCTs provided anticipated positive clinical outcomes [28,29]. Figure 2 illustrates the body
Nutrients 2023, 15, x FOR PEER REVIEW 3 of 35
systems dependent on vitamin D sufficiency for proper functioning. Common disorders
are worsened by chronic vitamin D deficiency.

Figure1.1.PRISMA
Figure PRISMAflow
flowchart.
chart.Selection
Selectionpath
pathof
ofreference
referencetotoadvances
advancesininknowledge
knowledgeofofvitamin
vitaminDD
with particular emphasis on infections, autoimmunity, and the immune system.
with particular emphasis on infections, autoimmunity, and the immune system.

1.3. Search, Data Abstraction, Synthesis, and Scope

Rationale, eligibility, and exclusion criteria for the evidence-based PICO process (pa-
tient problems, intervention, comparison or control, and outcome elements) were ob-
served, and potential bias in individual studies and design failures were noted for exclu-
sion [18,21]. The strength of the evidence concerning the biology and physiology of vita-
min D related to human health, specifically immunity, autoimmunity, and combatting in-
fections, was assessed. Synthesized results were included as narrative conclusions [18].
In addition to the association between vitamin D and the musculoskeletal system,
 quality RCTs with proper clinical study designs to test hypotheses regarding health out-
comes attributable to the nutrient vitamin D [1] and (b) the need for eliminating poorly
designed studies from meta-analyses. Positive vs. negative outcomes were predictable
based on the quality or errors of study designs. Whereas almost all well-designed, statis-
tically powered RCTs provided anticipated positive clinical outcomes [28,29]. Figure 2 il-
Nutrients 2023, 15, 3842 4 of 33
lustrates the body systems dependent on vitamin D sufficiency for proper functioning.
Common disorders are worsened by chronic vitamin D deficiency.

Figure 2. Relationships between vitamin D and a spectrum of non-skeletal diseases and disorders
Figure 2. Relationships between vitamin D and a spectrum of non-skeletal diseases and disorders
associated with vitamin D deficiency. The complicated relationships between beneficial 25(OH)D
associated with (sufficiency)
concentrations vitamin D deficiency. The organ
and various complicated
systems relationships
in the bodybetween beneficial
and diseases 25(OH)D Top
are depicted. con-
centrations
panel (light(sufficiency) and various organ D
green background)—vitamin systems in the White
sufficiency: body and diseases areofdepicted.
ovals—mode vitamin D Top panel
genera-
(light greentobackground)—vitamin
tion/entry D sufficiency:
the body. Yellow ovals—system White ovals—mode
dysfunction. of vitamin D generation/entry
Green ovals—endocrine functions of vit-
amin
to the D (circulating
body. 1,25(OH)2D: calcitriol)
Yellow ovals—system on calcium
dysfunction. Green metabolism. Bottom
ovals—endocrine panela of
functions (light yellow
vitamin D
background)—
(circulating vitamin
1,25(OH) 2 D: D deficiency:
calcitriol) on Dark
calcium blue ovals—functional
metabolism. Bottom and
panela pathophysiological
(light yellow relation-
background)—
ships with
vitamin tissues and
D deficiency: organ
Dark bluesystems. Light blueand
ovals—functional ovals—metabolic dysfunctions
pathophysiological associated
relationships with
with tissues
hypovitaminosis D. . Abbreviations: Ca ++, calcium; FGF23, fibroblast growth factor-23; IR, insulin
and organ systems. Light blue ovals—metabolic dysfunctions associated with hypovitaminosis
resistance; Mg++, magnesium; UV, ultraviolet rays. Arrows indicate increased (improved) or de-
D. Abbreviations: Ca++ , calcium; FGF23, fibroblast growth factor-23; IR, insulin resistance; Mg++ ,
creased incidence or severity (modified from Wimalawansa 2012 and 2016 [30,31]).
magnesium; UV, ultraviolet rays. Arrows indicate increased (improved) or decreased incidence or
severity (modified from Wimalawansa 2012 and 2016 [30,31]).
2. Vitamin D—Innate and Acquired Immunity
2. Vitamin D—Innate and Acquired Immunity
1,25-dihydroxycholecalciferol (calciferol) is the most active vitamin D metabolite and
a potent immune modulator essential for combating pathogens [32,33]. As described below,
the circulating hormonal form of calcitriol does not affect immune cell functions. The func-
tionality of these cells depends on adequate generation of calcitriol within them. Calcitriol
(a) activates cytosol’s vitamin D (calcitriol)receptors (VDRs) following translocation into
the nucleus to modulate genomic functions, and (b) acts as signaling molecules for its
non-genomic actions, like membrane effects, and autocrine and paracrine signaling.
Nutrients 2023, 15, 3842 5 of 33

Calcitriol concentrations in the circulation are controlled mainly by parathyroid hor-

mone (PTH) partly via circulatory ionized calcium but not by tissue 24-hydroxylase. In
contrast, in the target tissues, the production of calcitriol is mainly regulated by a combina-
tion of the circulatory 25(OH)D concentration (and vitamin D) and the feedback catabolic
activity of tissue 24-hydroxylase enzyme and not by PTH or serum calcium. Vitamin
D has no known action and, thus, is not measured routinely. Consequently, vitamin D
physiologic correlations are focused on the serum 25(OH)D concentrations—“physiological
concentrations of vitamin D status”.

2.1. Vitamin D Activates Immune Cells

The interaction of calcitriol with its receptor leads to the translocation of the receptor
complex to the nucleus, where it binds to the genome and modulates over 1200 genes [34].
Calcitriol down-regulates inflammation and oxidative stress through multiple mechanisms,
primarily by suppressing inflammatory cytokines. The immunomodulatory effects of
vitamin D include activation of immune cells such as T and B cells and macrophage and
dendritic cells, as well as increased production of antimicrobial peptides and neutralizing
antibodies [35–37].
As with certain vaccinations, like repeated bivalent COVID-19 booster doses, chronic
hypovitaminosis D also causes immune paresis, increasing the vulnerability to infections, es-
pecially to intracellular bacteria such as tuberculosis and [38] and respiratory viruses [39,40],
including SARS-CoV-2 [41,42]. Recent clinical studies have supported the latter [43]. The
vulnerability to SARS-CoV-2 was reported in those who were PCR-positive, symptomatic
SARS-CoV-2 infection, and had severe complications. They had a significantly higher preva-
lence of vitamin D deficiency—low serum 25(OH)D concentrations—mean concentration
of 11.1 ng/mL; p = 0.004, compared with those with negative results (24.6 ng/mL) [44].
In addition, vulnerable people, such as older people with comorbidities, strongly
correlate with low vitamin D status and cytokine storm—a hyper-inflammatory condition
caused by an uncontrolled, overactive immune status [45]. Symptomatic disease, complica-
tions, and deaths from viral infections, including SARS-CoV-2, are based on the underlying
vulnerability (i.e., weak immune system) and the viral load. Thus, while vitamin D does
not prevent viral infections or a person from contracting COVID-19, it significantly reduces
symptomatic disease, complications, and deaths [43,46–51].
It was reported that, in the period before the infection (e.g., immediate pre-pandemic),
hypovitaminosis D increases these risks and vulnerability [52–55]. Besides, vitamin D
deficiency at the time of diagnosis of SARS-CoV-2 infection significantly increased the
severity and mortality [43,48,56,57]. In contrast, vitamin D sufficiency is protective against
severe COVID-19 disease and deaths [46,48,58,59]. These data are relevant for establishing
the Bradford Hill criteria [60]: vitamin D deficiency as a cause for infection, severity, and
mortality from SARS-CoV-2 virus [43,46–51].
Vitamin D controls autoimmunity by suppressing adaptive immunity via T- and
B-lymphocyte activity [61]. Consequently, hypovitaminosis D leads to a dysfunctional
immune system; the prime reason for initiating autoimmune responses [62–66]. In
addition, having low serum 25(OH)D concentrations worsens existing autoimmune
diseases [67,68], such as multiple sclerosis (MS) [69]. Hypovitaminosis D also increases
risks for autoimmune diseases [65,66]. Persons with several autoimmune disorders,
such as type 1 diabetes, autoimmune adrenal disease, MS, Hashimoto’s thyroiditis,
etc., are known to have lower concentrations of serum 25(OH)D (calcifediol) [63,64,70].
These data strongly support an inverse relationship between vitamin D status and
autoimmunity: the lower the serum 25(OH)D concentrations, the higher the risks for
autoimmunity—both incidence and severity [64–66]. Figure 3 summarizes the critical
negative outcomes of chronic vitamin D deficiency.
In contrast, vitamin D sufficiency reduces not only acute infections like SARS-CoV-2
but also the risks of chronic infections, such as tuberculosis. Sufficient generation of calcitriol
within the immune cells regulates innate and adaptive immunity, potentiating the innate
 Nutrients 2023, 15, x FOR PEER REVIEW 6 of 35

Nutrients 2023, 15, 3842 6 of 33

have lower concentrations of serum 25(OH)D (calcifediol) [63,64,70]. These data strongly
support an inverse relationship between vitamin D status and autoimmunity: the lower
the serum
response 25(OH)D concentrations,
(monocytes/macrophages theanti-microbial
with higher the risks for autoimmunity—both
activity) [10–13,71]. Calcitriol inci-
also
dence and severity [64–66]. Figure 3 summarizes the critical negative
modulates B lymphocytes and plasma cells for immunoglobulin production outcomes
andof chronic
stabilizes
vitamin
B-cells D deficiency.
[61,72], increasing anti-microbial peptide synthesis (Sections 3.5 and 3.6).

