Clinical Science Session (CSS)

*Program Studi Profesi Dokter / G1A220002 / Januari 2022

**Pembimbing / Dr. dr. Fitriyanti, Sp.KK, FINSDV, FAADV

Serum Vitamin D Levels at Different Stages of Acne Vulgaris Patients Treated

with Isotretinoin: A Prospective Study

Disusun Oleh :
Try Wira Putranto, S.Ked
G1A220002

Pembimbing:
Dr. dr. Fitriyanti, Sp.KK, FINSDV, FAADV

PROGRAM STUDI PROFESI DOKTER

SMF/BAGIAN ILMU PENYAKIT KULIT DAN KELAMIN
RUMAH SAKIT UMUM DAERAH RADEN MATTAHER
FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN
UNIVERSTAS JAMBI
2022
 LEMBAR PENGESAHAN
Clinical Science Session (CSS)

Serum Vitamin D Levels at Different Stages of Acne Vulgaris Patients Treated

with Isotretinoin: A Prospective Study

Disusun Oleh :
Try Wira Putranto, S.Ked
G1A220002

PROGRAM STUDI PROFESI DOKTER

SMF/BAGIAN ILMU PENYAKIT KULIT DAN KELAMIN
RUMAH SAKIT UMUM DAERAH RADEN MATTAHER
FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN
UNIVERSITAS JAMBI
2022

Jambi, Januari 2022

Pembimbing

Dr. dr. Fitriyanti, Sp.KK, FINSDV, FAADV

i
 KATA PENGANTAR

Segala puji dan syukur kepada Allah SWT atas segala limpahan rahmat dan
karunia-Nya sehingga penulis dapat menyelesaikan CSS yang berjudul “Serum
Vitamin D Levels at Different Stages of Acne Vulgaris Patients Treated with
Isotretinoin: A Prospective Study” sebagai salah satu syarat dalam mengikuti
Pembelajaran Program Studi Profesi Dokter di Bagian Ilmu Penyakit Kulit dan
Kelamin RSUD Raden Mattaher Provinsi Jambi.
Penulis mengucapkan terima kasih kepada Dr. dr. Fitriyanti, Sp.KK,
FINSDV, FAADV yang telah bersedia meluangkan waktu dan pikirannya untuk
membimbing penulis selama menjalani Rotasi Klinik Program Studi Profesi Dokter
di Bagian Ilmu Penyakit Kulit dan Kelamin RSUD Raden Mattaher Provinsi Jambi.
Penulis menyadari bahwa masih banyak kekurangan pada CSS ini, sehingga
penulis mengharapkan kritik dan saran untuk menyempurnakan CSS ini. Penulis
mengharapkan semoga CSS ini dapat bermanfaat bagi penulis dan pembaca.

Jambi, Januari 2022

Penulis

ii
Serum Vitamin D Levels at Different Stages of Acne Vulgaris Patients Treated
with Isotretinoin: A Prospective Study
Mohammed Al-Dhubaibi, Ghadah Alhetheli, Adel Alsenaid and Ahmed Abd
Elneam

ABSTRAK

Latar belakang:
Acne vulgaris adalah kelainan kulit inflamasi kronis yang umum pada unit
pilosebasea. Isotretinoin (13-cis retinoic acid) adalah pengobatan multifungsi yang
paling efektif untuk acne sedang hingga parah dan nodulocystic. Vitamin D
berperan dalam sistem kekebalan tubuh, dan kekurangannya mungkin berkontribusi
pada patogenesis acne.
Tujuan:
Untuk menyelidiki apakah isotretinoin meningkatkan kadar serum 25-
hidroksivitamin D pada pasien acne vulgaris.
Metode:
Penelitian kohort prospektif ini melibatkan 68 pasien dengan acne vulgaris. Profil
lipid, tes fungsi hati, dan kadar serum 25-hidroksivitamin D [25(OH)D] diukur pada
awal dan tiga bulan setelah memulai pengobatan isotretinoin.
Hasil:
Ada peningkatan yang signifikan dalam kadar serum vitamin D tiga bulan setelah
memulai pengobatan isotretinoin pada pasien acne ringan (P=0,0003).
Kesimpulan:
Kadar vitamin D berubah pada acne vulgaris. Terapi isotretinoin dikaitkan dengan
peningkatan kadar vitamin D, yang secara statistik signifikan pada pasien acne
ringan. Mengingat peran vitamin D dalam acne, pengobatan yang efektif dengan
isotretinoin mungkin menyoroti vitamin D sebagai target yang mungkin untuk
terapi acne atau sebagai biomarker untuk aktivitas penyakit dan remisi.
Kata kunci: Acne vulgaris, Vitamin D, Defisiensi Vitamin D, Isotretinoin, Terapi
Acne, Terapi Isotretinoin.

