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REVIEW ARTICLE
Year : 2019  |  Volume : 9  |  Issue : 4  |  Page : 117-135

Vitamin D: Public Health Status Regional Gulf Region


1 Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat, Oman
2 Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat; Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman
3 Ageing and Dementia Research Group, Sultan Qaboos University, Muscat; Department of Behavioral Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
4 Research & Policy Department, World Innovation Summit for Health (WISH), Qatar Foundation, Doha, Qatar

Date of Submission09-Oct-2019
Date of Decision16-Oct-2019
Date of Acceptance04-Nov-2019
Date of Web Publication28-Nov-2019

Correspondence Address:
M. Walid Qoronfleh
Research & Policy Department, World Innovation Summit for Health (WISH), Qatar Foundation, P. O. Box 5825, Doha
Qatar
Musthafa Mohamed Essa
Ms. Neela Sampat, Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat
Oman
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnpnd.ijnpnd_68_19

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   Abstract 


Background: Vitamin D and its metabolites have a vital role to play in human health and disease like cancer, Type 1 Diabetes, cardiovascular diseases, Osteoporosis, Osteomalacia, immune system, and the nervous system. In the nervous system vitamin D could influence the proliferation, differentiation of neurons also it plays an important role in neuro-trophism, neurotransmission and neuroplasticity. Further, in some cases it was reported that vitamin D could provide neuroprotection by reduction of oxidative stress, induction of synaptic structural proteins, and regulation of calcium-mediated neuronal excitotoxicity, neurotrophic factors and deficient neurotransmitters. Generally, there is hype and variations associated with the integrity of evidence on vitamins and their effect on health. Vitamin D deficiency continues to attract a renewed attention and an adequate maintenance of vitamin D levels can prevent and reduce the risk of many diseases as the active form acts at the cell nucleus (gene upregulation) and cell membrane (rapid response) in over 30 tissues and organs targeting over 200 genes. Vitamin D tends to exert endocrine actions on Kidneys, bone and intestine. Paracrine role in tissues which are under cytokine control which are able to locally metabolize vitamin D to its active form to modulate immune functions, cell proliferations and differentiations and hence maintenance of adequate levels of vitamin D has a significant impact for optimal health. Establishing what constitute vitamin D deficiency is currently replete with contradictory information. Objective: The present discourse aim is first to scrutinize and assess the literature on vitamin D function on the central nervous system (CNS). Another related aim of the present review is to highlight current data from countries with high exposure to the sun yet the people living in the region have been documented to have deficit in vitamin D. Results and conclusions: In this review, we provide a Gulf centric view on vitamin D status among all age groups including public health impact and policy recommendations for the region. The role or status of vitamin D in the various disease states, the benefits of vitamin D and how to obtain an adequate daily amount.

Keywords: Brain development, brain health, CNS, Gulf Cooperation Council (GCC) countries, Malnutrition, Neurological disorders, Nutrition and chronic conditions, vitamin D


How to cite this article:
Sampat N, Al-Balushi B, Al-Subhi L, Al-Adawi S, Essa MM, Walid Qoronfleh M. Vitamin D: Public Health Status Regional Gulf Region. Int J Nutr Pharmacol Neurol Dis 2019;9:117-35

How to cite this URL:
Sampat N, Al-Balushi B, Al-Subhi L, Al-Adawi S, Essa MM, Walid Qoronfleh M. Vitamin D: Public Health Status Regional Gulf Region. Int J Nutr Pharmacol Neurol Dis [serial online] 2019 [cited 2019 Dec 6];9:117-35. Available from: http://www.ijnpnd.com/text.asp?2019/9/4/117/271856




   Introduction Top


The first proof of the existence of vitamin D was demonstrated by Elmer McCollum in 1922 who discovered that cod liver oil was efficacious in preventing rickets in children.[1] Scientists have proposed that vitamin D is not a vitamin in the traditional sense rather it is actually a hormone since it fits the standard description of a hormone because a hormone-receptor has been identified for vitamin D; the standing of vitamin D as a classical calciotropic hormone is well established.[2] Vitamin D could be also furnished from vitamin D-rich foods or is produced endogenously when sunlight’s ultraviolet (UV) radiation strikes the skin triggering vitamin D synthesis. This synthesis is non-enzymatic in nature and it is purely a photochemical reaction. However, this reaction requires adequate 7-dehydrocholesterol (7DHC) concentration and UV-B 290–315 nm wavelength; hence it is known as the sunshine vitamin.[2] There is renewed attentiveness in individuals’ vitamin D status since it is inversely associated with the incidence of several chronic diseases such as cancers, cardiovascular and neurodegenerative diseases, besides its traditional role in bone metabolism and immunity. Classical function of vitamin D for skeletal maintenance and bone health is well known.[3] The non-classical function of vitamin D has been increasingly recognized with the discovery of vitamin D receptors (VDRs) in various tissues and its biological function at the cellular or molecular level. Physiological processes like immune modulation, cell proliferation, differentiation, and gene regulation are some of the non-classical functions of vitamin D and thereby impacting human health and diseases like cancer, hypertension, diabetes, autoimmune disorders, neurodevelopmental, neurodegenerative etc.[4],[5]

Without vitamin D, dietary calcium is not absorbed at all efficiently and it does affect overall mineral homeostasis. Vitamin D deficiency leads to osteomalacia and rickets in children. In utero vitamin D deficiency can cause multiple sclerosis later in life and increase the risk of developing schizophrenia. Vitamin D deficiency in neonates during the first year of life increases the chances of developing diabetes.[6] Deficiency in vitamin D is considered the foremost preventable public health issue worldwide irrespective of age, location, ethnicity, and gender.


   Methods Top


This is a literature review article for vitamin D concerning the Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and United Arab Emirates [UAE]) and not a systematic review per se. This discourse’s aim is first to scrutinize and assess the available literature on vitamin D function on the central nervous system (CNS). Standard literature/database searches were implemented, relevant information extracted were then assessed.

Results and discussion

The finding from the literature for vitamin D concerning the GCC countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and UAE) and role in human health and disease largely the nervous system is presented below. Moreover, public health impact and recommendations for the region is described including the benefits of vitamin D and how to obtain an adequate daily amount.

Vitamin D metabolism

Vitamin D is a secosteroid hormone classified into two major types. One is vitamin D2 (ergocalceiferol) which is derived from plant and vitamin D3 (cholecalciferol) that is linked to animal origin. Evidence suggests that vitamin D3 can be acquired through diet or synthetized photochemically upon exposure of the skin to ultraviolet-B irradiation (UVB) and action on 7-dehydrocholesterol. Biologically, both vitamin D2 and D3 are inactive and require two separate hydroxylation by 25-hydroxylase (liver) and 1-α-hydroxylase (primarily in the kidney).[7],[8] Vitamin D2/D3 is transported through the blood to the liver by vitamin D–binding protein (DBP), a specific binding protein for vitamin D and its metabolites in the serum. In the liver, the first hydroxylation step takes place at the C-25 to make 25-hydroxyvitamin D3 (25(OH) D3) by one or more of the cytochrome P450 vitamin D 25-hydroxylases (including CYP2R1, CYP2D11 and CYP2D25). This circulating metabolite form, 25(OH) D3, is then transported by the DBP to the kidney where the second hydroxylation step takes place on the C-1. Endocytic internalization of 25(OH) D3 is supported by magalin, a member of the LDL receptor superfamily, which plays an essential role in this regard. In the proximal renal tubule 25(OH) D3 is hydroxylated resulting in the hormonally active molecule of the vitamin, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), which is responsible practically for most of vitamin D biological activities.[7] Similar synthesis transpires in the brain as well.[9] Active synthesis of the 1, 25(OH)2D3 has been confirmed in microglial cells in vitro and in cultured glial cells so is indigenous inactivation of 1,25(OH)2D3 via hydroxylation by CYP24A1.[10] The presence of the enzymes 25-hydroxylase and 1-α-hydroxylase activities outside renal sites including the brain strongly indicate the possibility of paracrine production of (1, 25(OH)2D3) in the CNS.[11] Rodent model studies by Spach and Hayes (2005) provided such evidence for calcitriol synthesis in situ in the CNS pointing to the importance of this active hormone in brain health and disease.[11] Discovery of high affinity calcitriol receptors in the pituitary, forebrain, hindbrain and spinal cord of rats suggested a role to vitamin D in the brain and highlighted the paracrine production of vitamin D in the CNS.[10] Nuclear effect of vitamin D is exerted through VDRs. Calcitriol expression was noted in neurons, in glial cells, in the nuclei of Schwann cells in peripheral neurons and in different CNS regions. VDR upon binding to calcitriol heterodimerizes with the retinoid X receptor (RXR), and subsequently binds specific genomic sequences known as vitamin D response elements (VDREs) to influence gene transcription and will be tissue specific thereby influencing disease pathogenesis through unique mechanism.[12] Genome-wide association studies showed enrichment of VDR-binding sites near autoimmune and cancer- associated genes.[13] Vitamin D is thought to play a role in a variety of cellular processes, including immune function through the assembly of MHC class I molecules, DNA binding and gene expression, and molecular chaperoning through membrane associated, rapid response steroid binding receptor (MARRS)[14],[15] also known as Erp57/Grp58. The action of vitamin D is based on gene transcription modulation through a specific nuclear receptor, the VDR that presents numerous genetic polymorphisms associated with various degenerative diseases.[16],[17],[18] Experimental studies have highlighted the main paracrine role of vitamin D in immunomodulation within the nervous system, and neurological functions predominantly brain development, reduction of oxidative stress, neuroplasticity, neurotransmission, and neuroprotection.[19] Vitamin D is also linked to its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue and thereby emphasizing the neuroprotection role.[20] Studies in rodent models implicate vitamin D autocrine/paracrine activities in each of the major bone cell types where it also regulates cell proliferation and differentiation.[21] Osteomalacia occurs when low dietary calcium intake along with serum 25D, 1,25D levels are below 20 nmol/L. 25D levels between 20 and 80 nmol/L results in the loss of normally mineralized bone at both the trabecular and cortical compartments. This activity is not related to plasma 1,25D suggesting an autocrine or paracrine action within the bone tissue itself.[21] Autocrine and paracrine activities of vitamin D have been also observed in skin tissues and the immune system where it regulates cell differentiation and maturation as well as the innate immune system and has a significant implications for optimal health [Figure 1].[21]
Figure 1 Vitamin D2 and D3: Vitamin D2 and D3 are inactive biologically and require two separate hydroxylations by 25-hydroxylase (liver) and 1-α-hdroxylase (kidney) to give rise to the active form (1,25-dihydroxyvitamin D3; calcitriol). Source: Adapted from “The role of vitamin D in nervous system health and disease” (C., M., J., V., & C., 2013).