Figure3.3.Major
Figure Majornegative
negativeconsequences
consequencesare
arecategorized
categorizedinto
intogroups
groups of
of chronic
chronic vitamin
vitamin D
D deficiency.
defi-
ciency.
2.2. Modes of Stimulating the Immune System by Vitamin D
In contrast,the
Following vitamin D sufficiency
interactions reduces
of vitamin D and notVDR
onlyandacute infectionssecond
activating like SARS-CoV-2
messenger
but also the
signaling risks of
systems in chronic
immuneinfections,
cells leadssuch as tuberculosis.
to selective Sufficient generation
immunosuppressant activity of [73],
cal-
citriol within
decreasing the immune
autoimmune cells regulates
tendencies innate and
[74]. However, adaptive
those with immunity, potentiating the
sustained hypovitaminosis
Dinnate
have response (monocytes/macrophages
less effective innate and adaptive immune with anti-microbial
systems. They activity)
have [10–13,71]. Calcit-
impaired second
riol also modulates B lymphocytes and plasma cells for immunoglobulin
messenger signals and genomic stimulations through calcitriol–VDR interactions [62], production and
stabilizesinB-cells
resulting [61,72], increasing
hypo-responsivity anti-microbial
of autoreactive peptide
T cells synthesis
[75,76]. (Sections
In contrast, when3.525(OH)D
and 3.6).
concentrations are adequate, T-cell responsiveness is restored, and autoimmunity risks are
2.2. Modes
reduced [72].of Stimulating the Immune System by Vitamin D
The active form
Following of vitamin D
the interactions of calcitriol
vitamin Dis andessential
VDR for andimmunomodulating
activating second messenger immune
cells, such as monocytes, macrophages, dendritic cells, and T
signaling systems in immune cells leads to selective immunosuppressant activity [73],and B lymphocytes [76,77].
de-
These cellsautoimmune
creasing express the enzyme CYP27B1
tendencies that hydroxylase
[74]. However, those with calcifediol
sustained [25(OH)D] to calcitriol
hypovitaminosis D
and
havevitamin D receptor
less effective innate (VDR)—the
and adaptiveprime stimulisystems.
immune for activating
They havethe immune
impaired system
second [76,77].
mes-
These
sengerinteractions
signals andproducegenomicanti-microbial peptides,calcitriol–VDR
stimulations through such as cathelicidin and β-defensin
interactions [62], result-2
(see Section 3.6). Furthermore, in infected cells, calcitriol also increases
ing in hypo-responsivity of autoreactive T cells [75,76]. In contrast, when 25(OH)D con- the expression of
nucleotide-binding
centrations are adequate, oligomerization domain-containing
T-cell responsiveness protein
is restored, and 2, autoimmunity
which damagesrisks the cell
are
membranes
reduced [72]. of bacteria and viruses by activating signaling cascades [72].
In
The addition to anti-microbial
active form of vitamin D peptides,
calcitriol iscalcitriol
essentialinduces autophagy and gap
for immunomodulating immunepro-
tein [78]
cells, suchwithastight gap junctions
monocytes, [79]—strengthening
macrophages, the integrity
dendritic cells, and T and of Bepithelial and endothe-
lymphocytes [76,77].
lial cellscells
These andexpress
preventing viral penetration
the enzyme CYP27B1 that andhydroxylase
fluid leaks [80]. Vitamin
calcifediol D also enhances
[25(OH)D] to calcit-
the
riolexpression
and vitamin of Dangiotensin-converting
receptor (VDR)—the prime enzyme-2 (ACE-2)
stimuli [81], suppressing
for activating the immune thesystem
renin–
angiotensin system and dampening inflammation [82]. Increased
[76,77]. These interactions produce anti-microbial peptides, such as cathelicidin and β- expression of soluble
ACE-2
defensin neutralizes circulatory
2 (see Section viruses by binding
3.6). Furthermore, in infectedto them, thus preventing
cells, calcitriol SARS-CoV-2
also increases the ex-
from binding to cell membrane-bound ACE-2 receptors and cellular
pression of nucleotide-binding oligomerization domain-containing protein 2, which dam- entry [83,84].
ages the cell membranes of bacteria and viruses by activating signaling cascades [72].
2.3. Vitamin D and Immune System
In addition to anti-microbial peptides, calcitriol induces autophagy and gap protein
Evaluation
[78] with tight gap of epidemiological studies illustrates
junctions [79]—strengthening that vitamin
the integrity D deficiency
of epithelial increases
and endothelial
susceptibility
cells and preventing viral penetration and fluid leaks [80]. Vitamin D also enhances[63].
to infections and autoimmunity [62,64,66,85] and acquired autoimmunity the
1α-hydroxylase (CYP27B1) and VDR are expressed in all immune cells, including by
neutrophils, lymphocytes, dendritic cells, macrophages (antigen-presenting cells), and B
lymphocytes, CD4+, and CD8+: these are stimulated when pathogens and foreign antigens
are detected by Toll-like receptors-4 (TLR-4) [85,86].
Nutrients 2023, 15, 3842 7 of 33

With such intracellular signaling and sufficient quantities of calcitriol, they accelerate
the 1α-hydroxylation of 25(OH)D to 1,25-(OH)2 D and the synthesis of VDR. Calcitriol then
suppresses the transcription of inflammatory cytokines and blocks IgE-mediated mast cell
degranulation. The latter is one of the mechanisms to alleviate hives, allergic reactions, and
disorders that exacerbate inflammation [72]. In contrast, vitamin D adequacy stabilizes
mast cells, suppressing the release of histamine and TNF-α [62].
Vitamin D modulates several types of immune cells, including monocytes/macrophages,
dendritic cells, and B and T cells [71]. Hypovitaminosis D increases vulnerability to inflamma-
tory diseases and disorders with an autoimmune element, such as lupus, metabolic syndrome,
and T1D [87–91] (see below). Following supplementing with vitamin D, clinically meaningful
disease risk reductions have been reported in persons with MS, chronic fatigue syndrome,
Behcet’s disease, inflammatory bowel diseases [77,92–94], and rheumatoid arthritis [95,96].
Still, not all study results agree [97,98].
In addition to the anti-inflammatory effects of vitamin D on T-helper cells, B cells,
macrophages, and dendritic cells, vitamin D has broader immunomodulatory actions on
innate and adaptive immune responses [99,100]. Regulation of immune responses by
calcitriol partially inhibits B-cell expression of IgE and increased expression of IL-10 via
dendritic cells and T cells [75,101–103]. Many of the above-mentioned biological functions
occur following the genomic effects of calcitriol. The following section discusses some
non-genomic effects of calcitriol on the immune cells.

2.4. Vitamin D Is Fundamental to the Defense against Microbes and Preventing Autoimmunity
Vitamin D deficiency leads to a dysfunctional immune system, creating increased
susceptibility to bacterial infections, mainly intracellular bacterial infections [104,105], such
as mycobacteria tuberculosis [106,107], and a variety of viral infections, including influenza
A [40,105,108] (Table 1). In contrast, adequate circulating 25(OH)D concentrations are asso-
ciated with decreased incidences of infections [109], enhanced immunity, and improved
ability to overcome bacterial and viral infections [105,110]. Table 1 illustrates some exam-
ples of infections and autoimmune disorders improved with adequate serum 25(OH)D
concentrations, demonstrating multiple mechanisms; calcitriol combats pathogens [24,111]
and prevents autoimmunity [32,33] (Table 1).

Table 1. Infections and autoimmune diseases significantly improved by vitamin D *.

