Correlation between Serum 25-Hydroxy Vitamin D Levels and the Severity of Acne Vulgaris: A Systematic Review.

Background: Vitamin D is thought to play a role in the pathogenesis of acne, and its levels can change in patients with acne vulgaris. Several studies have revealed that serum 25-hydroxy vitamin D levels tend to be low and statistically significant in acne vulgaris patients. However, the relationship between vitamin D levels and acne severity is still poorly understood. Objective: This study aims to identify the correlation between serum 25-hydroxy vitamin D levels and the severity of acne vulgaris. Method: This systematic review study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline based on several studies taken from the PubMed, PMC, Semantic Scholar, and ResearchGate databases until June 2021. Full-text case-control, randomized controlled trial, or cross-sectional study in English or Indonesian language reporting on the serum 25-hydroxy vitamin D levels and the severity of acne vulgaris on human participants were included. Result: From a total of 401 studies, 10 studies met the criteria. Almost all studies (8 of 10) revealed lower serum 25-hydroxy vitamin D levels as the acne severity progresses, although 2 of them were not statistically significant.
Conclusion: The evidence of an inverse correlation between serum 25-hydroxy vitamin D levels and the severity of acne vulgaris suggests the need for screening of vitamin D levels in acne patients and offers a new prospect in the field of acne prevention and treatment. Copyright:

Introduction

Vitamin D has been known primarily to play an important role in maintaining bones and calcium/phosphorus homeostasis.[12] Publications about vitamin D have been increasing very fast, and the extra-skeletal effects of vitamin D have become apparent. With the discovery of vitamin D receptors in various tissues, several other biological functions of vitamin D are increasingly recognized and its role in many human diseases, including dermatological diseases, is being profoundly investigated.[234]

Acne vulgaris is the most common skin disorder affecting millions of people worldwide, making it the eighth-most prevalent disease worldwide.[5] A few in vitro studies have published data that suggest the possible association between vitamin D and acne pathophysiology.[6789] The development of acne vulgaris can be seen through the degree of severity, where the degree is very important to guide the decision of treatment options.[10]

Many studies revealed that serum 25-hydroxy vitamin D[25(OH)D] levels tend to be significantly low in acne vulgaris patients.[11121314] However, the relationship between vitamin D levels and the degree of severity is still inconclusive. Therefore, to further investigate this possible relationship, we conducted a systematic review that compared the serum 25(OH) D levels in acne vulgaris patients according to its severity. We hope that this review can offer evidence for consideration of new acne vulgaris prevention and treatment options using vitamin D. Following the outcomes of our research, we also would like to encourage people, especially young adults, to gain the benefit of sun exposure properly. Thus, hopefully, it can benefit patients not to fall into a more severe degree of acne while improving their health in general.

Material and Methods

This systematic review was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with the following research question: Is there any correlation between serum levels of 25(OH) D and the severity of acne vulgaris?

Information sources and search strategy

We independently searched published articles from PubMed, PMC, ResearchGate, and Semantic scholar databases from inception until June 2021. The keyword that we used is “Vitamin D” AND “Acne Vulgaris” AND “Severity.”

Inclusion and exclusion criteria

Using the population, intervention, comparison, and outcome (PICO) strategy, the studies that meet the following criteria were included in the study.

Populations: Adolescents and young adults with acne vulgaris

Intervention: Low level of vitamin D

Comparison: Normal level of vitamin D

Outcome: Acne vulgaris severity

The eligibility criteria included the following: (1) human participants diagnosed with acne vulgaris, (2) acne vulgaris divided into severity classification (The Global Acne Grading System/GAGS or others), (3) a randomized controlled trial (RCT), case-control, or cross-sectional study, and (4) full-text journal in English or Indonesian language.

Exclusion criteria were (1) animal studies, (2) studies in which participants receive any acne therapy/drugs or vitamin D supplements, or certain conditions/diseases that could affect acne severity (e.g., PCOS or other hormonal disorders) and vitamin D levels (e.g., musculoskeletal disorders), (3) studies not clearly depicting vitamin D levels according to acne severity, (4) studies with only one level of acne severity (no comparison between acne severity), (5) unrelated topic, (6) non-accessible full-text studies, and (7) studies other than Indonesian and English.