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 2

1. PENDAHULUAN

Acne Vulgaris (AV) adalah kelainan kulit inflamasi primer yang umum
pada unit pilosebasea. Secara klinis, AV ditandai dengan komedo terbuka dan
tertutup, papula, pustula, dan nodul [1, 2]. AV mempengaruhi kedua jenis kelamin
secara setara, dan biasanya dimulai pada masa remaja antara usia 14 dan 17 tahun
pada wanita dan usia 16 dan 19 tahun pada pria; namun, kemunculannya mungkin
tertunda hingga usia 25 hingga 30 tahun. Waktu di mana AV memudar bervariasi
[3]. Patogenesis acne melibatkan empat faktor utama: peningkatan produksi sebum,
peningkatan hiperkeratinisasi folikel, kolonisasi dengan cutibacterium acnes
(sebelumnya dikenal sebagai propionibacterium acnes), dan proses inflamasi [4].
Beberapa modalitas pengobatan telah digunakan untuk mengobati AV.
Terapi topikal termasuk antibiotik, asam azelaic, benzoil peroksida, dan retinoid.
Perawatan sistemik termasuk antibiotik, terapi hormonal, dan isotretinoin [5].
Isotretinoin (13-cis-retinoic acid) adalah retinoid nonaromatik sistemik
yang sangat efektif dalam pengobatan nodulocystic dan acne sedang hingga parah,
dan mempengaruhi keempat faktor yang mendasari patogenesis AV. Oleh karena
itu, isotretinoin dianggap sebagai obat paling efektif yang tersedia saat ini untuk
acne, dan juga merupakan pengobatan yang efektif untuk banyak kondisi
dermatologis lainnya [6]. Isotretinoin diindikasikan terutama untuk kasus acne yang
parah tetapi dapat digunakan dalam kasus sedang untuk meminimalkan jaringan
parut. Dosis yang dianjurkan untuk pengobatan isotretinoin adalah 0,5-1 mg/kg
setiap hari, dengan dosis kumulatif antara 120 dan 150 mg/kg [7, 8]. Isotretinoin
memiliki banyak efek samping, yang paling penting adalah hepatotoksisitasnya,
efek psikologis, efek sosial, teratogenisitas, dan xerosis [9].
Vitamin D adalah hormon steroid yang larut dalam lemak yang berasal dari
asupan makanan dan disintesis melalui kulit melalui paparan sinar matahari.
Vitamin D3 (cholecalciferol) dan vitamin D2 (ergocalciferol) diproduksi melalui
radiasi ultraviolet B matahari (UVB). Penyerapan radiasi UVB di kulit
menyebabkan konversi provitamin D menjadi pre-vitamin D, diikuti dengan
produksi vitamin D3 [10].
 3

Vitamin D memiliki sifat antikomedogenik dan antioksidan; hal itu

menunjukkan efek pengaturan pada sistem kekebalan tubuh, proliferasi,
diferensiasi sebosit dan keratinosit. Oleh karena itu, defisiensinya dapat
berkontribusi pada patogenesis acne [11, 12].
Dalam penelitian ini, efek isotretinoin dalam peningkatan kadar serum
vitamin D pada pasien AV dieksplorasi. Diketahui, ini merupakan penelitian
pertama di Kerajaan Arab Saudi yang membahas masalah ini.