Examples of Infections Autoimmune Diseases and Others

Tuberculosis, leprosy, common cold
Allergy/eczema
(intracellular microorganisms)
Influenza type A $ Asthma
Coryza (common cold) Chronic hives
Upper respiratory tract infections Fibromyalgia
Lower urinary tract infections Inflammatory bowel disease
Bacterial vaginosis in pregnant women Multiple sclerosis
Periodontal gum disease and infections Myositis and periostitis
Osteonecrosis of the jaw Primary biliary cirrhosis
Miscellaneous fungal infections Psoriasis
Yeast infection Polyautoimmunity
Coxsackie A and B Rheumatoid arthritis/ Behcet’s disease
SARS-CoV-2 Type 1 diabetes mellitus
* From multiple sources, including http://www.vitamindwiki.com/VitaminDWiki (accessed on 10 May
2023) [30,31,112]. $ Influenza type B risk is not affected by vitamin D status [113].
Nutrients 2023, 15, 3842 8 of 33

3. Mechanisms of How Vitamin D Controls Infections and Autoimmunity

Calcitriol functions as a hormone following secretion into the bloodstream from the kid-
neys. This alters the behavior of the cells involved in calcium–phosphate–bone metabolism,
intestinal mucosal cells, and bone and parathyroid cells. Generally, the circulatory concen-
trations of vitamin D and 25(OH)D (in ng/mL) are approximately 900-fold higher than
calcitriol (in pg/mL) [114]. Consequently, the diffusion of hormonal calcitriol from the
blood to peripheral target cells is too little to influence their biological activity [115]. Thus,
unsurprisingly, circulatory calcitriol has no clinical and evidentiary impact outside the
musculoskeletal, parathyroid, and fat cells [115]. Consequently, peripheral target cells’
physiological activities depend on the synthesis of calcitriol intracellularly. In response to
membrane-based signaling from TLR-4, immune cells increase intracellular synthesis of
calcitriol and VDR, generating genomic functions [116].
Calcitriol down-regulates inflammation and oxidative stresses by suppressing inflam-
matory cytokines and enhancing anti-inflammatory cytokines’ synthesis via the abovemen-
tioned mechanisms [117]. The immunomodulatory effects of vitamin D include activation
of immune cells such as T and B cells, macrophage and dendritic cells, and enhanced
production of several antimicrobial peptides and neutralizing antibodies [35–37].

3.1. The Importance of Intracellular Generation of Calcitriol for Immune Cell Signaling
Approximately 75% of the innate [32] and over 50% of the adaptive [118] immune
systems are driven by intracellularly generated calcitriol [26]. The average circulatory
concentration of calcitriol is approximately 0.045 ng/mL. However, its diffusible free form
is less than half in the blood [119]. Even though unbound (free-form) calcitriol is fully
diffusible into target cells, it occurs in a low pico-molar range (much less than the minimum
concentration needed). These minute concentrations are far below the threshold required
to initiate intracellular signaling or genomic activity [115]. Whether such has any biological
function is not yet known.
As per present data, calcitriol’s hormonal form is unlikely to impact intracellular
biological signal transduction or genomic functions in immune cells. This is yet another
reason to avoid using pharmacological doses of synthetic calcitriol in infections or to
overcome autoimmune conditions. The correct approach is to provide appropriate higher
amounts of the precursor—vitamin D (including an upfront loading dose if indicated) [120],
except for oral administration of calcifediol in emergencies [24,26].
Intracellular calcitriol is critical for modulating genomic [121] and non-genomic activi-
ties such as signal transduction [122,123]. The non-genomic functions include the tightening
of the gap-junctions [124] and autocrine (intracrine) and paracrine signaling [24,36,37]. In-
tracrine signaling is initiated following the detection of foreign proteins, microbes, etc.,
by a series of cell surface receptors. The most important is the membrane-bound (sens-
ing/detecting) TLR-4 [125], which is also involved in the production of antimicrobial
peptides [86]. Intermittent signals derived from TLR-4 lead to over-drive peak production
of calcitriol and VDR in mitochondria/microsomes [126] (see below for details).
Immune cells do not have active (energy-dependent) cell-membrane transportation
mechanisms, such as megalin–cubulin; only diffusible low concentrations of calcitriol
get into immune cells from circulation. Consequently, in addition to a smaller quantity
via endocytosis, only the diffusible calcitriol can enter immune cells from the circulation.
The estimated intracellular calcitriol concentration in active status exceeds 1 ng/mL—an
estimated minimum intracellular concentration needed for initiating immune cell functions.
However, the average circulating concentration of hormonal calcitriol is approximately
0.045 ng/mL [118], which is less than the 20-fold required for intracellular signaling [127].
Therefore, at equilibrium conditions in immune cells, the free hormonal form of calcitriol
diffusing into immune cells (~0.02 ng/mL) is too little to activate their functions, such as
intracellular signaling or binding with VDR, leading to gene transcription [118].
This is another reason pharmacological doses, such as one or more micrograms of
calcitriol, have little beneficial effects in infectious diseases, including SARS-CoV-2, as
Nutrients 2023, 15, 3842 9 of 33

shown in failed RCTs [128,129]. The exceptions are calcitriol/VDR-resistant syndromes, hy-
poparathyroidism, and chronic renal failure, where exogenous calcitriol is lifesaving. [130].

3.2. Intracellular Calcitriol Signaling

When immune cells detect external threats, such as circulating antigens by key innate
immunity pattern recognition receptors such as membrane-bound TLR-4 [131], they send
signals to increase the expression of 1α-hydroxylase and VDR [118] and microsomal-
apparatus to increase cytoplasmic concentrations of both [117,127]. As a result, immune
cells synthesize higher (low nmol range) concentrations of non-hormonal calcitriol and
VDR in situ [115,118]. This results in generating peaks of calcitriol in the cytosol, driving
autocrine and paracrine signaling [36,37,114,127] and calcitriol/VDR complexes (not from
the circulatory hormonal calcitriol) [24,132,133]. As described above, the latter does not
enter meaningful amounts into peripheral target cells. (See Section 4.4 for more detail).
This provides a physiologically balanced intracellular autocrine/intracrine signal-
ing, crucial for immune cell functions [118]. This critical early warning TLR-detection
system evolved to identify and overcome threats from infection (or foreign antigens) and
autoimmune responses. Since this is also a threshold mechanism, further increasing serum
25(OH)D concentrations (i.e., beyond 60 ng/mL) would not produce additional beneficial
immune cell functions from an infection's point of view.
When no external signaling exists, calcitriol and VDR synthesizing revert to a baseline
steady state. This is an efficient evolutionary mechanism to stimulate immune cells as
needed, intermittently, as needed—when an external threat—detecting unfamiliar (foreign)
proteins or antigens in the circulation or local tissues. This sporadic phenomenon ensures
the formation of sufficient calcitriol-VDR complexes to modulate gene transcriptions and
calcitriol for intra-cellular autocrine regulations when needed and enough intracellular
concentration of calcitriol for internal signaling, as described in the next section.

3.3. The Importance of Autocrine and Paracrine Signaling for Immune Cell Functions
TLR-4-mediated calcitriol synthesized within the immune cells also enhances the
expression of anti-microbial peptides and antibodies [134,135]. The exact mechanism of
stimulation of these pathways is unclear, but it is known to involve transcription factors
C/EBPβ and the inhibition of NR4A2, an orphan receptor [136]. The regulation of the
CYP27B1 gene (1α-hydroxylase enzyme) by a transcription factor promoter, NR4A2, is
inhibited by C/EBP-beta. Furthermore, over-expression of C/EBP-beta decreases NR4A2
and CYP27B1 mRNA levels [136].
In contrast, FGF-23 counteracts the activity of the 1α-hydroxylase enzyme through
FGF receptors in the presence of the co-receptor (an aging-related factor), Klotho [31]. The
ablation of Klotho leads to over-expression of FGF23, which is consistent with Klotho
deficiency [31]. This signaling also activates the mitogen-activated protein kinase (MAPK),
but its role in CYP27B1 expression remains unclear [137].
When the circulating D and 25(OH)D are low and at insufficient concentrations to
enter immune cells, it hinders the generation of intracellular calcitriol. One example of
calcitriol intracrine signaling is switching T helper cell 1 (Th1) to T helper cell 2 (Th2)
and Th17 to Treg cells, which transforms pro-inflammatory status to anti-inflammatory
status [36,37]. This maintains the inflammatory statutes of Th1 and Th17 cells; severe viral
infections such as SARS-CoV-2 in vulnerable people could initiate cytokine storms and the
development of ARDS [138,139].

3.4. Mechanisms of Decreasing Inflammation with Vitamin D Adequacy

Vitamin D has anti-inflammatory, anti-oxidant, and anti-mitotic actions. In addi-
tion, it stabilizes endothelium and improves smooth muscle cell functions. There is a
statistically significant inverse relationship between serum 25(OH)D concentrations of
less than 21 ng/mL and higher serum C-reactive protein (CRP) levels (an inflammatory
marker) [140], suggesting an essential anti-inflammatory effect of vitamin D in humans.
Nutrients 2023, 15, 3842 10 of 33

This generalized anti-inflammatory effect is one of the critical reasons for the observed
cardiovascular-protective effects associated with calcitriol [141,142].
Vitamin D signaling decreases inflammatory responses, including reduction of the ex-
pression of pro-inflammatory cytokine and mediators (e.g., cyclooxygenases; 5-lipoxygenase),
as demonstrated by genome- and transcriptome-wide studies. It also modulates transcription
factors, such as the nuclear factor kappa light-chain (NF-κB) of activated B cells that regulate in-
flammatory gene expression and reduce mitogen-activated protein kinases’ activation [91,99].
Calcitriol also downregulates cytokine production and the biosynthesis of pro-inflammatory
cytokines in the prostaglandin pathway and through NF-κB [99]. These actions explain a
strong association between low serum 25(OH)D concentrations and the many inflamma-
tory diseases mentioned. Despite these findings, no vitamin D or analog has been used in
adequately powered RCTs to test efficacy in controlling inflammatory conditions [99,100,143].
Increased local generation of calcitriol has been reported in those with diabetic foot
ulcers. This is considered a physiological response to chronic inflammation and an attempt
to enhance immunity in local tissues to combat infections [40,144] (see Section 3.6 for the
effects of cathelicidin). However, such chronic inflammations (in this case, vitamin D
deficiency-induced) will increase the risks for other disorders like myocardial infarction
and stroke. Moreover, an increased intake of micronutrients during periods of high stress
reduced inflammatory processes and plasma lipids, particularly in males [145]. This may
also have clinical relevance for those with diabetic foot ulcers and other chronic infections.
These data support vitamin D’s important immunomodulatory and anti-inflammatory
roles [144]. Examples of these are discussed below.