Study selection and data extraction

Five reviewers conducted independent screening from each search engine and decided whether the study should be included or excluded. The decision was visible to other reviewers (not blinded) and gathered altogether via Rayyan Systems Inc. Differences between decisions were discussed by all reviewers. The selected journals were assessed to extract the following information: data of authors, title of the study, time and location of the study, study design, inclusion and exclusion criteria, total participants, variables analyzed (mainly serum 25(OH)D levels and acne severity), and the results based on P value and correlation coefficient (r).

Risk of bias assessment

Researchers assessed study quality using the Effective Public Health Practice Project (EPHPP) score, which assessed selection bias, study design, confounders, blinding, data collection methods, and withdrawals and dropouts. The final assessment is in the form of strong, moderate, and weak study quality.

Result

Study selection

As shown in the flow diagram [Figure 1], 401 studies were searched from all databases. Of which, 24 were excluded as duplicates by using Rayyan software and manually. The remaining 377 studies were filtered according to the titles and abstracts, outcome, and language; 238 studies were excluded due to unrelated themes; 109 studies were excluded due to wrong outcome; 12 studies were excluded due to foreign language. A full-text review was done for the remaining 18 studies and identified 10 studies that meet the inclusion criteria for this review.

Figure 1

PRISMA flow diagram

Study characteristic

Ten studies met the inclusion criteria, with a total of 1.262 participants and 695 acne patients included. The sample size of the studies ranged from 15 to 150. The studies were conducted in South Korea,[6] Egypt,[13151617181920] Saudi Arabia,[12] and Iran [Table 1].[14]

Table 1

Studies characteristic

Author, Year	Country	Study Design	Participants (mean age in years)	Adjusted confounding variables
Lim et al., 2016	South Korea	Case-control combined with a randomized controlled trial	Control: 80 (21.0±5.7) Case: 80 (20.9±4.1)	Age, sex, BMI, smoking habit, and sunscreen use
Elkamshoushi et al., 2021	Egypt	Case control	Control: 15 (17.7±2.3) Case: 30 (17.4±2.7)	Age, BMI, smoking habit, sunscreen use, sun exposure, and dairy intake
Fawzi et al., 2018	Egypt	Case control	Control: 50 (24.7±4.74) Case: 50 (23.5±4.95)	Age, sex, BMI, and smoking habit
El-Hamd et al., 2018	Egypt	Case control	Control: 60 (23.80±7.37) Case: 90 (20.73±3.32)	Age, sex, and BMI
Abd-Elmaged et al., 2019	Egypt	Case control	Control: 150 (23.1±4.6) Case: 135 (21.04±2.8)	Age, sex, and BMI
Abdelaziz et al., 2021	Egypt	Cross-sectional combined with a Randomized Controlled Trial	80 (NA)	None
Alheteli et al., 2020	Saudi Arabia	Case control	Control: 50 (NA) Case: 68 (NA)	None
El-Tahlawi et al., 2020	Egypt	Case control	Control: 30 (24.7±4.5) Case: 30 (23.7±2.8)	Age, sex, and BMI
Goodarzi et al., 2020	Iran	Case control	Control: 72 (26.4±8.8) Case: 72 (25.5±7.9)	Age and sex
El-Ramly et al., 2016	Egypt	Case control	Control: 60 (24.65±5.57) Case: 60 (20±4.63)	Age, sex, and sun exposure

Moreover, eight studies were case-control studies, one case-control combined with a randomized controlled trial study,[6] and one cross-sectional combined with a randomized controlled trial study [Table 2].[18]

Table 2

Main outcome of the studies included in this systematic review of the correlation between serum 25-hydroxy vitamin D and acne vulgaris