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Vitamin D and the Vitamin D receptors in CNS- brain synthesis, metabolism, and transcriptional regulation

Vitamin D and its metabolites play a major role in the CNS by being involved in the process of the neuro-transmission and neuroplasticity; moreover, the active form actually can be metabolized and regulated in the CNS itself. Besides its role in proliferation, differentiation, and immunomodulation, vitamin D has an intricate role in brain development and function. Vitamin D is present all over in the embryonic brain, and most predominantly in the neuroepithelium and in proliferation area of the embryonic brain.[22] Furthermore, the presence of the VDR in high levels in the developing brain substantiate the notion that vitamin D is involved in neurodevelopment.[23]

Vitamin D is a nuclear steroid transcription regulator and employs transcriptional control over genes. Vitamin D functions through two kinds of receptors: (i) the VDR, a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the MARRS receptor, also known as Erp57/Grp58.[24] Vitamin D mostly exerts its influence over numerous genes through VDR.[25] The VDR and the 1-α-hydroxylase, one of the enzymes associated with the synthesis of the active form of the hormone, have been detected in the human brain.[9] In a postmortem brain experiment of patients with Alzheimer’s disease (AD) or Huntington’s disease VDR was shown to be expressed in the human brain.[26],[27] Vitamin D metabolites have been found to cross the blood brain barrier and the combined discovery of the VDR mRNA and protein throughout the brain and spinal cord reinforced the importance of its role in regulating CNS functions. The VDRs have also been reported in the nuclei of Schwann cells and in peripheral neurons and Glia.[27] The intense expression of the VDR was also seen in large cells in the substantia nigra one of the largest groups of dopamine neurons in the brain. The presence of vitamin D metabolites, activating enzymes and the VDRs in the CNS shows that vitamin D plays a role in maintaining normal brain function. It has been proposed that it can act as a neuro-protector for epilepsy, multiple sclerosis (MS), Parkinson’s disease (PD), and chronic stress to certain extent. Vitamin D deficiency during developmental stages (Developmental Vitamin D, DVD) has been suggested as a risk factor for several psychiatric disorders of developmental origin, such as schizophrenia and autism. In short, this gene regulation has distinct part to play in shaping brain development and ongoing function.[28],[29]

Causes of Vitamin D deficiency

Vitamin D3 is formed in human by exposure of the pre-vitamin cholesterol-related precursors in the skin to UVB then undergoing thermally induced transformation. Various factors affect skin synthesis of vitamin D3. People residing in latitudes above the equator the UVB accessibility is constrained to the summer. Skin D3 synthesis is only activated between ∼11am and 3pm in temperate climates from April/May to late September. Traditional and fully covered clothing, modern and indoor work lifestyle, use of sunscreens, contemporary transportation, sedentary lifestyle, indoor exercise all diminish skin exposure to UVB including the intentional avoidance of UVB exposure due to risk fears of skin cancers and melanoma altogether reduces the synthesis of vitamin D. Many elderly people spend significant amount of time indoors than outdoors when compared to younger age people.[30] Ageing reduces the skin capacity to synthesize vitamin D.[31] Older people’s skin makes approximately one-third of the vitamin D than the youthful skin exposed to equal doses of optimal UVB wavelength.[32] Collectively, these factors contribute to vitamin D deficiency.

Sun exposure: The most important source of vitamin D is sunlight accordingly it is mostly referred to as “sunshine vitamin”. Anything that reduces the transmission of solar UVB irradiation into the earth’s surface or anything that obstructs the infiltration of the UVB into the skin will affect the synthesis of vitamin D. Increased skin pigmentation can reduce the synthesis of vitamin D as well since melanin is very efficient in absorbing UVB radiation. Sunscreens with a Sun Protection Factor (SPF 15) and above are able to absorb nearly 99% of the UVB irradiation thusly lessening the synthesis of vitamin D, therefore most African Americans who live in a temperate climate are vitamin D deficient, whereas Africans living near the equator their vitamin D3 synthesis is more efficient because of the higher flux of UVB photons.[33] The amount of UVB photons getting to the earth’s surface depends on the angle at which the sun’s radiation reaches the earth. Henceforth, when the Zenith angle increases in winter time little synthesis of vitamin D takes place during early morning and late afternoon.[34] The practice of purdah where the women are fully covered put them in danger of vitamin D deficiency condition and partially expounds why in the sunniest regions of the world (few being traditionally conservative cultures like the GCC) vitamin D deficiency is very common in both children and adults.[35]

Diet and nutrition: Dietary inadequacy usually results from nutrients deficiency, compromised absorption and use, increased person’s requirement, and/or amplified excretion. Over time, vitamin D deficiency occurs when intake is lower than the recommended levels, sunlight contact is limited, conversion of 25(OH) D3 to its active form is impaired, or absorption of vitamin D by the digestive tract is compromised. The principal natural (unfortified) dietary sources of vitamin D are oily fish (salmon, mackerel, and sardines), cod liver oil, liver organ meats, and egg yolk. Vitamin D-deficit diets such as strict dairy-free regime, ovo-vegetarianism, veganism, or those who suffer either from milk allergy or lactose intolerance run greater risk encountering vitamin D deficiency. Gulf countries traditional diet comprises primarily of dates, milk, rice, brown bread, vegetables, whole wheat, meat, and fish. Additionally, the practice of fasting and current day unhealthy foods choices such as fried foods and burgers which are low in vitamin D could be few of the reasons for prevalent hypo-vitaminosis in the GCC countries.[36]

Vitamin D bioavailability and affecting factors: The bioavailability of vitamin D is assumed to be a function of various factors such as absorption, transportation elements, and metabolism. Nevertheless, research in this area is scant and at times contradictory. There are various factors hypothesized that potentially affect the upper gastrointestinal tract absorption of vitamin D in humans. Some of these factors that are assumed to affect its absorption efficiency [37],[38],[39] are the following:
  1. Gastrointestinal tract − digestive tract acidic pH and enzymes.
  2. The physiochemical state of vitamin D − dietary vitamins D2 (ergocalciferol) and D3 (cholecalciferol) are apparently absorbed with similar efficiency by the gastrointestinal tract, however, the D3 molecular form appears more effective at enhancing blood levels of calcifediol perhaps due to higher metabolic clearance of D2 form. The liver metabolite hydroxylated form 25-hydroxyvitamin D (25(OH)D) is better absorbed than the non-hydroxy vitamin D2/D3 forms may be due to the molecule polarity differences.
  3. Food − the food amount or matrix seems to have negligible effect on vitamin D bioavailability. The amount of fat with which vitamin D is ingested does not seem to significantly modify the bioavailability of vitamin D3, likewise fatty acids amount or type and dietary fibers (though some literature suggests otherwise).
  4. Human situation − conditions like age, heaviness, disease state, genetic background, gut secretions, host nutrients interactions or the type of delivery vehicle/formulation, and presence of fat inhibitors possibly impose variation on vitamin D bioavailability.