3.5. Anti-Microbial Activities of Vitamin D

Mycobacteria and/or activation of macrophages leads to enhanced intracellular 1α-
hydroxylase activity within macrophages (e.g., in granulomatous tissues), leading to the
generation of 1,25(OH)2 D3 . These increases in intracellular calcitriol accompany the in-
creasing expression of the VDR in macrophages., as a defense mechanism in those with
sufficient vitamin D status. Because this activity is not subjected to feedback control, if not
intervened in a smaller number of patients, in some, it may increase serum concentrations
of 1,25(OH)2 D3 , leading to (granuloma-related) hypercalcemia.
The seasonal peaks of influenza have been attributed to a higher prevalence of vitamin
D deficiency during the winter months [146]. Thus, persons with hypovitaminosis D are
more susceptible to viral infections [62]. This hypothesis is supported by two recent RCTs:
one was in black postmenopausal women with a baseline mean 25(OH)D concentration
of 48 nmol/L [147], and the other was in a group of schoolchildren in Japan with low
serum vitamin D [148]. In the latter, daily supplementation with 1000 IU of vitamin D3
significantly reduced the risks of type-A influenza by two-thirds but did not affect type-B
influenza.
Moreover, a meta-analysis of 11 RCTs on vitamin D supplementation concluded that
once-daily dosing with vitamin D supplements had a significantly better response rate
than did intermittent dosing regimens, such as monthly dosing (odds ratio = 0.51 vs. 0.86;
p = 0.01) [149]. Those who experience pneumonia also had an increased prevalence of
vitamin D deficiency [150]. Low serum 25(OH)D concentration is associated with low
cellular immune functions and an increased risk for hyponatremia, as reported with H7N9
pneumonia [151]. However, the relationship between these two entities is unknown, and
not all RCTs support this concept [152,153].

3.6. Vitamin D Enhances the Expression of Bactericidal Proteins

T cells and macrophages both have a high concentration of VDRs [71,154]. Vitamin
D—receptor interactions increase the expression of potent bactericidal and viricidal
protein cathelicidin, which combats mycobacterium organisms, such as tuberculosis and
lepra, and other intracellular bacteria [107]. In addition to cathelicidin, VDR activation
increases the synthesis and secretion of multiple other bactericidal peptides, including
Nutrients 2023, 15, 3842 11 of 33

defensins [155,156]. Thus, calcitriol adequacy, while reducing the expression of inflam-
matory cytokines, also increases the secretion of bactericidal peptides in vivo [141,157],
complementing the immune system to combat invading microbes.
Although individual studies indicate positive results, when data from multiple micro-
biological studies are pooled, the results may not necessarily lean in a positive direction
because of the heterogeneity of studies used in meta-analyses. Inclusion of studies that
differ concerning population, ethnicity, age range, types of infections, severity, study de-
sign, and duration, mode of observation or randomizations, and baseline serum 25(OH)D
concentrations and/or the serum concentrations achieved have muddled the situation and
led to inaccurate conclusions.
Vitamin D reduces risks for and the spread of chronic infections [10,11,13], partic-
ularly mycobacterium tuberculosis, by regulating innate and adaptive immunity. Suffi-
cient amounts of intracellular calcitriol in immune cells augment innate responses (mono-
cytes/macrophages with anti-microbial activity) and suppress adaptive immunity (T- and
B-lymphocyte activities) [61]. In addition, calcitriol modulates B lymphocytes, immunoglob-
ulin production, and B-cell homeostasis [61].
Because of the variability of studies and poor study designs, vitamin D dosing, and
recruitment, the pooled RCT data from a vitamin D, many meta-analyses cannot be relied
upon [158]. Thus, to generate meaningful conclusions, future RCTs should be focused on
subjects with documented vitamin D deficiency measured at recruitment to confirm low
serum 25(OH)D concentration and subjects in the treatment arm provided with adequate
vitamin D supplements to achieve a predefined target serum 25(OH)D concentration
(but prohibited from taking over the counter nutrients in both arms), and standardized
measurable hard outcomes.

3.7. Multiple Sclerosis and Autoimmune Encephalomyelitis

Without supplements, serum 25(OH)D concentrations can be a reliable surrogate
marker of UVB exposure. However, there are additional, non-vitamin D-related beneficial
effects of UVB exposure, such as reductions in the severity of depression and the risk of
MS [159–162], of which mechanisms are ill-understood. In addition, exposure to UVB
potentiates the suppression of experimentally induced autoimmune encephalomyelitis in
animal models [163,164]. In people with MS, low 25(OH)D concentrations are an inde-
pendent, positive predictor of disease progression [165]. Furthermore, a better response
has been reported with interferon beta (IFN beta) in those with higher serum 25(OH)D
concentrations [166,167].
In persons with MS, serum adipocytokine concentrations are positively correlated with
inflammatory mediators and negatively correlated with Foxp3 expression [168]. In that
study, positive correlations were also reported between leptin and resistin concentrations
with TNF-alpha and interleukin 1β (IL-1β), with the highest levels of TNF-alpha, IL-1β,
CRP, resistin, and leptin reported in persons with progressive MS [168]; some of these are
positively modulated by calcitriol.
Overall data suggest a clinically meaningful suppression of autoimmune disorders
when serum 25(OH)D concentrations are maintained at greater than 40 ng/mL [5,31,112],
preferably over 50 ng/mL (range 50 to 80 ng/mL). Supporting this, a longitudinal,
prospective observational study by the author demonstrated that in those with chronic
MS (n = 64), keeping serum 25(OH)D concentrations above 40 ng/mL over an average
2-year period resulted in an 80% reduction in recurrences (i.e., reactivation rate) [31].

3.8. Autoimmunity—Rheumatoid Arthritis and Lupus

As with calcitriol therapy, supplementation with high doses of vitamin D improves cell-
mediated immunity [169]. One study reported that monthly administration of 140,000 IU
of vitamin D3 over three months significantly increased the regulatory T-cell population in
healthy people compared with the administration of a placebo. Similarly, doses of vitamin
Nutrients 2023, 15, 3842 12 of 33

D3 (4000 IU daily) significantly decreased CD4 cytotoxic T-cell activation compared with
low-dose vitamin D3 (400 IU/day) therapy [170].
Another study using vitamin D, 10,000 IU/day over six months, reported favorable
immunomodulatory effects, including suppression of IL-17 production and improvement
in the effector CD4+ memory cells, with a concomitant increase in central memory CD4+
cells [171]. These data confirmed that vitamin D supplementation effectively elevates
circulatory 25(OH)D concentrations in persons with inflammatory diseases and vitamin D
deficiency, benefitting them [172].
In vitro, animal studies have suggested that 25(OH)D and 1,25(OH)2 D have indepen-
dent immunomodulatory effects. However, cell culture and animal studies use micromolar
concentrations of calcitriol (i.e., about 1000-fold higher concentrations than present in
humans), thus should not extrapolate to humans. In a study of patients with arthritis, a
decrease in the Disease Activity Score-28 and a 25% reduction in serum CRP levels occurred
with each 10-ng/mL increase in serum 25(OH)D concentration [173], demonstrating a
powerful and protective anti-inflammatory effect of vitamin D, as in the case of rheumatoid
arthritis [174].
Those with genetic resistance to calcitriol, a rare genetic disorder, have a higher
incidence of autoimmune diseases such as rheumatoid arthritis [175]. Therefore, patients
with rheumatoid disorders also benefit from vitamin D repletion. A recent study suggested
that an acquired tissue resistance to calcitriol in those with rheumatoid arthritis may require
vitamin D analogs [176]. In addition, those exposed to adequate doses of UVB reduced
their complications and progression of rheumatoid arthritis [61,177,178]. Nevertheless, post
hoc analysis of the Women’s Health Initiative study failed to show an association between
rheumatoid arthritis and solar irradiation [179]. However, such piggyback studies and
secondary analyses are neither designed nor statistically powered to address such issues.

4. Improving Clinical Outcomes via Vitamin D Sufficiency

When circulating D3 and/or 25(OH)D is adequate (e.g., over 50 ng/mL), these precur-
sors diffuse into peripheral target cells, such as immune cells, in adequate quantities from
the circulation. This process allows the intracellular generation of sufficient calcitriol for
signaling and genomic activity. Calcitriol suppresses the pathological process and hyper-
immune reactions with its genomic actions and autocrine signaling mechanisms [36,37].
These actions reduce the risks of cytokine storms and ARDS and are associated with severe
pulmonary and cardiovascular complications in persons with severe infections such as
COVID-19 [180,181].