Author, Year	Mean Serum 25-hydroxy Vitamin D		Outcome - Result
	Control	Case
Lim et al., 2016	15.2±7.2	13.1±9.8 Acne severity (GAGS) Mild: 17.37±0.6 Moderate: 11.89±1.0 Severe: 7.04±0.5	Vitamin D status - Deficiency is significantly higher in cases Serum vitamin D level - No significant difference between cases and controls Serum vitamin D and acne severity - Significant negative correlation
Elkamshoushi et al., 2021	16.4±7.5	25.0±6.5 Acne severity (GAGS) Severe: 25.7±6.5 Very severe: 20±6	Vitamin D status - Deficiency is significantly higher in control Serum vitamin D level - significantly higher in cases Serum vitamin D and acne severity - Significant negative correlation
Fawzi et al., 2018	27.4±5.25	21.6±7.69 Acne severity (GAGS) Mild: 32.8±3.15 Moderate: 23.7±3.77 Severe: 13.4±2.12	Vitamin D status - Deficiency is significantly higher in cases Serum vitamin D level - Significantly lower in cases Serum vitamin D and acne severity - Significant negative correlation
El-Hamd et al., 2018	44.83±11.91	17.34±7.58 Acne severity (GAGS) Moderate: 18.54±8.30 Severe: 14.56±3.98 Very severe: 11.32±6.45	Vitamin D status - NA Serum vitamin D level - significantly lower in cases Serum vitamin and acne severity - significant negative correlation
Abd-Elmaged et al., 2018	51.7±2.7	33.3±9.7 Acne severity (GAGS) Mild: 43.6±2.2 Moderate: 35.5±2.2 Severe: 20.9±1.5	Vitamin D status - NA Serum vitamin D level - significantly lower in cases Serum vitamin and acne severity - significant negative correlation
Abdelaziz et al., 2021	NA	NA Acne severity (Tutakne) Grade I: 15.8±4 Grade II: 11.02±6.6 Grade III: 8.2±2.9 Grade IV: 5.2±1.7	Vitamin D status - Deficiency was found in 82.5% of acne patients. Serum vitamin D level - NA Vitamin D level and acne severity - significant negative correlation
Alheteli et al., 2020	40±11.7	28.8±7.9 Acne severity (GAGS) Mild: 26±9.4 Mild: 26±9.4 Moderate: 31.4±6.9 Severe: 28.4±6.7	Vitamin D status - NA Serum vitamin D level - significantly lower in cases Vitamin D level and acne severity - No significant correlation
El-Tahlawi et al., 2020	33.8±17.3	23.2±11.7 Acne severity (GAGS)* Mild: 24,7 Moderate: 21,3 Moderate: 21,3 Severe: 15,4	Vitamin D status - NA Serum vitamin D level - Significantly lower in cases Vitamin D level and acne severity - No significant correlation
Goodarzi et al., 2020	20.39±14.89	29.30±16.21 Acne severity (IAEM) Moderate-severe: 26.67±15.83 Very severe: 32.97±16.27	Vitamin D status - NA Serum vitamin D level - Significantly higher in cases Vitamin D level and acne severity - No significant correlation
El-Ramly et al., 2016	32±18.15	28.7±10.65 Acne severity (GAGS) Mild: 31.40±15.19 Moderate: 26.82±4.24 Severe: 25.68±10.65	Vitamin D status - No significant difference between cases and controls Serum vitamin D level - No significant difference between cases and controls Vitamin D level and acne severity - No significant correlation

Notes: GAGS=Global Acne Grading System; IAEM=Indonesian Acne Expert Meeting. *Median

Outcomes

Some of the studies stated vitamin D status in the form of deficiency, insufficiency, or sufficiency. Vitamin D status in cases and controls was found to be varied. In two studies, vitamin D deficiency was found to be significantly higher in cases.[615] One study also stated that 82.5% of vitamin D deficiency occurred in the case group or acne patients.[18]

Seven studies showed that mean serum 25(OH) D was lower in cases[6121516171920] and five of them reached statistical significance.[1215161719] Almost all studies (8 of 10) revealed lower serum 25(OH) D levels as the acne severity progresses, although two of them were not statistically significant.[1920] A total of eight studies used GAGS for acne severity grading, while two other studies used Tutakne and IAEM.