Lack of food fortification: Studies have revealed that the Gulf regions do not have a large range of vitamin D fortified foods.[40] For instance, in Saudi Arabia, fortified foods are narrowed to handful of dairy products and cereals.[41] In the majority of the Middle Eastern countries, legislation mandates wheat flour fortification. Yet, some countries such as Lebanon and Syria have no fortification of any type of wheat, while Qatar and the UAE have voluntary fortification.[42] A survey disclosed that without food fortification or use of supplements less than 10% of vitamin D is derived from dietary sources.[43] The Ministry of Health of the Kingdom of Bahrain along with the World Health Organization assessed the feasibility of adding vitamin D to the fortification profile of wheat flour due to an apparent spread of deficiency of this vitamin in the population. Fortification of wheat flour with vitamin D seems to be a feasible intervention to tackle low serum vitamin D concentrations in Bahrain. The standard numbers GSO 1347/2002 and GSO 785/1997 establish that vitamin D at 300-400 IU/L should be added to pasteurized, flavored, sterilized milks, and yoghurt. Standard GSO 1754-5/1998 considers the voluntary addition of vitamins A and D in oils. The proposed addition rate of vitamin D3 will provide 550 IU per kilogram of wheat flour. This level aligns closely with the current standard for fortified wheat flour by the GCC Standardization Organization (GSO) standards body. The existing GCC standards for wheat flour, which include the addition of vitamin D, can be used by the responsible government ministry for revising the current regulation and legislation. The reported prevalence of inadequate or low levels of serum vitamin D in Bahrain and the unreported but apparently high use of supplements among population, make important to consider if the technically feasible levels proposed to be added in wheat flour, will have a significant impact on prevalence of low levels of serum vitamin D.[44]

Others: Ageing is another factor associated with vitamin D deficiency because of declined levels of 7-dehydrocholesterol, the precursor of vitamin D3 in the skin. Skin’s ability to synthesize vitamin D is reduced by more than 50% at 70 years of age compared to 20 years of age. With ageing, the body only retains ≈25% of what a young adult has of 7-dehydrocholesterol thusly, being with 75% reduced biosynthesis capacity of vitamin D3 in the skin.[45] Age ostensibly does not affect vitamin D absorption efficiency.[39]

Persons suffering from obesity display vitamin D deficiency as well.[46] Use of obesity drugs like Orlistat (tetrahydrolipstatin a lipase inhibitor) and artificial fats like the sucrose polyester Olestra probably diminish vitamin D absorption.[39] People who have undergone bariatric surgeries are unable to absorb vitamin D therefore becoming deficient at some future point. Fat malabsorption disorders, nephrotic syndrome, hyperparathyroidism, chronic granuloma-forming disorders, some lymphomas are also among the common causes of vitamin D deficiency.[47] Individuals on a wide range of medications for HIV/AIDS, anticonvulsant/anti-seizure drugs and glucocorticoids are at risk for vitamin D deficiency as these drugs enhance the catabolism of 25(OH)D and 1,25(OH)2D.[46]

Involvement of Vitamin D in brain health and diseases

Vitamin D is widely recognized to play a crucial role in the nervous system health and disease conditions. Vitamin D contributes to neurotrophic support, neurotransmission, neuroprotection, and neuroplasticity [Figure 2].
Figure 2 Diagram showing vitamin D crucial role in the nervous system health and disease conditions. Vitamin D contributes to neurotrophic support, neurotransmission, neuroprotection, and neuroplasticity.

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Neurotrophic: The neurotrophic role of vitamin D was first demonstrated from in vitro studies which indicated that vitamin D3 is involved in the synthesis of nerve growth factor (NGF). Further in vivo studies in models of adult rats established that vitamin D3 upregulated the expression of glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) and downregulate the expression of neurotrophin-4 (NT-4), and it also revealed that it participates in gene expression regulation of the low-affinity NGF neurotrophic receptor, p75NTR. In an experiment where vitamin D was added to the cultured embryonic hippocampal cells enhanced neurite outgrowth and NGF production were observed.[12]

Neurotransmission: Vitamin D3 and its metabolites are responsible for mediating the synthesis of various neurotransmitters like dopamine, serotonin, catecholamine, and acetylcholine. Several studies have suggested that vitamin D3 affect changes in neurotransmitters level and that this influence have a transgenerational impact. In a rat study treated with vitamin D3 during the neonatal period it caused increase in dopamine levels beyond the exposure period leading to the effect being transported to the offspring of these treated rats,[48],[49] thus having a genetic imprinting effect.[50] Other studies have also proposed epigenetic regulation effect of vitamin D converting enzymes.[51] For instance, exposure to vitamin D early on in life (or lack thereof) may induce epigenetic alterations that affect gene expression consequently possible susceptibility to neurodegenerative diseases later in life.[52]

Neuroprotection: 1, 25(OH)2D3 is described to have neuroprotective role because of its ability to regulate certain neurotrophic factors and influence inflammation. Pre-treatment with 1, 25(OH)2D3 displays pleiotropic effect. It causes plummet in glutamate-mediated cell death in cortical[53], hippocampal,[54] and mesencephalic neurons cultures [55] decreased L-type calcium channel expression [56] and increased VDR levels.[53] In addition, it causes reduction in reactive oxygen species (ROS) induced cell death through controlling proteins that either decrease the levels or inhibit the toxicity of ROS, or that increase antioxidant species in glia and neurons. Taken together, these results validate the neuroprotective role of 1, 25(OH)2D3. The mechanism for neuroprotection is thought to be through the regulation of NGF, which is known to act on cholinergic neurons in the basal forebrain, and the GDNF, which is known to act on basal ganglia dopaminergic neurons, leading to neuroprotection of these neuronal subtypes in cognitive impairment and PD patients. Various animal studies have shown that vitamin D or its metabolites reduce neurological injury and/or neurotoxicity and involve diverse mechanisms summarized below:
  1. through presumed GDNF upregulation as indicated by the reduction of the size of cerebral infarction in adult male Sprague-Dawley rats; [57]
  2. by NGF depletion prevention via the preservation of mechanical hyperalgesia in a streptozotocin-diabetic rat model;[58]
  3. by means of decreasing neuronal death caused by calcium-mediated neurotoxicity through downregulation of L-type voltage-sensitive Ca2+ channels in rat fetal hippocampal cultures;[56]
  4. by way of sequestrating free radicals and ROS herein the reduction of dopamine neuronal toxicity and hypokinesia was observed in a rat model of 6-hydroxydopamine-induced neurotoxicity;[59],[60]
  5. as a consequence of oxidative stress reduction by facilitating antioxidant cellular functions such as enhancing intracellular glutathione concentration per cultured rat mesencephalic dopaminergic neurons treated with glutamate and dopaminergic toxins;[61],[62]
  6. via regulation of gene expression, to illustrate, in cultured rat cortical neurons protection against glutamate neurotoxicity (glutamate-induced cell death) is achieved by VDR upregulation (increased mRNA expression).[53] Another example, gamma-Glutamyl transpeptidase (g-GT) in astrocytes which plays a vital role in CNS detoxification pathways (removal of reactive oxygen and nitrogen species − ROS/RNS like nitric oxide). In astrocyte primary cell culture, the augmented expression and specific activity of g-GT leads to enhanced intracellular glutathione pool thus nitrite reduction.[63] Yet another case, in a rat model of brain inflammation the ability to downregulate the expression (at the mRNA and protein levels) of inducible nitric oxide synthase (iNOS) and subsequently nitric oxide.[64]


Neuroplasticity: Studies utilizing gene array and proteomics of adult rat brains deprived of vitamin D during gestation period have shown that numerous genes are involved in CNS development are differentially regulated.[23] Paucity of vitamin D has been shown to affect the transcript profiling of multitude of genes [23],[65] including cytoskeletal maintenance, mitochondrial function, synaptic plasticity, and cellular proliferation and growth.