4.1. Importance of cofactors and micronutrients for the full functions of vitamin D
The full activity of vitamin D, VDR, and associated enzymatic reactions require either
the endogenous presence, or the administration of several cofactors [182,183]. These include
magnesium, vitamins A, B2 , C, and K, anti-oxidant trace minerals (zinc and selenium),
resveratrol, essential fatty acids such as omega-3, and boron [3,184]. Besides, the functioning
of the immune system and other target cells continues to consume vitamin D and its
metabolites and cofactors [41]. This requirement is enhanced due to the multiple immune
and metabolic pathways in which vitamin D is intimately involved in vivo.
Consequently, a continuous supply (preferably daily intake during an illness) of the
mentioned micronutrients is necessary to attain optimal potentials of vitamin D and better
clinical outcomes [41,183]. The lack of this is another reason for the little benefits reported
in some clinical studies, including RCTs. This is important in both acute and longer-term
clinical trials. In clinical studies, including RCTs, and clinical practice, scientists/physicians
have ignored this critical factor (considered as another study design error). At the minimum,
study subjects (active and placebo participants) and clinical patients should be provided a
multivitamin and essential mineral supplements (e.g., magnesium, zinc, selenium, boron,
etc.) during an illness [182–184], enabling them to recover faster.
Nutrients 2023, 15, 3842 13 of 33

4.2. Consequences of Hypovitaminosis D

Severe vitamin D deficiency is associated with immune dysregulation. Consequently,
when subjected to a severe infection, they could develop hyperinflammation, oxida-
tive stress, and autoimmunity [85,185,186]—an over-reactive pathological immune re-
sponse [187]. The failure to correct vitamin D deficiency rapidly could lead to cytokine
storms with an increased risk of death [188,189]. This could precipitate acute respiratory
distress syndrome (ARDS) in severe respiratory tract infections [62] and asthma [66]. This
is preventable with an appropriate dose and type of vitamin D (e.g., calcifediol instead of
vitamin D3 ).
Due to the impairment of the formation of intracellular calcitriol in the immune cells,
hypovitaminosis D also impairs intracrine and paracrine signaling, further weakening
the immune system, and increasing vulnerability [37,190]. Cytokine storms are associated
with pro-inflammatory and hyper-oxidative stress responses in severe viral infections.
This increases intensive care unit (ICU) admissions and the risk of death, as observed
during the COVID-19 pandemic [48–51]. Children infected with SARS-CoV-2, having less
than 12 ng/mL of serum 25(OH)D concentrations (i.e., severe vitamin D deficiency), are
at very high risk for developing life-threatening hyper-inflammatory conditions, such as
Kawasaki-like disease or multi-system inflammatory syndrome [191–193].
Moreover, hypovitaminosis D leads to weakened adaptive immunity, which reduces
the capacity to generate neutralizing antibodies (including after vaccination) and impairs
the cytotoxic action of immune/killer cells. It also reduces the effectiveness of memory
cells and macrophages and causes weaker responses following (any) vaccine. Overall, it
causes immune paresis with inadequate antibody responses.
In those with a fragile immune system, as in severe hypovitaminosis D, not only
SARS-CoV-2 infection but also immunization against it could lead to significant adverse
effects [194–197]. The latter include hyper-immune and autoimmune reactions, generalized
hyper-inflammation, and pathological oxidative stress, which increase the risks for systemic
complications (blood clots, strokes, etc.) and death. Consequently, in 2020/21, due to the
prevailing high incidence of hypovitaminosis among older people and those with comor-
bidities, COVID-19 primarily affected them, sparing children, and the youth [2,3]. However,
the vaccine-related adverse effects continue among those with hypovitaminosis D.

4.3. One Serum 25(OH)D Concentration Would Not Control All Diseases
Different diseases require varying serum 25(OH)D concentrations to obtain the best
clinical outcomes and prevent complications [5,31,112]. Many conditions require maintain-
ing serum 25(OH)D concentrations greater than 30 ng/mL for anticipated clinical outcomes.
There is no one optimal serum 25(OH)D concentration that provides maximum beneficial
outcomes for all body systems [198,199]. While the musculoskeletal system may benefit
from lower levels of approximately 20 ng/mL, other body systems require more than
40 ng/mL. Examples include T2D and metabolic syndrome [200,201]. However, alleviating
others, such as cancer [202], asthma [66], autoimmunity, infections, and cancer [31,203], etc.,
requires the maintenance of serum 25(OH)D concentrations greater than 50 ng/mL (See
Section 4.4 for more details).
Dark-skinned people in central Africa living traditional lifestyles have a mean serum
25(OH)D concentration of 47 ng/mL (119 nmol/L) (range, 30 to 70 ng/mL) [204,205].
However, with imbalanced macro-nutrient diets, micro-nutrient deficiencies, unwholesome
modern dietary constituents and practices (e.g., unhealthy processed food, fast-food, trans
fat, and preservatives, some of which also increase the catabolism of micronutrients),
environmental pollution, and passive indoor lifestyles, many people likely require much
higher vitamin D intakes than those recommended by governments and health-related
societies and need to maintain a higher range of serum 25(OH)D concentration, such as 50
to 80 ng/mL to obtain vitamin D-related benefits.
Nutrients 2023, 15, 3842 14 of 33

4.4. Minimum and the Range of Serum 25(OH)D (ng/mL) Necessary to Minimize Diseases and
Obtain Maximum Benefits
Considering broader biological and physiological fundamentals, changing disease
patterns (metabolic diseases, obesity, diabetes, and increasing prevalence of viral infec-
tions), the behavior of people (sun avoidance), and broader risk factors (pollution, harmful
diets, medications, etc.) [206], and passive lifestyles acquired in this Millenium [207], the
published evidence justifies the above-mentioned higher range of serum 25(OH)D (50 to
80 ng/mL). Based on the data, it is also reasonable to contemplate that the minimum serum
25(OH)D concentration needed for a healthy life for all ages of humans is 50 ng/mL.
In addition, evidence strongly suggests that there are tissue-specific differences in
serum 25(OH)D concentration thresholds to elicit full biological effects. The previously
suggested minimum serum level of 25(OH)D—30 ng/mL—would only protect less than
a third of common disorders (primarily calcium homeostasis and musculoskeletal). In
contrast, the one suggested above—50 ng/mL—is the minimum adequate level (with a
range of 50 to 80 ng/mL) and would cover 99% of health conditions with no adverse effects.
In contrast, if one considers 80 ng/mL as the minimum level (as some indicated),
it will cover 99.8% of health conditions but is likely to increase adverse effects; thus,
it is not justified or recommended. Data supports the idea that less than 0.01% of the
population requires very high doses of vitamin D with a high response rate (see Section 4.4).
Examples include prevention of intractable migraine headaches, asthma, psoriasis, specific
autoimmune reactions and diseases, tissue/organ graft rejection, and vitamin D-resistant
syndromes. These persons must be treated by specialists in this field (not general specialists,
including immunologists and endocrinologists) under their close medical supervision to
maximize benefits and minimize adverse effects. As per common sense and medical ethics,
healthcare workers must strike a safe and cost-effective approach, the correct dose for a
given person (individualized therapy), and a condition to obtain maximum benefits while
avoiding adverse effects. Precautionary steps are taken with higher daily vitamin D doses
(e.g., above 7000 IU/day or 50,000 IU/week) to prevent potential soft tissue calcification.
These include avoiding calcium supplements and high calcium-containing food and taking
vitamin K2 (MK-7: Menaquinone-7, present in fermented food), 100 micrograms/day or
800 micrograms, once a week.
Since having physiological serum 25(OH)D concentrations can control several acute
and chronic conditions [208], it is logical to aim to maintain a population serum 25(OH)D
above 40 ng/mL [115], and the concentrations of individuals to above 50 ng/mL [24,26].
To benefit the population and to reduce all-cause mortality, doubling the current prevailing
population serum 25(OH)D concentration of approximately 20 ng/mL is needed [209,210].
This would mitigate the ongoing low-grade inflammation and chronic diseases in the
population and open doors to obtaining broader benefits from vitamin D, such as controlling
inflammation and oxidative stress [85], including reducing myocardial infarctions and
strokes. It can enhance cellular effects such as membrane stabilization, protection from
DNA damage (and repair), and minimizing infectious outbreaks and sepsis.

