Introduction

The essential role of vitamin D in bone health, immune function, and overall cell health links it to several health problems. Vitamin D deficiency (VDD) has been shown to result in an increased risk of skeletal fractures, infections, autoimmune disease, and cancer.[1]

VDD is considered a major health problem globally with people residing in places receiving more sun, also affected with it.[2] VDD has also been shown to be highly prevalent in different regions of Saudi Arabia across different age groups in both genders.[3-5] VDD prevalence in sickle cell disease (SCD) is 65–100% in countries such as the USA, Spain, and the UK. This is due to the increased frequency of hospitalizations, inadequate nutrition, and an increased energy expenditure, resulting in several comorbidities.[6,7] SCD is indicated by repeated episodes of unbearable pain called crisis, which may require hospitalization at times, with either medication such as hydroxyurea, or in certain cases transfusion or even bone marrow transplantation. As Saudi Arabia fights against the prevention of genetic diseases, they yet pose extreme emotional as well as economic drain to the family as well as the kingdom. As symptoms of pain along with comorbidities start expressing in childhood itself, the need to attend to it at this stage itself is imperative.[8] There is therefore the need to look for associations and pathways which might help improve their condition to at least some extent at inception itself.

According to a study in the eastern province of Saudi Arabia, 67% of SCD children were found vitamin D deficient. This deficiency appeared commonly in the younger age group of patients and those experiencing crisis.[1] Among all vitamins in SCD patients, VDD should be carefully monitored since low amounts develop due to a combined effect of increased concentration of melanin in the skin, lesser physical activity, and inadequate food intake. A decreased calcium and vitamin D being crucial for bone metabolism lead to a reduction in the ideal bone mass peak in SCD children which determines their growth failure. Therefore, the prevalence of osteoporosis was found to be common in SCD.[9]

Vitamin D metabolism involves different organs of the body including the liver, kidney, intestines, skin, and the parathyroid. Therefore, its deficiency in SCD patients has essentially been recognized as one of the most common. Apart from nutritional impairments, SCD patients may possibly have renal impairment, which could cause hindrance in converting vitamin D to its active form. Furthermore, the ability to synthesize vitamin D from sunlight in dark-skinned individuals is compromised. Finally, the inflammatory condition in SCD could affect the vitamin D metabolic pathway.[10] Associations between vitamin D supplementation in SCD children on hydroxyurea treatment have shown a decrease in the inflammatory markers including high-sensitivity C-reactive protein (hsCRP), which supports the immune-modulatory properties of the vitamin.[11] A negative cross-sectional association between 25(OH)D and hsCRP concentrations in a Danish mother-child cohort was observed, proposing a role of the vitamin in systemic low-grade inflammation that is important for child health and future disease outcomes.[12]

We therefore conducted a small observational study on children with SCD not experiencing crisis. This would help increase the awareness among caregivers and patients for early diagnosis and management.

Methods

An observational study was performed on 40 SCD pediatric patients aged 5–16 years during the period August 2018–December 2019 at King Fahd Medical Research Center (KFMRC), King Abdulaziz University (KAU), Jeddah. The concerned Ethics Committee approved the protocol which was registered with registration number 2/36/8390. Guardians of all the subjects were given a brief of the project and their written informed consent was taken before participating in the study. Patient demographics included age, gender, diagnosis, and status.

Results

Low vitamin D levels were observed in all the SCD children (12.337 ± 8.857 ng/mL), representing a deficiency with an average of (12.465 ± 8.812) in males and (12.164 ± 8.901) in females [Figure 1].

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Figure 1

Vitamin D levels in pediatric patients with sickle cell disease. *Age in years; All male and female 5–16, n=40; total male 5–16, n=23; male 5–10, n=20; male 11–16, n=3; total female 5–16, n=17; female 5–10, n=10; female 11–16, n=7

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All patients had normal calcium levels except the females of 11–16-year age group. Low levels of Hb ranging between 7 and 8 mg/dL were observed in all patients of both genders, as is typical of SCD patients. Higher than normal hsCRP values were seen in all patients showing a risk for cardiovascular problems.

As seen in Table 1, majority of the children (80%), irrespective of their age, were vitamin D deficient. Among males, 78.26% were VDD, while 13.043% were vitamin D insufficient and only 8.695% of patients exhibited vitamin D sufficiency. Similarly, among females, 82.352% were VDD, while 5.882% were vitamin D insufficient and only 11.764% patients exhibited vitamin D sufficiency. When observed according to their ages, the males of age group 5–10 years showed 5% vitamin D sufficiency as compared to 33.333% in older males of the age group 11–16 years. On the contrary, 20% of younger females of the age group 5–10 years showed vitamin sufficiency as compared to 0% of the older females of age group 11–16 years.