Analysis of neuronal expressed genes highlights the involvement of vitamin D and VDR system in neural development, in areas of neurite and axonal outgrowth and retraction, dendritic spine morphogenesis, axonal guidance, actin-filament and microtubule reorganization, integrin mediate adhesion, and growth cone spreading and collapse.[53],[65],[66],[67],[68],[69] Neural developmental regulatory genes are impacted by the deficiency of vitamin D during gestational period as well potentially exhibiting an impact on the phenotypic expression of neurodegenerative disease.[11]

Neurodegeneration and neurobehavioral disorders: Despite contradictory findings on low vitamin D health parameters, there are compelling signs to suggest that diet deficient in vitamin D combined with inadequate sun exposure have the potential to trigger various conditions, not only the well-known ones such as rickets and osteomalcia but also neurocognitive disorders, Amyotrophic Lateral Sclerosis (ALS), AD and PD. [Figure 1] depicts pathways that have been suggested to be directly hinging on vitamin D homeostasis and when there is a vitamin D deficiency many neurological disorders manifest including neurobehavioral ones. Moreover, there is strong evidence to support the notion that with a vitamin D-deficient diet, several neurobehavioral disorders are supposed to ensue. Vitamin D plays a key role in the regulation of neuroprogenitors cells, the proliferation and differentiation of the nervous tissue, and the control of the CNS metabolic pathways during embryogenesis.[70] Vitamin D is engaged in regulating, directly and/or indirectly, a very large number of genes (0.8–5% of the total genome) involved in a variety of cellular functions which encompass growth regulation, DNA repair, differentiation, apoptosis, membrane transport, metabolism, cell adhesion, and oxidative stress.[71] Some of these genes are involved in CNS development such as RhoA, microtubule associated protein-2 (MAP2), growth associated protein-43 (GAP43), neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), ATPase H+ transporting V1B2, Mn-containing superoxide dismutase (MnSOD), cytochrome c (Cyt C), catalase, aquaporin-4, apolipoprotein B (ApoB), myristoylated alanine-rich C kinase substrate, DNA-damage-inducible 45 alpha (GADD45A), growth arrest specific 5 (GAS5), insulin-like growth factor 1 (IGF-1).[53],[65],[66],[67],[68],[69] Finally, an unbalance in vitamin D homeostasis can affect its functioning in neuroplasticity, neuroprotection, neurotransmission, dopamine system as explained in [Figure 2].

Prenatal vitamin D deficiency potentially is a risk factor for schizophrenia according to some scholarly opinion. [72] Low levels of vitamin D during neuroformation could interact with susceptibility genes ZNF804A[73]; vitamin D clearly has a crucial role in mediating the effects of nutrition on brain function. Their receptors act as transcription factors interacting with multiple genes and prompting epigenetic changes involving (histone modifications like acetylation and chromatin remodeling)[74] thus, modifying the development of the brain through epigenetic regulation and favoring the occurrence of psychosis. Gestational vitamin D deficiency during a critical developmental period can influence the phenotypic expression of neurodegenerative disease. [25] After calcitriol stimulation, 2,776 genomic positions are occupied by a VDR and that 229 genes display substantial changes in expression in response to vitamin D.[13] Vitamin D possess an epigenetic effect by regulating gene expression through DNA methylation or modifying histones where many persist into later life.[75] Animal studies on gene expression of adult, prenatal rat brain that experienced vitamin D deficiency led to an expansive alteration in the developing brain. For example, a dysregulation of 36 brain proteins involved in several biological pathways including oxidative phosphorylation, redox balance, cytoskeleton maintenance, calcium homeostasis, chaperoning, PTMs, synaptic plasticity, and neurotransmission was caused due to developmental vitamin D deficiency.[76] Mitochondrial dysfunction may be a consequence of impaired synaptic network and mitochondrial metabolisms have been associated with both multiple sclerosis and schizophrenia. Therefore, developmental vitamin D deficiency could be a potential risk factor.[67]

Offspring of maternally obese rodents also exhibit adverse long-term cognitive function effects largely the result of epigenetic mechanisms.[74] Animal models investigation indicated that expression of multiple genes in specific brain regions is affected, which might modify the developmental program of key fetal brain cell networks involved in neurological disorders in later life.[77] Indeed, diet impinges on histone modifications, ncRNAs and DNA methylation epigenetic modifications. The antioxidant polyphenol kaempferol acts as an inhibitor of oxidative stress and an inhibitor of histone deacetylase.[78] Kaempferol is known to be neuroprotective and promote memory retention. There is a remarkable connection between low levels of vitamin D and AD suggesting a role for vitamin D in brain development and function.[74] It appears that alterations in the epigenetic regulators, microRNAs, have an essential purpose in Alzheimer’s pathogenesis. Vitamin D exerts its effects on AD by regulating calcium-sensing receptor expression, regulating interleukin-10, downregulating matrix metalloproteinases (MMPs), suppressing the expression of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), enhancing amyloid-β peptides clearance, modulating the expression of vascular endothelial growth factor (VEGF), enhancing toll-like receptors, advanced glycation end products, and modulating angiogenin [Figure 2].[79]

Status of Vitamin D in the GCC

The aforementioned discussion supports the view that vitamin D is critically involved in the cascade of [Figure 3] biological system including, when its integrity is compromised, the development of neurobehavioral disorders. The geography has been suggested to play a role in this disorder. On one hand, the countries that lie in the lower latitude, that is away from the equator, have been documented to have high risk factors for vitamins where existing literature suggest they are strongly related to compromised integrity of functioning of vitamin D. Conversely, the populations who dwell in geographical entity ‘closer to the sun’ have been speculated to suffer less the vagary of lack of vitamin D.[42]
Figure 3 Vitamin D status key points. Vitamin D deficiency biological system manifestation.

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Vitamin D deficiency has become a public health concern affecting individuals across all life stages including pregnant women, neonates, infants, children, adolescents, adults, and the elderly. This has been observed throughout the entire Middle East countries. Arabian Gulf represents an interesting geographic region. It is part of rift valley where large basins drop in altitude. Such geologic rift has rendered the region to be hot and sunny by its closer proximity to the equator. Interestingly, some research have suggested that gulf populations, are likely to exhibit vitamin D deficiency despite the sun. Then again, lower level of vitamin D might stem from the lack of sun exposure as the sunlight is associated with inducing exhaustion and heatwave.[80],[81] Aesthetic reasons or socio-cultural teaching that impels the population to cover their body might also play part. It is also known that diet plays a minute contribution to the level of vitamin D in human’s body, and the lack of food fortification in the GCC in general and for vitamin D specifically might contribute to the prevailing deficit in the level of vitamin D.[42]

The GCC countries are comprised of Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the UAE. The ensuing paragraphs will summarize and interpret emerging literature on vitamin D deficiency in the GCC. The GCC region register some of the lowest 25-hydroxyvitamin D [25(OH)D] serum concentrations; worldwide vitamin D deficiency [defined as 25(OH)D levels lower than 50 nmol/L (20 ng/ml)] is most prominent in women of varying ages.[82]

UAE: UAE is located north of the equator, so it is located in the northern hemisphere (25° 15’ N, 55° 18’ E) receiving plenty of sunshine throughout the year. Vitamin D deficiency in the general population of UAE at various age groups remains alarmingly high. Vitamin D deficiency in UAE was found to be at 82.5% among Emiratis and expatriates. A 2012 UAE study found that the incidence of hypo-vitaminosis in women, irrespective of their dressing style, was highest in those covered but face exposed.[83] A recent study conducted in the UAE showed that 64% of subjects were vitamin D deficient, 26.5% were vitamin D insufficient and only 9.5% were vitamin D sufficient among their 237 study subjects. Further, the authors found that vitamin D deficiency was highly prevalent in the younger age group (21–30 years) and in females than males.[84] Another study has suggested that the sunlight exposure is very less or in some cases it is absolutely nil.[85]

Saudi Arabia: Saudi Arabia is positioned above the equator (25°00′ N, 45°00′ E) located in the northern hemisphere. The prevalence of hypo-vitaminosis D in Saudi Arabia is significantly high. The overall prevalence of vitamin D deficiency (<50 nmol/L) in Saudi Arabia from 2011 to 2016 is 81.0%.[86] In a study where 10,709 patients were analyzed the rate was 83.6% and it is especially high among women.[87] A separate study corroborated the high prevalence of hypo-vitaminosis D results among Saudis than expats living in the same geographical area with very similar diet type implying a genetic link influencing vitamin D levels.[88] A recent meta-analysis study revealed that the vitamin D deficiency is approximately 60% only and not 100%.[89] Additionally, this study concluded that there are other factors that are possibly influencing vitamin D deficiency among Saudis besides genetic reasons. The main contributing factors were diet and limited sun exposure. A recent cross-sectional study conducted on 257 pre-menopausal women (aged 20–50 years) in Jeddah, Saudi Arabia, indicated that 65% of the population studied were below the estimated average requirement (EAR) of 400 IU/Day of vitamin D, which is largely due to limited sunlight exposure among women because of their traditional clothing which essentially covers most of the body.[90] A multiplier effect is the region’s very hot weather that further restricts outdoor activities vis-à-vis limited sun exposure. Therefore, dietary intake represents the foremost source of vitamin D among Saudis.