4.5. Vitamin D Intakes and Optimum Circulating 25(OH)D Concentrations Needed to

Overcome Diseases
Vitamin D and 25(OH)D have a high affinity to VDBP. This provides the means for
transporting and increasing the half-life of 25(OH)D in circulation [115]. In addition,
some cells, such as renal tubular cells, fat, and muscle cells, have an evolutionary mecha-
nism of the active transportation of compounds such as vitamin D bound to VDBP. This
megalin–cubulin mediated membrane internalization of vitamin D and 25(OH)D molecular
complexes bound to VDBP provides an energy-dependent entry mechanism for these
molecules into renal, parathyroid, fat, and muscle cells. This active transportation offers
the generation of calcitriol in proximal renal tubular cells and storage of the nutrient in
others [211,212].
 Nutrients 2023, 15, 3842 15 of 33

This entry facilitates the synthesis of the hormonal form of calcitriol in proximal
renal tubular cells, work via calcium-sensing receptors in parathyroid cells in conjunc-
tion with parathyroid hormone (and negative control by FGF-23) [115], maintaining the
calcium homeostasis via modulating bone resorption and intestinal calcium absorption,
and the renal tubular reabsorption of calcium [115]. In contrast, muscle and fat cells have
the mentioned active cell membrane-based transportation system for storage for D3 and
25(OH)D transfer. Unlike pharmaceuticals, these active mechanisms prolong the half-
life of 25(OH)D [1,38]. For administered vitamin D and serum 25(OH)D concentration,
dose-response is not linear [213–216].
Minimum serum 25(OH)D concentrations are needed to prevent or lessen the effects
of common diseases. Figure 4 indicates the relationships between various disease states
and the approximate minimal serum 25(OH)D concentrations needed to improve different
Nutrients 2023, 15, x FOR PEER REVIEW 16 of 35
conditions [31]. It summarizes the varying steady-state serum 25(OH)D concentrations
required to prevent or lessen the effects of common diseases based on many published data.

Figure 4. 4.
Figure Different
Differentdiseases (andtissues)
diseases (and tissues) require
require different
different steady-state
steady-state serum 25(OH)D
serum 25(OH)D concentra-
concentrations
tions to achieve improvement: the need for varied serum 25(OH)D concentrations
to achieve improvement: the need for varied serum 25(OH)D concentrations to subdue various to subdue various
disease statuses is illustrated (modified from Wimalawansa, S.J. Steroid Biochemistry
disease statuses is illustrated (modified from Wimalawansa, S.J. Steroid Biochemistry [31]. [31].

4.6.4.6. Vitamin
Vitamin DDDose-Responses
Dose-Responses
Administrationof
Administration of high
high oral
oraldoses
dosesofof
nutrient vitamin
nutrient D in D
vitamin D-deficient personspersons
in D-deficient leads to leads
a meaningful, measurable change in the serum 25(OH)D concentrations within three to four
to a meaningful, measurable change in the serum 25(OH)D concentrations within three to
days [115,215,216]. The lower the serum 25(OH)D concentration, the higher the percentage
four days [115,215,216].
increase The lower
(∆) in the circulation and thethe serum
higher the 25(OH)D
likelihood concentration,
of demonstratingthe higher the per-
a significantly
centage
better increase (∆) in the
clinical outcome. circulation
However, such aand the higher
dose-clinical the likelihood
response ofdoes
relationship demonstrating
not exist a
significantly better clinical outcome. However, such a dose-clinical response relationship
in those who are vitamin D sufficient. Figure 5 illustrates a typical dose-clinical response
does notfor
curve exist in those
nutrients suchwho are vitamin
as vitamin D. D sufficient. Figure 5 illustrates a typical dose-
clinical response curve for nutrients such as vitamin D.
Nutrients 2023,
Nutrients 15, x
2023, 15, 3842
FOR PEER REVIEW 1716of
of 35
33

Figure 5. Illustration of the dose/25(OH)D concentrations achieved in the circulation vs. responses
Figure 5. Illustration of the dose/25(OH)D concentrations achieved in the circulation vs. responses
(clinical health benefits and potential risks). It also provides the basic pharmacodynamics of a typi-
(clinical health
cal nutrient, benefits
taking and D
vitamin potential risks). ItWhen
as an example. also provides the basicoccurred,
tissue sufficiency pharmacodynamics of a
generally, there
typical not
would nutrient, taking vitamin
be additional benefitsDby
as raising
an example. When tissue
the circulatory sufficiency occurred,
concentration generally,
by increasing there
the intake.
would notthere
However, be additional benefits
are exceptions in aby raising
small the circulatory
percentage; concentration
pharmacological dosesby
areincreasing the intake.
needed under med-
However,
ical there
guidance are than
in less exceptions in population
1% of the a small percentage; pharmacological
to overcome doses the
resistance to achieve aredesired
neededclinical
under
goals
medical(indicated
guidance inin
the dashed
less blue line)
than 0.01% [115].
of the population to overcome resistance to achieve the desired
clinical goals (indicated in the dashed blue line) [115].
The current study strongly suggests that most health benefits are seen when serum
The current
25(OH)D study strongly
concentrations suggestsatthat
are maintained moremost health
than benefits
40 ng/mL (100 arenmol/L)
seen when[217],serum
with
25(OH)D
further concentrations
improvements are when
seen maintained
levelsatkeptmore than
over 5040ng/mL
ng/mL (100 nmol/L)
[24,115]. This can[217], with
be cost-
further improvements seen when levels kept over 50 ng/mL [24,115].
effectively achieved by providing safe sun exposure guidance and appropriate intakes This can be cost-
of
effectively achieved by providing safe sun exposure guidance and
vitamin D supplements. The emphasis is on sensible, safe, balanced vitamin D (and otherappropriate intakes of
vitamin D supplements. The emphasis is on sensible, safe,
micronutrient intake) that provides cost–benefits to the public [218–220]. balanced vitamin D (and other
micronutrient intake) that provides cost–benefits to the public [218–220].
5. Other Considerations with Vitamin D
5. Other Considerations with Vitamin D
5.1. Adverse Effects of Vitamin D Are Rare
5.1. Adverse Effects of Vitamin D Are Rare
Vitamin D toxicity rarely manifests after consuming very high amounts (e.g., intake
Vitamin D toxicity rarely manifests after consuming very high amounts (e.g., intake
of above 20,000 IU/day by a non-obese 70 kg person) for prolonged periods. It has been
of above 20,000 IU/day by a non-obese 70 kg person) for prolonged periods. It has been
demonstrated
demonstrated that that daily
daily oral
oral vitamin
vitamin D D doses
doses of of up
up to
to 10,000
10,000 IU
IU are
are safe
safe and
and devoid
devoid of of
adverse
adverse effects. Reported data suggest that daily doses greater than 40,000 IU can
effects. Reported data suggest that daily doses greater than 40,000 IU can harm
harm
individuals with normal
individuals with normalcalcium
calciumabsorption
absorptionprofiles.
profiles.However,
However,a afew few patients
patients with
with mor-
morbid
bid obesity, gastrointestinal absorption issues, or those who are vitamin
obesity, gastrointestinal absorption issues, or those who are vitamin D resistant might need D resistant might
need
higherhigher
daily daily
doses.doses. The numbers
The numbers requiring
requiring such remain
such remain very small.
very small.
While
While adverse
adverse effects
effects are
are rare,
rare, the
the few
few reported
reported cases
cases of
of vitamin
vitamin D D toxicity
toxicity were
were due
due
to mistaken doses or accidental use. Because of the built-in feedback
to mistaken doses or accidental use. Because of the built-in feedback control mechanisms control mechanisms
within
within the
the skin,
skin, excessive
excessive exposure
exposure to to UVB
UVB fromfrom sunlight
sunlight does
does not
not cause
cause vitamin
vitamin D D over-
over-
production. These rescue catabolic pathways will divert the vitamin
production. These rescue catabolic pathways will divert the vitamin D metabolism D metabolism to inert
to
compounds such as 24(OH)D, 24,25(OH) D, and other inactive metabolites
inert compounds such as 24(OH)D, 24,25(OH)2 D, and other inactive metabolites [221].
2 [221]. Never-
theless, excessive
Nevertheless, sun exposure
excessive without
sun exposure protection
without is notisrecommended,
protection not recommended, as itascould in-
it could
crease
increasethe risk
the ofof
risk skin
skindamage
damageand andpotential
potentialmalignancies
malignanciesbut butwould
wouldnot notresult
result in
in vitamin
vitamin
D toxicity [6,30].
Hypervitaminosis D-induced toxicity should not be diagnosed solely based on ele-
vated 25(OH)D levels. Instead, it should be recognized as a clinical syndrome in the pres-
Nutrients 2023, 15, 3842 17 of 33

ence of hypercalcemia, suppressed PTH, and hypercalciuria in conjunction with markedly

elevated serum 25(OH)D levels (>150 ng/mL). The rare occurrence of vitamin D-related
symptomatic adverse effects, such as hypercalcemia and hypercalciuria, could result from
individuals taking extremely high doses of vitamin D (especially activated vitamin D
analogs) for a prolonged time or taking large amounts inadvertently. The clinical signs and
symptoms of vitamin D toxicity include hypercalcemia (e.g., nausea, dehydration, irritation
(dryness) of the eyes, confusion, constipation, and electrocardiographic abnormalities),
irritability, and hypercalciuria (e.g., polyuria and kidney stones).
Asymptomatic elevation of 25(OH)D without hypercalcemia needs to be investigated
for the etiology of increased vitamin D levels. Unlike hypercalcemia (i.e., higher ionized
calcium in the blood), increased vitamin D [25(OH)D] levels are not a medical emergency. If
the issue is too much intake, it is essential to stop taking vitamin D supplements, including
multivitamins. Lower doses of vitamin D supplements can be restarted once the 25(OH)D
level reaches a low normal range with modification of the amount and diet. Most patients
with vitamin D toxicity have serum concentrations greater than 150 ng/mL.
Data indicate that regimens of vitamin D supplementation with 10,000 IU/day or
50,000 IU bimonthly (even weekly) are not associated with laboratory or clinical variables
of toxicity (manifested as serum calcium, bone alkaline phosphatase, and 24-h urine cal-
cium), confirming the safety of such regimens [222]. Eleven patients with symptomatic
hypercalcemia caused by hypervitaminosis D had taken supplement doses greater than
50,000 IU/day or 600,000 IU (injectable form) too frequently for various ailments, includ-
ing back pains, osteoarthritis, or osteoporosis, for several months. Such toxicity is easily
avoidable [223,224]. In rare occasions, macrophage-driven, autonomous production of
1,25(OH)2 D may occur in granulomatous tissues. This is caused by a lack of feedback
control of 1α-hydroxylase enzyme in granulomas, such as sarcoidosis and tuberculosis. It
can cause hypercalcemic syndrome [225,226].