Table 1 Vitamin D status in pediatric HbSS patients

The association of age and gender with vitamin D, Ca, WBC, Hb, and hsCRP levels is depicted in Table 2. Males of only the age group 5–10 years showed a significant association with vitamin D (P = 0.0375) and WBC (P = 0.0015) levels. When correlation “r” values were considered, males of the 11–16-year age group showed a very strong-positive correlation with vitamin D (r = 0.9862) and a very strong-negative correlation with Hb (r = −0.9819) and hsCRP (r = −0.9907). Among females, only the 11–16-year age group patients exhibited a significance with vitamin D (P = 0.0487), Ca (P = 0.0118), Hb (P = 0.0007), and hsCRP (P = 0.0001) levels. This was also reflected in the r values showing a strong-negative correlation with WBC levels (r = −0.6525) as well as hsCRP (r = −0.6550) as seen in Table 2.

Table 2 Association of age and gender of pediatric HbSS patients with vitamin D, Ca, WBC, Hb, and hsCRP levels

While vitamin D levels in males showed a significant association with Hb values (P = 0.0066), the females did not show any significant P-value in both the age groups. In males, a marked significance was observed only in the 11–16-year age group with a P = 0.0061 for hsCRP. The 11–16-year age group males depicted very strong-negative correlation for Hb (r = −0.9372) and hsCRP (r = −0.9546). In females, correlations presented a strong-negative association with WBC in the 5–10 age group of females (r = −0.6963) and with calcium (r = −0.6330) in the 11–16-year age group as seen in Table 3.

Table 3 Association of Vitamin D with Ca, WBC, Hb, and hsCRP in male and female pediatric HbSS patients

When associations of WBC with Hb and hsCRP were observed, a significant P = 0.0046 was observed with Hb in males. This association was observed only in the males of age group 5–10 years with a P = 0.0034. The r values exhibited weak-negative correlations. Among the females, only the 11–16-year age group showed an association of WBC levels with Hb exhibiting a P = 0.0052 as well as hsCRP with a P = 0.0011. Here too, the correlations were found to be very weak [Table 4].

Table 4 Association of WBC with Hb and hsCRP in male and female pediatric HbSS patients

Association of Ca with WBC, Hb, and hsCRP did not show any significance. Similarly, the association of Hb with hsCRP did not show any significance.

Discussion

Hypovitaminosis of vitamin D in a sunshine-abundant area like Saudi Arabia reiterates that VDD is a global issue that is short of becoming a pandemic. Contributory factors toward VDD in SCD patients could likely be due to lesser sun exposure or/and lower consumption of vitamin D or/and malabsorption of vitamin D.[14]

In our study too, vitamin D sufficiency was found only in 3 out of the 23 males and 1 out of 17 females with SCD. In an earlier study, although low vitamin D levels were observed in SCD children younger than 5 years of age, a higher deficiency was seen during the aging process, as they aged above 5 years. This was attributed to decrease in osteocalcin which is among the most abundant of bone proteins.[9] This deficiency was observed in our study wherein almost all the children were above 5 years of age. Especially, in the females, of ages 5–10 years, there was 20% sufficiency as compared to 0% of age group 11–16 years. Values for controls for serum vitamin D and calcium in this region of Saudi Arabia have been shown to be 23.06 ± 0.25 ng/mL and 2.6 ± 0.15 nmol/L, respectively, for the age group 6–12 years according to earlier studies.[15] Although insufficient vitamin D was displayed in the control group too, their values were slightly higher than those of the sickle cell group in our study. Past research reports that the frequency of VDD in the SCD population was not much different from the control within the same ethnic group as also observed from a study from Saudi Arabia. These VDD patients also experienced frequent hospitalization during crisis showing the possibility of an association. Like this large study from the eastern province of Saudi Arabia, our work also included patients in a steady state without SCD crisis which mostly represents the SCD population.[1]

Certain characteristics, like decreased ability to absorb nutrients due to damage to the intestinal mucosa as well as an increased basal metabolic rate, appear specific to SCD patients. Apart from this, higher nutritional demands[16] resulting from higher energy expenditure to sustain normal physiologic functioning may contribute to a VDD status.