Bahrain: Bahrain is located north of the equator (26° 13’ N, 50° 34’ E) and has an alarmingly high rate of vitamin D deficiency in the general population. In a Bahraini study conducted on apparently 500 healthy subjects, the prevalence of those whose 25(OH)D serum level fell below 50 nmol/L was 86.4%.[86] In a cross-sectional study performed on a 500 healthy Bahraini cohort, with equal distribution of gender, aged 15-65 years with no obvious history of major health problems, vitamin D deficiency was ominously higher in females 169 (67.6%) than males 78 (31.2%).[91] The prevalence of vitamin D deficiency among the younger age group, <30 years, 139 (53%) was significantly higher than the older age group, >30 years, 108 (45.4%) as well. Vitamin D deficiency was pointedly higher during the period October to March (n = 121 (69.2%)) than the period of April to September 41 (12.5%).[92]

Qatar: Located in the Middle East, Qatar is situated in the northern hemisphere as well as the eastern hemisphere, located above the equator (25° 30’ N, 51° 15’ E). Qatar like other GCC states is experiencing a rise in prevalence of non-communicable diseases (NCD). This increased frequency has been attributed to two reasons: 1) genetic predisposition and 2) fast shifting socio-economic growth-related changes.[93] The literature suggests that low serum vitamin D levels as a factor impelling the development of a range of chronic conditions such as obesity, metabolic syndromes and cardiovascular disease.[93] In 2012, Badawi and colleagues conducted a systematic review on vitamin D insufficiency in the Qatari population. [94] This study reported weighted-average vitamin D concentration (±SD) of 45.3±14.3 nmol/L (95% CI: 44.6–46.0; range 29.2–66.9 nmol/L). The weighted-average prevalence of low vitamin D status was 90.4% (95% CI: 90.1–91.0; range 83%–91%). The male to female ratio was 1:1 and found that vitamin D levels have inverse correlation with age and direct association with its insufficiency/deficiency prevalence. The oldest age group when compared to the youngest had approximately 50% lower concentration of vitamin D. In a study done on Qatari children aged 11–16 years the prevalence of vitamin D deficiency was reported to be 68.8%, mostly among girls (51.4%) than boys (48.6%).[95] A clinical study conducted in Qatar highly recommended vitamin D supplementation without exception to Qatari infants and young children.[96] Among the elderly, a retrospective study on 889 elderly patients’ ≥65 years of age the majority of whom being females (66%) that were recruited from geriatrics facilities indicated high prevalence of vitamin D deficiency (72%). Additionally, it is noteworthy to mention that poor vitamin D levels were associated with higher HbA1c and lower HDL concentrations suggesting NCD higher risk in the Qatari population.[94]

Recently, Qatar University presented information suggesting that 80% of the Qatari population suffers from one form or another from low levels of vitamin D.[97] This is corroborated independently by an earlier Qatar Biobank (QBB) presentation where 86% are considered vitamin D deficient [98](QBB Conference 2017). However, in a recent analysis by Al-Dabhani [96] from a cross-sectional study of 1,205 participants (aged 18–80 years) from QBB samples, the prevalence of vitamin D deficiency was concluded to be very high in Qatar (64%, [<20 ng ml−1]) with more men being deficient (68.6%) than women (61.3%) despite being a country with almost year around sunshine. The authors also observed positive correlation between waist circumference, HDL, and high triglyceride levels with vitamin D deficiency hinting to an association with metabolic syndromes or increased odds of NCD risk. In a cohort of 523 middle-aged Arab women from Qatar the prevalence of vitamin D deficiency was observed to be 84.7%.[86] In another study of 340 healthy healthcare professionals volunteers it was found that women had lower levels (10.3 ng/ml) of vitamin D than men (13.7 ng/ml) and it showed that 97% of all participants had a mean level <30 ng/ml. Overall, only 2% had an optimal level of vitamin D (>30 ng/ml). Further, 87% of the sample had a mean level of <20 ng/ml.[99] In a cross-sectional investigation of Qatar University females (n = 92) aged 19–27 years old, severe deficiency (<10 ng/ml) and insufficiency (10-30 ng/ml) in vitamin D were reported in 53.5% and 43.6% of the participants, respectively.[100] A prior study on post-menopausal Qatari women revealed that only 14.6% had a normal vitamin D level.[101] A more recent cross-sectional study in menopausal and postmenopausal women ([n = 1,106] aged 45–65 years) found considerably lower levels of vitamin D among these women and a strong association between vitamin D level, bone mineral density and depressive symptoms in Arab women residing in Qatar.[102]

In a series of research papers, Bener and his colleagues[95] explored the role of vitamin D deficiency in few chronic conditions in Qatar and determined the validity of vitamin D deficiency as a risk factor. In a matched case-control study they demonstrated high prevalence of vitamin D deficiency among children with type 1 diabetes compared to children without diabetes and that these children their family history also showed substantially higher deficiency as well. The subjects were Qatari nationals male and female aged below 16 years. In another case and control study (2,224 subjects above 30 years of age) vitamin D deficiency/insufficiency along with other variables were significant predictors of diabetes.[103] In a similar cohort case and control study (546 subjects per group aged 25-65 years), which examined the relationship between vitamin D deficiency and type 2 diabetes indicated association of low vitamin D levels with thyroid disease among patients with diabetes and that it is an increased risk predictor of thyroid disease and cancer.[104] An earlier study addressing adverse pregnancy outcomes revealed that maternal vitamin D deficiency during pregnancy is significantly associated with elevated risk for gestational diabetes, iron deficiency/anemia, and preeclampsia.[105] In a previous study of 635 patients with breast cancer, the authors showed a high prevalence of vitamin D deficiency and osteoporosis plus significantly lower dietary intake of vitamin D and calcium in the cohort.[106]

An intriguing link to allergy and asthma was also discovered by this group. In a case-control study of 483 subjects under 15 years old they observed high prevalence of vitamin D deficiency among patients with allergy and asthma with the vitamin D serum level differences between asthmatic patients and controls being statistically significant. Herein, lower vitamin D levels were also associated with more allergic conditions and elevated serum IgE, [107] thus an indicative evidence for asthma and allergy risk. In a follow up work with further analysis on this cohort, the authors confirmed the considerably reduced serum vitamin D levels compared to healthy children with 68.1% of all asthmatic patients were vitamin D deficient moreover, they concluded that vitamin D deficiency was the strongest forecaster of asthma in this population (OR = 4.82; 95% CI 2.41–8.63, p < 0.001).[108] Later, in an expanded cross-sectional study on 1,833 subjects under the age of 16 years the group reported severe vitamin D deficiency was meaningfully higher in children suffering from asthma/allergy than healthy children. Furthermore, there was a significant correlation with asthma (OR = 2.31; p < 0.001), and allergic rhinitis (OR = 1.59; p < 0.001).[109]

It has been proposed that reduced vitamin D level might be a risk factor for autism spectrum disorder (ASD).[110] In a couple of key research papers, Bener and colleagues not only established that vitamin D deficiency was higher in Attention Deficit Hyperactive Disorder (ADHD) children (mean = 16.6 ± 7.8 ng/ml) compared to healthy children but also there is a significant association between ADHD and vitamin D deficiency (OR = 1.54; 95% CI 1.32–1.81; p < 0.001).[111] These studies were case-control conducted on 1,331 children below 18 years of age where only 8.1% of ADHD patients had sufficient serum vitamin D concentrations (>30 ng/ml).[111] Extending their work to autism though to a smaller sample size (254 case-control from highly endogamous population) revealed that 86.2% had vitamin D levels <30 ng/ml with statistically significant differences between autism and control individuals with respect to vitamin D serum concentration.[111] In another case-control study on 308 subjects they showed that serum iron deficiency (mean = 74.13 ± 21.61 µg/dL) and serum vitamin D levels (mean = 18.79 ± 8.35 ng/ml) are both robust predictors and major factors associated with ASD.[112]

In summary, the vitamin D deficiency status in Qatar is analogous to that of the other GCC States. Despite the sunshine, exposure seems limited. In addition, dietary intake of vitamin D or supplementation is very poor. These and other factors contribute to high prevalence of vitamin D deficiency in its various forms among the population. What is more, females in the region seem to extra susceptible or suffer more than males from vitamin deficiency which partly can be explained due cultural practices. Another female segment in the population that appears to be sensitive and experience vitamin deficiency is post-menopausal, menopausal and pregnant women. On the other hand, children and infants seems to be truly vulnerable and encounter vitamin deficiency particularly with a family history of low vitamin D. Vitamin D deficiency also is a risk factor and correlates with several conditions such chronic diseases (diabetes and cancer), asthma/allergy, and neurodevelopment disorders like autism and ADHD. Indeed, numerous surveys, investigations, and organizations recommend supplementation plus diet modification as an effective strategy for reducing the risk of vitamin D deficiency. This area warrants further research to verify some of these findings and shed light on the link between vitamin D deficiency and NCDs.