5.2. Personal Vitamin D Response and Targeted Serum 25(OH)D Concentrations

Standardized technology assesses vitamin D status by measuring serum 25(OH)D—
the predominant circulatory and storage form [227]. Normal serum concentrations of
25(OH)D and 1,25(OH)2 D are essential for optimal musculoskeletal and soft tissue health.
However, the circulating physiologic calcitriol concentrations are unrelated to extra-skeletal
health and, thus, do not affect the functions of peripheral target cells (such as immune cells).
Consequently, what matters for extra-skeletal body systems is the ability to diffuse enough
vitamin D and/or 25(OH)D into peripheral target cells, enabling them to function optimally.
While a personal vitamin D response index may provide better guidance for optimiz-
ing vitamin D supplementation for individuals than broader population-based recommen-
dations [228,229], its associated unnecessary cost and associated impracticality prevent its
use. Such an index could be helpful only if performed inexpensively, like finger-stick blood
sugar measurement [230]. Even if an index and testing provide theoretical benefits of a
targeted increase of serum 25(OH)D concentration, such results may be difficult to sustain.
Circulating 25(OH)D sufficient for target tissue cell activation of calcitriol (and VDR)
allows beneficial modulatory effects on cellular functions, especially mitochondrial activity,
enzymatic reactions, and hormone synthesis and secretion. Examples of the latter include
insulin PTH, renin–angiotensin–aldosterone, and FGF23–Klotho system. In conjunction
with adequately supplemented clinical studies, data from metabolomics and transcrip-
tomics would provide better information on longer-term extra-skeletal benefits. In addition,
adequate vitamin D supplementation allows personalized and targeted measures to reduce
skeletal and soft tissue health risks cost-effectively [9,228].

5.3. Vitamin D Is a Threshold Nutrient

As with some others, vitamin D is a threshold nutrient; its beneficial effects can be
demonstrated only in those deficient in vitamin D [215]. Unlike pharmaceutical agents,
in those who are vitamin D sufficient, no matter how high the doses provided, there will
Nutrients 2023, 15, 3842 18 of 33

not be additional benefits [115] (with very few exceptions discussed above). This view
is supported by adequately powered and well-conducted RCTs in vitamin D-deficient
subjects for the required duration; using proper amounts of vitamin D (daily or once a
week) almost always provided positive results.
Because vitamin D is a threshold nutrient (with different tissue sensitivities), the only
way to demonstrate the intended favorable clinical outcomes in an RCT or a prospective
clinical study is by conducting properly designed investigations in subjects with vitamin
D deficiency [231–235]. Those tested for vitamin D deficiency-related primary clinical
outcome(s) (i.e., testing a hypothesis—pre-determined health benefits) reported substantial
benefits following the correction of vitamin D deficiency [236–238].
Empirical evidence establishes the connection between exposure and clinical outcomes.
Clinical studies show that infections can be prevented by proactively correcting vitamin D
deficiency in individuals who are vitamin D deficient and, in the community, [239–241]. In
RCTs, with proper daily or once-a-week vitamin D supplementation in the intervention
group, the serum 25(OH)D concentration must be meaningfully increased to a pre-planned
level to ensure the validity of the clinical study. Instead of the administered dose, the serum
25(OH)D concentration achieved and maintained in the circulation (a pre-determined level)
should be used for correlations with clinical outcomes (authentic dose responses), especially
in longer-term studies.
Well-designed and conducted clinical studies, as mentioned above, have reported a
significant reduction in the risks of SARS-CoV-2 infection and complications [239–241].
Such will boost and maintain a robust immune system that lessens the risks from SARS-
CoV-2 infection and its complications—altering the cause-and-effect and leading to better
clinical outcomes (Koch’s postulates). This data provides strong evidence for a causal
relationship between vitamin D and its physiological effects, as demonstrated in UK
BioBank data [49–51].

5.4. Vitamin D Deficiency Increases Vulnerability to SARS-CoV-2 Infections

Evidence strongly supports that low vitamin D status increases the rates of infections,
complications, and mortality rates for intracellular bacterial diseases such as tuberculo-
sis and viral respiratory illnesses in both children [242] and adults [40,243], including
from SARS-CoV-2 infection [231–235]. In addition, pre-existing vitamin D deficiency
increases the risks of SARS-CoV-2 infection [239–241], its complications [240,244,245], hos-
pitalizations [49–51,57,246], and deaths [48,59,245,247,248]. In contrast, proper doses, and
frequency of vitamin D supplements in deficient persons significantly reduce risks for
infections, complications, and deaths from SARS-CoV-2 [48–51,57,239–241,244–248].
Reported data validate Bradford Hill’s criteria for causation of diseases [60]: vitamin
D deficiency causing cancer [249–251], multiple scleroses [252,253], the risk of contracting
SARS-CoV-2 infection [46,47,51,239,240,254], and the severity [255], and the vulnerability
and complications for SARS-CoV2 [231–235,239–241]. Further, the crucial mechanism of
action of intracellular calcitriol in immune cells supports the biological plausibility that low
vitamin D increases the risks for infections, including SARS-CoV-2 [53,56,247,251,255–257].
In addition, data demonstrated that vitamin D significantly reduces complications and
deaths from SARS-CoV-2 [32,48–51,56,57,239–241,244–248,257].

5.5. Issues with Published RCTs and Limitations of Data and Interpretation
Adequately powered, well-designed epidemiological studies and RCTs that used ade-
quate doses of vitamin D supplementation to achieve a predefined target serum 25(OH)D
concentration in subjects with hypovitaminosis D reported favorable outcomes. Such
studies have demonstrated the importance of maintaining an optimum serum 25(OH)D
concentration for normal physiologic functions and improved quality of life. While in some
areas, definitive evidence is lacking, it is mainly due to published RCTs with major study
design errors. The overall data support the protective effects of vitamin D in humans when
25(OH)D serum concentration is maintained above 50 ng/mL [115]. From the practical and
Nutrients 2023, 15, 3842 19 of 33

community’s point of view, the goal for sufficiency should be above 40 ng/mL to achieve
a balance.
Despite the above, there is little evidence from RCTs regarding the optimum serum
25(OH)D levels for preventing various disease-related complications. This confusion de-
rives from the non-standardized, poorly designed clinical studies using different serum
25(OH)D concentration targets or no targeted serum 25(OH)D concentrations and at-
tempted to correlate clinical outcomes with administered dose than with what achieved
(or effective) circulatory concentrations [258]. These confusions partly derived from failing
to understand that vitamin D is a threshold nutrient [214,215,259], not a synthetic phar-
maceutical agent. This major misunderstanding exists even in extensive and expensive,
public-funded vitamin D RCTs and almost all pharma-designed vitamin D-related RCTs, as
they have done for pharmaceutical agents [115,215].
Irrespective of the number of participants enrolled in recent RCTs, as in the case of
the VITAL study [260,261], it led to disarray because of poor study design [26]. Before
studies commenced, these errors were pointed out to the NIH—the funding agency, but
they failed to rectify them. Adequately powered studies with an appropriate format
and suitable study duration recruited 25(OH)D deficient participants. The target serum
25(OH)D concentrations achieved and maintained during the RCT allow proper testing of
specific vitamin D-related hypotheses [115]. While such studies are not so frequent, they
have ubiquitously demonstrated the protective effects of vitamin D [262].
Future clinical studies must target predefined serum 25(OH)D concentrations for
statistical correlations and use vitamin D supplementation as the only (or at least as the key)
intervention to address vitamin D-related risk reductions as the primary hard endpoint
specifically. Despite the accumulating data, awareness lags behind the beneficial effects and
the optimal serum 25(OH)D concentrations concerning humans in non-musculoskeletal
diseases [5,30]. Disagreements abound regarding optimal serum 25(OH)D concentrations,
recommended oral supplementation doses, properly designed and adequately powered
randomized clinical studies (RCTs), and outcome data. Nevertheless, it is fruitless to
repeat the jargon that ‘more RCTs are necessary to conclude’ should not be included in
metanalyses. If the studies are insufficient, authors should not have done such repeats of
meta-analyses.