VDD has been associated with skeletal issues, cardiovascular problems, asthma nephropathy, chronic pain, etc. It also affects growth, maturation, skeletal health, and severity of the disease in SCD patients. Moreover, SCD patients have been found to be susceptible to all these complications, and VDD intervention is potentially simple and easy to improve their health.[10] Supplementation of vitamin D2 and vitamin D3 to SCD patients in a steady state for a 6-week period was effective in improving vitamin D status.[17]

Appropriate vitamin D levels may reduce inflammation, causing a lowering of the inflammatory cytokines, thereby leading to a decrease in vitamin D binding protein.[18] The low vitamin D levels are also reflected in the higher concentration of hsCRP which is an inflammatory marker in all the patients. In our present study too, all the patients irrespective of gender and age exhibited hsCRP levels in the range of >3 mg/L (mean 8.395 ± 7.296 mg/L) which is indicative of moderate-to-high cardiovascular risk.[11,19] Healthy controls aged 4–13 years exhibited hsCRP levels of 1.65±0.82 mg/L.[20]

Average calcium levels of all patients were 8.53 mg/dL which is in the normal range of 8.5–10.5 mg/dL. This could be due to the dietary intake, as milk is an integral part of a child’s meal.

Hb levels have been found to be low in SCD patients and the same was observed in our study too.[21] Earlier studies have shown that supplementation of vitamin D to sickle cell anemia patients not only reduced the pain episodes but also increased Hb levels in these patients.[22,23] Many reports also suggest the direct association of VDD with anemia related specifically to either inflammation or a chronic disease.[24,25]

WBC counts detect many disorders and evaluate the severity of the problem. It has been noted that WBC counts were found significantly increased during bacterial infection and crises among SCD children which help it being a marker for hospital admissions. In our study, we found that WBC counts were slightly raised, though not significant in almost all the patients (normal WBC range 4–11×10⁹ cells/L), displaying a strong predisposition to acute chest syndrome and other infections common to SCD children.[26] VDD has been found related to decrease pulmonary function in SCD children but not to other morbidities of sickle cell anemia.[7]

The World Health Organization considers the VDD in Saudi Arabia surpassing the average deficiency observed globally. Past research done on children and adolescents in Saudi Arabia reflects an alarmingly high VDD prevalence of 78% and 98.1% in the urban population. Children with special health conditions like diabetes faced a similar deficiency of around 88.9%. This calls for urgent interventions addressing this issue.[27]

Another study demonstrated that the VDD in children with sickle cell anemia is so high (median being 15 ng/mL) that increasing this is a herculean task. Interventions should address this serious health issue by educating families and creating nutritional awareness.[28]

It was noted that SCD children were calorie deficient with a reduced intake of essential nutrients such as fiber and minerals such as magnesium and calcium along with vitamins D, E, and folate. This contributed to a compromised and reduced growth which is apparent during adolescence. Special care should therefore be taken to ensure appropriate micronutrient and energy intake.[29]

VDD in SCD leads to immune-compromised condition as is also the case in many infections. One study found such immune-compromised women in Saudi to be more prone to toxoplasmosis for which vitamin D could provide protection.[30] The inflammatory condition of psoriasis was also found to be correlated with the deficiency of vitamin D.[31] Even among the healthy Saudi population in the region of Qassim, the deficiency or insufficiency was found to be 67.8% which needs to be attended on a robust scale.[32]

The most accessible source of vitamin D being sunlight could keep us safe from various ailments such as cancer, cardiovascular problems, and autoimmune disorders. A potential link of the dangerously increasing cardiovascular problems was observed with vitamin D.[33] This warrants an urgent attention from governmental organizations to increase awareness in the public to regain vitamin D sufficiency.[34]

Conclusions

The prevalence of VDD in SCD children has gained global focus due to its manifold health implications. Our study too revealed the deficiency status in almost all SCD children in our cohort, which reiterates the need for effective governmental vitamin D screening and counseling programs. There is also a need to address the issue by the medical fraternity and health departments, for better health outcomes in this population. A close monitoring of the vitamin D status in early years of SCD is warranted. Supplementation studies for the different VDD, and insufficiency groups, in the non-crisis set of patients, would establish supplementation therapies in the early stages and avoid certain complications.

Consent to Participate

Before the start of study, consent forms were collected from all the guardians/parents of the patients participating in the study.

Data Availability

Relevant data can be made available upon reasonable request.

Competing Interests

None.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ Contributions

Conceptualization and design of the study – Shahida A Khan, Sarah Khan; Acquisition of data, formal analysis, and interpretation of data – Shahida A Khan, Torki Al Zughaibi, and Sarah A Khan; Manuscript writing – (review & editing) Shahida A Khan, Torki Al Zughaibi, and Sarah A Khan.

All authors critically read the manuscript and approved the final manuscript to be published, ensuring their integrity.