Kuwait: Located north of the equator (29° 30′N, 47° 45′ E) data from Kuwait’s first National Nutrition Survey of the State of Kuwait (NNSSK) suggests a very high prevalence of vitamin D deficiency midst Kuwaiti adults. The NNSSK, with 960 adults enrolled, examined vitamin D status in association with the prevalence of diabetes and pre-diabetes. About 56 % of the Kuwaiti adults had vitamin D inadequacy (25(OH)D = 12–19.9 ng/ml), and 27 % had vitamin D deficiency (25(OH)D < 12 ng/ml).[113] In Kuwait, vitamin D deficiency prevalence was 83.0% based on a the recent national survey.[113] In another study, performed on 50 veiled volunteers and 22 unveiled volunteers Kuwaiti women aged between 14 and 45 years who had three children or less, it documented a high prevalence of vitamin D deficiency midst veiled Kuwaiti women.[114] High prevalence of vitamin D deficiency was noted among adolescents in Kuwait. It was observed that the prevalence of vitamin D deficiency was 81.21%, while severe deficiency [(25-OH-D levels <25.0 nmol/L) ≈10 ng/mL]was 39.48% and only 3.60% of adolescents were vitamin D-sufficient in a cross-sectional study which was recently completed on 1416 adolescents aged 11–16 years from middle schools in all governorates of Kuwait highlighting that the prevalence of vitamin D deficiency was significantly higher among girls compared to boys.[115]

Oman: Even though Oman is close to the north of the equator (21° 00′ N, 57° 00′ E) thus offering the people opportunity to produce the sunshine vitamin D year round, still the population suffers from vitamin D deficiency chiefly because the exposure to direct sunlight is limited. This population registers some of the lowest levels of vitamin D and the highest rates of hypo-vitaminosis D worldwide were the prevalence of serum 25(OH)D deficiency/insufficiency reportedly varies between 30% and 93%.[116] The combination of fortified foods and foods rich in vitamin D consumption plus sunlight exposure are indispensable for maintaining a healthy vitamin D status. For certain sub-populations, vitamin D dietary supplementation might be necessary to meet the daily requirement. Importantly, like other countries, Omani diet was found to be lacking in necessary nutrients, high in fats (saturated fats and trans fats) and sodium. Some of the nutrients with low intake were fiber, vitamin D, zinc, and iron Omani youth are uninformed about food choices as unhealthy diet dominates the Omani table and sedentary activity is widespread. Lifestyle changes over the last three decades in Oman resulted in a dramatic alteration in the Omani diet.[117]

Women, when compared to men, had markedly lower concentrations of vitamin D and the prevalence of vitamin D deficiency in the studied Omani population was as high as 87.5%.[118] Vitamin D provided by foods and supplements are inadequate compared to the amount generated by skin exposure to sunlight. A study conducted by Al-Kindi in 2011 found[119] that 100% of the women in their study group had vitamin D deficiency. Furthermore, they stated that the combination of lack of sun exposure and lack of vitamin D through food sources were the primary reasons.

A 2007 report pronounced that Omani diet currently supplies on average 1.6 μg of vitamin D whereas the requirements are 4.5–9.0 μg per day. There is no information on sun exposure in Oman, which is a major contributing factor to vitamin D synthesis and individual’s status. As a result it is recommended that strategies to improve vitamin D standing should also focus on adequate exposure to the sun.[117] Lack of awareness and due to cultural reasons body remains fully covered which again does not expose the skin to sunlight leading to lack of sunshine vitamin in the body.[119] A recent cross-sectional study among 309 female students of A’Sharqiyah University, Ibra, Oman was done to assess the knowledge, awareness, and basic concepts about vitamin D along with attitudes and behavior practice toward sunlight exposure among Omani female students which demonstrated ignorance, confusion, lack of awareness, inconsistent knowledge, blasé attitude, and negative approach toward sunlight exposure, especially among the female students. Additionally, the study suggested that a negative approach toward exposure to sunlight and use of sunscreen products and ointments would prevent them from obtaining the benefits of sunlight and predisposes them toward vitamin D insufficiency rather than deficiency status.[120]

Similar research found that 33% of subjects experienced vitamin D deficiency while 67% were at risk.[121] An investigation on healthy Omani school children (age 9–10 years) have reported severe vitamin D deficiency (<27.5 nmol/L; 10.5% boys and 28.5% girls), medium deficiency (27.5–44.9 nmol/L; 47.6% boys and 49.4% girls) or insufficiency (50–74.9 nmol/L; 34.6% boys and 21.5% girls) in the school population. Only 7.3% of the boys and 0.6% of the girls had a sufficient vitamin D level (≥75 nmol/L). Overall, vitamin D deficiency was greater in girls than boys. Since childhood is a period of skeletal mineral acquisition and bone modelling with vitamin D playing a vital role in muscle growth, cognitive function and adaptive immunity the high prevalence of vitamin D deficiency in school age children is a major public health concern.[122] Another study conducted on Omani children 9–12 years old investigated health-related fitness, body composition, and vitamin D in 54 girls and 42 boys conveyed that 82% of the females and 42% of the males were deficient in vitamin D (<50 nmol/L). Females deficient in vitamin D had higher fat percentage compared to those with normal vitamin D status.[123] A study performed on 41 healthy Omani women of child bearing age 18–45 years old revealed that all the participants had suffered from vitamin D deficiency (<50 nmol/L) and it was due to inadequate sun exposure and food intake.[119]

The latest Oman National Nutrition (ONN) survey was carried out in 2017 to measure the prevalence of several nutrition-related conditions including vitamin D. The group comprised children below 5 years of age and pregnant and non-pregnant women 15–49 years of age. It was observed that in children below 5 years of age, 8.5% were deficient and 53.4% of them had vitamin D insufficiency. In non-pregnant women, the prevalence was 16.4% for deficiency and 41.5% for insufficiency [Figure 4].[124]
Figure 4 Vitamin D status in Oman. Prevalence of vitamin D deficiency in Oman. Studies from 2011-2017.

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Groups at risk of Vitamin D deficiency

[Figure 5] depicts a summary of the main high-risk groups in vitamin D deficiency [Figure 5].
Figure 5 Groups at risk of vitamin D deficiency disease. Clusters of the vitamin D deficiency main high risk groups.

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Breastfed infants: Human milk vitamin D content is related to the mother’s vitamin D status. So, mothers who have satisfactory vitamin D levels may have correspondingly reasonable levels of this nutrient in their colostrum. Infants depend on dietary vitamin D or sunlight exposure for meeting their vitamin D requirement. Mothers, who are vitamin D deficient, have poor vitamin D status or concentration reaches subnormal levels, in turn, this will adversely affect the newborn/infant vitamin D state as the infant depends on the mother for its vitamin D.[125] Since human milk naturally contains very low levels of vitamin D, infants are hence prone to developing vitamin D deficiency when solely fed or completely dependent on human breast milk.[126] In a study conducted in the UAE on 90 exclusively breastfed infants and their mother 82% of the infants had hypo-vitaminosis D and the median serum concentration of 25-OHD was 11.9 nmol/L.[127] Hence, it is recommended by the American Academy of Pediatrics to supplement 400IU/day of vitamin D shortly after birth and continue to receive these supplements until they are weaned and continue to consume ≥1,000 ml/day of vitamin D-fortified formula or whole milk during infancy.[128]