5.6. New Vitamin D Recommendations

Individual countries and scientific societies need to re-assess vitamin D guidelines to
raise the recommended dietary allowance (RDA) of vitamin D, including higher amounts
for food fortification guidelines and new targets to achieve better health for the public,
as described above. Studies reported from Western Europe suggest that the use of such
approaches may reduce the economic burden of common medical disorders, such as type
2 diabetes (T2D), cardiovascular diseases (CVDs), and cancer [263].
Steady-state serum 25(OH)D concentrations primarily depend on the body weight
(BW) and the total fat mass. While body mass index (BMI) (validated only for White
Caucasians) is not a good indicator of body fat estimation in ethnic groups like Asians.
However, it is a helpful indicator encompassing fat and muscle mass, is readily available.
Therefore, for calculating vitamin D dose for individuals, one can use either the BMI or
the body weight, as illustrated below [24]. These simplified calculations are based on the
detailed tables published in Nutrients in 2022 [Wimalawansa, SJ, Nutrients, 14(14), 2997,
2022; https://doi.org/10.3390/nu14142997] [24]. The following summarizes vitamin D
dose calculation for an individual, applicable across all body weight groups.
I. Not obese (average wt.: BMI, <29): 70–90 IU/kg BW
II. Moderately obese (BMI, 30–39): 100–130 IU/kg BW
III. Morbid obesity (BMI, over 40): 140–180 IU/kg BW
All current vitamin D guidelines are based on decades-old concepts and research; they
are outdated. Based on recent data, raising the minimum and maximum serum 25(OH)D
concentrations to 50 and 80 ng/mL, the safe upper limit of intake to 15,000 IU/day, and
Nutrients 2023, 15, 3842 20 of 33

the average daily intake of vitamin D, recommendation based on 5000 IU for a non-obese
70 kg adult (70–90 IU/kg body weight) is logical. Such will significantly reduce disease
and hospital burdens, healthcare costs, loss of productivity and absenteeism.

6. Discussion
This systematic review examined the effects of vitamin D beyond calcium homeostasis
and the musculoskeletal system. The current paradigms related to vitamin D are primarily
based on retrospective analyses, case reports, and epidemiological studies (cohort, cross-
sectional, observational, prospective, and ecological studies) [5,31,112]. However, an
overwhelming number of reports support the positive effects of vitamin D outside the
musculoskeletal body systems [218,220,264–266].
The knowledge of the physiology of D3 and vitamin D–VDR has advanced the under-
standing of the biology, metabolism, and effects of gene polymorphisms on the vitamin
D axis. During the past decade, many advances have been made in understanding the
physiology and biology of vitamin D, and its receptor ecology has emerged. Notably, a
minimum serum 25(OH)D concentration of 50 ng/mL is crucial for immune cells and other
extra-musculoskeletal target cell physiological activity. The lack of inclusion in current
vitamin-related recommendations makes them outdated—another reason why guidelines
must be updated.
Evidence supports strong physiological associations of vitamin D with disease risk
reduction and improved physical and mental functions. Together, these data have facilitated
our understanding of new pathways for intervention to prevent and treat human diseases
cost-efficiently. Overall evidence suggests that vitamin D deficiency, as determined by
maintaining serum 25(OH)D concentrations of more than 40 ng/mL, is associated with
increased risks of illnesses and disorders and higher all-cause mortality, even among
otherwise healthy individuals [259]. The proper functioning of the vitamin D endocrine,
paracrine, and autocrine systems is essential for many physiological activities and for
maintaining good health. This systematic review addressed key functions of vitamin D
that extend beyond its calcium and phosphate homeostasis and prevention and treatment
of rickets, osteomalacia, and bone loss.
Recent data from epidemiological, cross-sectional, and longitudinal studies support
that having physiological serum concentrations of 25(OH)D, levels greater than 40 ng/mL,
significantly reduces the incidence of extra-musculoskeletal disorders. The latter includes
diabetes [267–269], MS [270], rheumatoid arthritis [271], osteoporosis [272,273], autoim-
mune diseases [274], and certain types of cancer [275–278], as well as reducing all-cause
mortality [259].
The dosages of vitamin D prescribed for non-obese deficient persons of average weight
of 70 kg should be between 4000 and 7000 IU/day, 20,000 IU twice a week, or 50,000 IU once
a week or once in 10 days [115]. Such doses would allow approximately 97.5% of people
to maintain their serum 25(OH)D concentrations above 40 ng/mL [5,30,204]. However,
intermittent doses at intervals longer than once a month are unphysiological and thus
ineffective [279,280]. Studies have shown that daily vitamin D supplements are more
beneficial than supplementation administered less frequently [281–285].
Furthermore, many medications, environmental pollutants, and physical activi-
ties/lifestyles influence vitamin D metabolism and actions, modulating the balance
between energy intake and expenditure [286]. The mentioned factors should be incor-
porated into guidelines, future RCT study designs, and clinical practice.
In contrast, using vitamin D analogs is inappropriate for alleviating hypovitaminosis
D or treating osteoporosis [115]. In the absence of adequate exposure to sunlight, average-
weight non-obese individuals require daily vitamin D intake (food plus supplements) of
between 5000 and 7000 IU to maintain serum 25(OH)D concentrations above 50 ng/mL
(125 nmol/L). Longer-term maintenance of a steady state of the serum 25(OH)D concentra-
tion is necessary to have a meaningful impact on reducing disease incidences and all-cause
mortality [287].
Nutrients 2023, 15, 3842 21 of 33

This study confirms the need to combine approaches to alleviate vitamin D deficiency.
Such strategies include enhancing awareness, fortifying food, advocating safe sun exposure,
and vitamin D supplementation. Clinical practice recommendations should be geared
toward healthcare professionals and the public, guiding patient education, and informing
the public regarding appropriate actions for avoiding micronutrient deficiency. However,
most countries neither have policies or guidance on sun exposure and vitamin D intake
nor cost-effective public health interventions, especially for micronutrients. They should
consider embracing cost-effective measures to prevent diseases, significantly reducing
healthcare costs.
Vitamin D deficiency increases the vulnerability and severity of common diseases
such as type 2 diabetes, metabolic syndrome, cancer, kidney diseases, and obesity. Vita-
min D adequacy is critical to overcoming infections and autoimmunity. Maintaining the
population’s vitamin D sufficiency (above 40 ng/mL) and individuals above 50 ng/mL
with vitamin D3 supplements and/or daily sun exposure is the most cost-effective way
to reduce chronic diseases, sepsis, overcome viral epidemics, and autoimmune disorders,
which provides better health and reduce healthcare costs.
Maintaining serum 25(OH)D concentrations above 50 ng/mL improves overall health
and reduces the severity of chronic diseases, infection and autoimmunity, and all-cause
mortality. Furthermore, it minimizes infection-related complications, including COVID-19-
related hospitalizations and deaths. Vitamin D sufficiency is the most cost-effective way
to reduce illnesses, infections, and healthcare costs. It should be a part of routine public
health and clinical care.

7. Conclusions
Maintenance of sufficient circulating 25(OH)D has a profound beneficial effect on the
body. Such would decrease musculoskeletal disorders and many common extra-skeletal
diseases and disorders, including insulin resistance, prediabetes, the severity of diabetes,
metabolic syndrome, inflammation, autoimmunity, and so forth. In addition to its endocrine
effects, vitamin D exerts genomic, membrane-based, and autocrine, and paracrine effects
in peripheral target tissues subject to epigenesis modulation [288]. Maintaining mean
population vitamin D status—serum 25(OH)D concentrations—above 40 ng/mL leads
to broader benefits, better health, and reduced healthcare costs. Vitamin D sufficiency
significantly impacts its physiological benefits, including reducing the risks of chronic
diseases, infections, and all-cause mortality [289]. Instead of waiting for people to develop
sicknesses and complications from chronic hypovitaminosis D-associated illnesses and
treating them, maintaining the population's vitamin D sufficiency should be the way
forward. This is the most cost-effective approach to keeping people healthy. Therefore,
adopting this to clinical practice guidelines and healthcare insurance protocols is warranted.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The author declares no conflict of interest. He received no funding for this
work or assistance in professional writing for this review.
Nutrients 2023, 15, 3842 22 of 33

Abbreviations

1:25(OH)2 D 1,25-dihydroxyvitamin D
25(OH)D 25-hydroxy vitamin D
BMI Body mass index
CRP C-reactive protein
CVD Cardiovascular disease
D3 Cholecalciferol
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses
PCR Polymerase chain reaction
PTH Parathyroid hormone
RAS Renin–angiotensin system
RCTs Randomized controlled clinical trials
ROS Reactive oxygen species
SR Systematic Review
T1D Type 1 diabetes mellitus
T2D Type 2 diabetes mellitus
UVB Ultraviolet B
VDR/CTR Vitamin D (Calcitriol) receptor
VDBP Vitamin D binding protein
VDR Vitamin D receptor

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