Discussion

This study systematically assessed the available scientific literature with respect to the influence of vitamin D levels in acne vulgaris severity. Vitamin D deficiency is defined as the level of 25(OH)D less than 20 ng/mL (50 nmol/L) in the blood.[21] Our synthesis indicated that being vitamin D deficient was at higher risk of developing more severe acne vulgaris as compared to vitamin D sufficient. There are few possible explanations of why this happened.

First is the anti-inflammatory effect of vitamin D. It is widely thought that vitamin D plays an important role in the modulation of the inflammation system by regulating the production of inflammatory cytokines and immune cells.[22] The presence of Propionibacterium acnes in acne vulgaris lesions promotes the secretion of various inflammatory cytokines, including IL-8 and IL-12, in addition to activated Th1 and Th17 lymphocytes at the site of acne vulgaris lesions. Vitamin D also inhibits T-cell proliferation and suppresses B-cell antibody production, and reduces Th17.[23]

The second explanation is related to the effect of vitamin D on the proliferation and differentiation of sebocytes and keratinocytes. Sebocyte cells were identified as 1,25(OH) 2D responsive target cells, suggesting that vitamin D analogs may be effective in the treatment of acne.[817] Lastly, vitamin D is also thought to have antioxidant and anti-comedogenic properties.[12] This may indicate that vitamin D may play a potential role in acne vulgaris or that acne vulgaris negatively affects vitamin D synthesis in the skin.[16] Further studies are needed to confirm the association between vitamin D and acne vulgaris.

Interestingly, 7 out of 10 studies included were located in Egypt, a country that is rich in sun exposure. One study in Egypt by Elkamshoushi et al.[13] showed that 75% of patients with acne had vitamin 25(OH)D levels less than 30 ng/ml. However, a similar distribution of hypovitaminosis D was found in healthy controls. This is probably caused by the study participants who are mostly women dressed in Muslim clothes (hijab) and with type III skin photos. Surprisingly, higher mean serum 25(OH)D levels were found in the case group. This finding can be explained by the presence of several factors that affect vitamin D levels such as BMI, use of sunscreen, and dairy intake.

A total of four studies showed no significant correlation between vitamin D levels and acne severity.[12141920] However, two of them showed lower vitamin D levels in the more severe degree of acne.[1920] This indicates the limitation of the study, which may be due to the small and uneven sample between the mild, moderate, and severe acne groups.

The two other studies revealed inconsistent results of vitamin D levels between acne severity groups.[1214] This may be explained through several confounding variables mentioned above. Goodarzi et al.[14] also found that serum 25(OH) D levels in the cases group were significantly higher than the control group. This is probably due to higher levels of sun exposure and consumption of dairy products in the acne vulgaris group. Sun exposure was significantly associated with serum vitamin D levels (P = 0.0001).[14] Dairy intake in acne patients also plays a major role in increasing serum 25(OH)D levels, which is associated with the presence of calcium in dairy products.[24] A meta-analysis found a positive relationship between milk, total milk, whole milk, low-fat milk, and skim milk on the incidence of acne vulgaris and these dairy products also contributed to the severity.[25]

In addition, three of the studies mentioned above also gave an intervention in acne vulgaris patients by giving vitamin D supplementation for 2–3 months.[61318] They generated the same outcome, which was elevation in serum 25(OH)D levels and improvement in acne severity compared to placebo. Significant improvement mainly showed by the reduction of inflammatory lesions in the group with vitamin D supplementation.

Limitations of the review

This review has several limitations. First, we did not determine the minimum number of participants in the selected study. Second, some prominent databases were not included. Our study also has a narrow focus, thereby reducing comprehensive coverage.

Conclusion

In conclusion, this systematic review indicates evidence of an inverse correlation between serum 25-hydroxy vitamin D levels and the severity of acne vulgaris. This study suggests the importance of screening of vitamin D levels in acne vulgaris patients and offers a new prospect in the field of acne prevention and treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.