Female gender: In an intense review of 103 articles from PubMed/Medline published in the last 10 years it was universally advocated that vitamin D deficiency is a global problem in all age groups. Particularly, it was gathered that it is more prominent in women and girls in the Middle East.[116] Middle Eastern and some South Asian countries where similar practices are followed women experience higher rates of vitamin D deficiency (prevalence ranges between 30 and 90%) than men due to their darker skin tone, limited sun exposure and lower ingestion of vitamin D food sources. It looks as if that skin pigmentation probably poses the prime risk factor in vitamin D deficiency regardless of the sun exposure as concluded in a study done on Arab populations were 108 women aged 18–45 yrs. living in the United Kingdom (around 51° North) were analyzed. A total of 43 consistently covered arms, hair, and neck when outdoors, whereas 65 consistently had arms, hair, neck, and possibly legs exposed.[129] [130] Another study showed that Emirati (UAE) women have more vitamin D deficiency than western women living in UAE.[40] In a study done on Saudi women about 83 % had low levels of vitamin D and complained of back pain. Women cultural norm practices in the Middle Eastern ranging from covering the whole/part of the body to indoor residence/activities are considered vitamin D deficiency risk factors.[40],[93] Women in the Middle East (70%) have more deficiency of <25 nmol/L of serum vitamin D than men (40%). On the other hand, men are routinely being exposed to sunlight partly because of their work/outdoor environment.[41] [131] About 70.5% of veiled women were deficient in comparison to unveiled women at 48.9% and severe deficiency level of serum vitamin D (12.5 nmol/L) commonly prevalent among a certain group of women.[132] Low serum vitamin D levels more prominent in female gender might be a result of differences in clothing most men were wearing lighter clothing than women and sun exposure.[131] According to Oman National Nutrition survey 2017, homebound women and women who wear long robes and head coverings for religious reasons, pregnant and non-pregnant women 15–49 years of age, and those who use sunblock, are vitamin D insufficient.[124] National Nutrition survey recommends reducing the prevalence of vitamin D deficiency in women of reproductive age and children and fortification compliance of flour, bread, and oil.

Older adults: Older adults are at high risk of developing vitamin D deficiency. As a result of aging the skin cannot synthesize vitamin D as efficiently. Also elderly spend a lot of time indoors and their diet may not be sufficient enough to adequately provide the daily requirement of vitamin D.[126] Interestingly, the intestinal absorption of vitamin D is not affected with aging. While hydroxylation at the C-25 position in the liver is not affected by aging,[133] age-related functional limitations of the kidneys reduces the ability for the hydroxylation at the C-1 position, and is less responsive to the parathyroid hormone stimulation of CYP27B1.[133] Illness related vitamin D deficiencies (levels 25(OH) D <30 ng/ml) are common in older persons. Illness could also lead to malnutrition which could be a causative factor not only for vitamin D deficiency, but for other fat and water-soluble vitamins that are important for neurocognitive function.

People with limited sun exposure: Lifestyle and living space have major impact on vitamin D status. With urbanization, indoor-oriented lifestyle, from the type of residence to office-based work, UVB radiation exposure is not only restricted but also it does not penetrate through glass windows accordingly impeding production of vitamin D. Usage of sunblock, geographic latitude locations and winter season were sunlight is limited are other obstructing factors. Certainly, individuals under limited sun exposure require vitamin D supplementation along with rich dietary sources of vitamin D. Females are a more vulnerable population segment particularly those who exhibit sensitivity to the sun’s UV radiation. They are unwilling to get a skin tan, so avoid being directly or indirectly exposed to sunlight.[134] One of the most important predictors of hypo-vitaminosis D in developing countries is the lack of sun exposure. In another study among Saudi married couples reported that males were significantly exposing themselves to sunlight more than their female partners.[131] Sedentary lifestyle in the Gulf region is another reason for lack of sun exposure.[93] Limited sun exposure in the Middle East appears to be mostly due to clothing styles, cultural practices and less outdoor activity.[93]

People with dark skin: Large amount of melanin in the epidermis layer is the basis of having a dark skin and concomitantly it reduces the synthesis of vitamin D. People with a dark skin appearance require at least three to five times longer exposure period to make the same amount of vitamin D as a person with a white skin tone.[135] Therefore, consuming foods rich in vitamin D and use of supplements[135] would maintain normal serum levels of vitamin D. Darker complexion features in Saudi Arabia among the population is a reason to increase sun exposure period to achieve the necessary vitamin D levels.[41]

People with neuro cognitive disorders and other health conditions: VDR and CYP27B1 are widespread in important regions of the human brain including the hippocampus, which is particularly affected in people with neurodegenerative disorders as well as memory impairment[136] and polymorphisms of VDR gene are associated with cognitive decline in AD [137],[138], PD,[139],[140] and multiple sclerosis. Vitamin D and its metabolites are involved in other neuroprotective mechanisms including amyloid phagocytosis and clearance and vasoprotection.[141],[142],[143] Individuals suffering from Amyotrophic Lateral Sclerosis, Alzheimer’s, schizophrenia, depression, PD, and other neuropsychiatric disorders and cognitive disorders tend to have low levels of serum vitamin D (25(OH)Ds <20 ng/ml). Research has shown that supplementation with vitamin D, as an adjunct therapy, have been suggested to modulate symptoms of those targeted neuropsychiatric disorders.[144] There is also evidence to suggest that vitamin D supplementation has the potential to retard depressive symptoms among people who have records of low vitamin D.[145] There is also evidence to suggest that cognitive decline or mild cognitive impairment is strongly associated with the status of vitamin D. Schlögl & Holick (2014) have reported that with the presence of low indices (25(OH)Ds <20 ng/ml) tend to increase risk for cognitive decline which is often associated with functional and structural changes in the brain. Low vitamin D status has been linked to autoimmune disorders and multiple sclerosis.[32]

In addition to affecting higher functioning, the pathological input of physical illness have also been documented in individuals suffering from diabetes type2, cancer, hypertension, and cardiovascular diseases.[146] Conversely, supplementation of with vitamin D to these conditions have been recommended.[143] In a large clinical trial examining the effects of vitamin D supplementation on the prevention of cancer, the protective role of vitamin D have been postulated as it reduced 23% of cancer incidence in African American.[147] Vitamin D deficiency can lead to development of Metabolic syndrome.[148] In a study conducted in two large cohorts of women suggesting the protective effect of vitamin D intake on the risk of developing MS.[149] Llewellyn et al in a study done on cognitive impairment and relationship with vitamin D concluded that those with 25(OH)D <20 ng/ml there was an increased risk for cognitive impairment in compared to those with a 25(OH)D level >20 ng/ml.[150]

In short, low vitamin D levels have also been associated with various diseases like osteoporosis, autoimmune disorders, certain cancers, and with metabolic syndromes like diabetes type 2, where some of the highest rates are reported in the Middle East and the GCC predominantly. Also, it has been demonstrated that vitamin D plays a role in brain health. Lifestyle changes have fueled a global epidemic of vitamin D deficiency that may be driving MS incidence upward in young Islamic women.[151] Despite the skin ability to synthesize vitamin D from exposure to UVB irradiation most of the year, both rickets and hypo-vitaminosis D are highly prevalent in this region across all age groups when compared to the western populations. This is due to limited sun exposure, cultural practices, dark skin color, and low calcium intake.

People with inflammatory bowel disease and other conditions causing fat malabsorption and medication affecting vitamin D metabolism: Fat malabsorption is associated with a variety of medical conditions and since vitamin D is a fat-soluble vitamin its absorption in the gut depends on the intestines ability to absorb fat. Individuals with this condition might have lower intakes of certain nutrients, such as dairy products fortified with vitamin D prompting a risk of deficiency.[126] Individuals on any of these medications anti-seizure medications, glucocorticoids, AIDS medications, anti-fungal, for example, Ketoconazole, Cholestyramine are at high risk for vitamin D deficiency because these medications increase the catabolism of 25(OH)D by enhancing the activation of the steroid xenobiotic receptor that results in the destruction of 25(OH)D and 1,25(OH)2D often require at least two to three times more vitamin D (at least 6,000–10,000 IU/d) to treat and prevent vitamin D deficiency.[47] [8],[46],[126] It is recommended that adults and children on these medications should be given at least two to three times more vitamin D for their age group to satisfy their body’s vitamin D requirement.[126] In obese patients, patients with malabsorption syndromes, and patients on medications affecting vitamin D metabolism, a higher dose of at least 6,000–10,000 IU/d) of vitamin D is needed to treat vitamin D deficiency in order to maintain a 25(OH)D level above 30 ng/ml, followed by maintenance therapy of 3,000–6,000 IU/d.[126]

Obesity and surgery: People who are obese or who have undergone gastric bypass surgery their vitamin D levels tend to be lower with a body mass index (BMI) of >30 compared to non-obese individuals. Obesity affects vitamin D bioavailability related to factors such as vitamin D trapping in adipose tissue due to its lipophilic structure and enhanced fat solubility.[93] [46] In a group of healthy, white, obese individuals aged 38–39 years (BMI [in kg/m2] ≥ 30] and matched lean control subjects aged 34–36 years (BMI ≤ 25) that received either a pharmacologic dose of vitaminD2 orally or whole-body ultraviolet radiation suggested that obesity-associated vitamin D insufficiency was due to the decreased bioavailability of vitamin D3 from cutaneous and dietary sources because of its deposition in body fat compartments.[46] Obese adults were able to raise their blood levels of vitamin D by no more than 50% compared with non-obese adults when they were exposed to simulated sunlight or received an oral dose of 50,000 IU of vitamin D2.

Following gastric bypass surgery vitamin D deficiency can occur nevertheless it can prevail pre-operative as well. In 60 morbidly obese pre-operative females 25-hydroxyvitamin D (25-(OH) D) levels were examined. About 62% of the subjects had 25-OHD concentrations below the normal range (16–74 ng/ml). Unlikely that hypo-vitaminosis D was caused by the surgery per se since the condition may be present to some degree pre-operatively.[152] Obesity can be due to lack of physical activity and leading a sedentary lifestyle hence more time spent indoors leading to lack of sun exposure leading to vitamin D deficiency.[126] Individuals who have undergone gastric bypass surgery may become vitamin D deficient since the upper part of the small intestine were vitamin D is absorbed is bypassed. Henceforth obese individuals may need larger than usual intakes of vitamin D to achieve 25(OH) D levels comparable to those of normal weight.[153] For obese, individuals supplementation of 2000 IU/day is recommended if cutaneous synthesis of vitamin D is not there. The goal of consuming supplements is to attain and maintain serum 25(OH) D levels of 30–50 ng/ml.[154] Weight loss is associated with increased serum 25 (OH) D concentrations in overweight or obese women. Data from 383 overweight or obese women who participated in a two-year clinical trial of a weight-loss program 49% of the participants were deficient (25(OH) D below 20 ng/ml (50 nmol/L)) at baseline. By the end of the study 36% of all participants were deficient with surprisingly 17% of those who have achieved a normal BMI still being identified as deficient.[155] Unhealthy dietary patterns and environmental factors, technology and entertainment services all contribute to limited physical activities lifestyle correspondingly the rise in obesity in the GCC.[36] Family gatherings are very frequent in the Gulf countries with the habit and the tendency to cook and overeat. The large caloric quantities consumption pushes further the already high obesity rates in the gulf countries. Urbanized lifestyles and changes in the food habits in GCC countries from healthy food choices of dates, milk, fresh vegetables, or fruits, whole wheat and fish to unhealthy fast, imported foods that are low in vitamin D compounds is the problem.[36],[93]

Prevention and treatment of Vitamin D deficiency

Urbanization of the GCC countries and a lifestyle predominantly based on technology, overall less physical activity, lack of sunlight, and unhealthy dietary patterns have led to the prevalence of vitamin D deficiency in the GCC. It is estimated that 1 billion people worldwide are vitamin D deficient or insufficient.[156] Demographic factors have an impact on the epidemiology of vitamin D deficiency.[157] Gulf region countries (Bahrain, Kuwait, Iran, Iraq, Oman, Qatar, Saudi Arabia, and the UAE) though close to the equator have a high prevalence of hypo-vitaminosis 25-hydroxyvitamin D 25(OH) D levels < 30ng/ml).[158] Since few epidemiological studies on vitamin D deficiency in GCC are available data is limited. French population epidemiological studies show that 43 to 50% of the population have a concentration of 25OHD < 20ng/mL and about 80% have a concentration < 30ng/mL[159]. In patients with chronic diseases, but also in some categories of the general population such as adolescents and the elderly, the percentage of people with a concentration of 25OHD < 20ng/mL is often well above 50%.[159] Such studies target patients or risk groups who can benefit from vitamin D supplements. Two forms of vitamin D D2 (ergocalciferol) and D3 (cholecalciferol) are available as supplements and fortified food and can effectively raise serum 25(OH)D levels but at high doses vitamin D2 is less potent.[8],[160] Supplements of Vitamin D3 are available over-the counter at daily doses of 400, 500, 800, 1,000, 2,000, and 4,000 IU. Vitamin D3 is also available as multivitamin preparations, in composite calcium supplements, cod liver.[161] The American Academy of Pediatrics recommends that all children and adults up to the age of 50 years receive minimally, 200 IU vitamin D/d and adults aged 51–70 and ≥71 yrs receive 400 to 600 IU vitamin D/day [Figure 6]. The National Osteoporosis Foundation recommended that all postmenopausal women take 800–1000 IU vitamin D/day. Higher doses may be required if fat malabsorption, obesity, or other causes that would enhance vitamin D catabolism and reduce its bioavailability exist. Holick recommends that 50,000 IU vitamin D2 every 2 weeks or its equivalent will sustain 25(OH) D concentrations above 75 nmol/L to maintain vitamin D sufficiency.[34] According to the Institute of Medicine (IOM) report the upper intake levels for vitamin D are set at 2,500 IUs per day for children ages 1 through 3; 3,000 IUs daily for children 4 through 8 years old; and 4,000 IUs daily for all others. [162] Preventive measures to maintain normal serum vitamin D levels would include foods rich in vitamin D and exposure to sunlight 5–30 minutes per day of 215–315 nm of wavelength between 10 am to 3 pm.[134] Modest sun exposure proved to increase the vitamin D levels in Saudi male population. Media and primary health care centers should play a vital role in creating more awareness and knowledge about vitamin D in female population. Routine checkups for status of vitamin D in women and children and recommend supplementation if required. Prevention of this deficiency could have an enormous impact on reducing health costs worldwide.[156]
Figure 6 Prevention and treatment of vitamin D deficiency key points. Vitamin D recommendations and food sources.

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   Conclusion Top


Hypo-vitaminosis D is a major public health problem across all life stages in the Middle East with deleterious immediate and latent manifestations. In general, significant predictors of low 25(OH) D levels were female gender, aging and body mass index, veiling, winter season, use of sun screens, lower socioeconomic status, and higher latitude. Sunlight is abundant in the Middle East. More than 90% of our vitamin D is provided by sunlight and it is therefore obvious that those persons affected in the Arabian countries have little sunlight exposure and a diet deficient in vitamin D.

Prevalence of vitamin D deficiency was observed more in female gender and in children in the GCC region. Long-term strategies to address this are often silent. Action should include public education, national health policies for screening and prevention through food fortification, and treatment through vitamin D supplementation. Vitamin D plays a crucial role in skeletal and extra-skeletal systems and its role can be defined as a protective and/or prognostic factor in the onset and progress of neurological conditions and in health and disease. In the GCC, low vitamin D levels may be attributed to social and cultural factors such as the conservative dress of GCC and Omani women, especially those who wear the veil, as it blocks exposure to sunlight. Added to that, the reduction in outdoor leisure time that has accompanied urbanization in Qatar, Oman, and other GCC countries including cultural norms toward leisure activities in particular for women has led to lack of or limited sunlight exposure. Absence of awareness of the magnitude of hypo-vitaminosis D and its effects on health owing to delay in the clinical manifestation of vitamin D deficiency among the general population is another grave reason. Changes to women’s lifestyles to enhance sunshine exposure have been a continuing challenge. We believe, media and primary health care centers should play a vital role in creating more awareness and knowledge regarding vitamin D. Public engagement is important to combat vitamin D deficiency. Public health education campaign and activities on how modest sunshine exposure of the face and hands for 30 minutes three times a week in adults along with diet rich in vitamin D may be sufficient to produce adequate vitamin D stores and that sun exposure of 2 hours/week in infants can be beneficial in preventing hypo-vitaminosis D.

Due to increased prevalence of vitamin D deficiency in the GCC countries, a pressing need for legislation and a requisite exists to inform the general population about the source, use, and role of vitamin D in daily life. Public health policies are needed to be formulated and enacted in this area. Also, how skin pigmentation affects the absorption of vitamin D from the sun, skin coverage, dietary choices, supplements, adiposity, malabsorption, demographics, and lifestyle.[163] Further, there is an urgent need for a well-thought-out program which incorporates a fortification of foods and drinks favored by children and adults as well as promoting outdoor activities for children and adults to help tackle this major public health issue.[123] One of the recommendations of the Oman Nutrition Survey of 2017 was to reduce vitamin D deficiencies in women of reproductive age and young children by checking fortification compliance of flour, bread, oil. [124]

Acknowledgement

The authors want to thank their respective institutions for their continued support. The author (NS) thanks Sultan Qaboos University for offering her PhD fee waiver scholarship to do her PhD. The authors declare no conflict of interest. All the authors acknowledge the financial support given by SQU in the form of bench fees to author (NS) to fund the publication of this article.

Authors’ Contributions

NS, BB and LS performed research and collected information, and generated short write-ups. SA, MME and MWQ conceptual work, framework, draft write-up and editing. All authors read and approved the final manuscript.

Financial support and sponsorship

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of interest

The authors declare that there are no conflicts of interest.



 
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