2. BAHAN DAN METODE

2.1 Subjek
Penelitian kohort prospektif ini dilakukan di klinik dermatologi rawat jalan
di Universitas Qassim, Arab Saudi, antara Oktober 2016 dan Maret 2017. Komite
Etik Penelitian Medis di Fakultas Kedokteran Universitas Qassim menyetujui
penelitian dengan nomor persetujuan 15/18/13. Penelitian dilakukan pada musim
cuaca dingin untuk meminimalkan pengaruh variasi musiman terhadap kadar
vitamin D. Dari pasien AV yang terdaftar (n=68), 30,88%, 38,24%, dan 30,88%
masing-masing memiliki acne ringan, sedang, dan berat.
Sebelum memulai penelitian, persetujuan tertulis diterima dari peserta
setelah menjelaskan tujuan, nilai, dan langkah-langkah yang diperlukan dengan
cara yang disederhanakan dan potensi efek samping obat isotretinoin.
Acne dinilai dan diklasifikasikan sebagai ringan, sedang, atau berat. Acne
ringan ditandai dengan <20 komedo, <15 lesi inflamasi, atau jumlah lesi total <30.
Acne sedang ditandai dengan 20-100 komedo, 15-50 lesi inflamasi, atau jumlah lesi
total 30-125. Acne parah ditandai dengan >5 pseudokista, jumlah komedo total
>100, jumlah inflamasi total >50, atau jumlah lesi total >125 [13].
Semua 68 subjek mengisi formulir pengumpulan data untuk memberikan
demografi, riwayat acne keluarga, paparan sinar matahari >2 jam/hari, usia onset,
durasi penyakit, lokasi acne (wajah, dada, atau punggung), riwayat medis masa lalu,
dan variabel lain yang relevan.
 4

Kriteria Inklusi: Pasien berusia 15 hingga 35 tahun dengan AV, terlepas dari
jenis kelamin, dan yang tidak memilih perawatan acne setidaknya selama empat
minggu sebelumnya dan pasien yang tidak responsif terhadap terapi topikal
konvensional atau antibiotik sistemik (selain isotretinoin sistemik) dimasukkan
dalam penelitian ini.
Kriteria Eksklusi: Hamil dan menyusui, pasien yang mengonsumsi
suplemen vitamin D untuk alasan apa pun, dan pasien yang menjalani pengobatan
bersamaan untuk acne dieksklusikan.

2.2 Pengobatan
Semua pasien diobati dengan isotretinoin (0,5-1 mg/kg/hari) yang
disesuaikan dengan 30-40 mg/hari selama tiga bulan. Tes serum beta HCG
dilakukan untuk semua pasien wanita sebelum memulai pengobatan.

2.3 Analisis Biokimia dan Laboratorium

2.3.1 Pengukuran Konsentrasi Serum Vitamin D
Pasien memiliki konsentrasi serum 25-hidroksivitamin D (25(OH)D) awal
yang diukur. Sampel darah dikumpulkan dari vena dan dianalisis dalam 24 jam
pengambilan sampel menggunakan Roche Cobas e411 (Sistem Diagnostik Roche,
Swiss). Berdasarkan pedoman Food and Nutrition Board of the Institute of
Medicine, kadar serum 25(OH)D dikategorikan menjadi kategori cukup (>20
ng/ml), tidak memadai (12-20 ng/ml), atau kurang (<12 ng/ml) [14].

2.3.2 Pengukuran Profil Lipid

Estimasi profil lipid: Kadar plasma untuk trigliserida (TG) dan Kolesterol
Total (TC) diukur dengan prosedur enzimatik standar, menggunakan kit yang
disediakan oleh Roche Diagnostics (Mannheim, Jerman) pada penganalisis kimia
klinis otomatis Olympus AU 400.
 5

2.3.3 Pengukuran Tes Fungsi Hati

Serum AST diperkirakan menggunakan Aspartate Aminotransferase (AST)
Activity Assay Kit Catalog Number MAK055 (Sigma-Aldrich, USA). Serum ALT
dievaluasi menggunakan Alanine Aminotransferase Activity Assay Kit Catalog
Number MAK052 (Sigma-Aldrich, USA).

2.3.4 Analisis Statistik

Data yang direkam dianalisis menggunakan Statistical Package for Social
Sciences, versi 20.0 (SPSS Inc., Chicago, Illinois, USA). Uji analisis varians
(ANOVA) dilakukan antara lebih dari dua mean t-tests dan chi-squares untuk
menganalisis rata-rata dan persentase perbedaan. Tingkat signifikansi P ≤0,001
dianggap sangat signifikan, dan P ≥0,05 dianggap tidak signifikan. Selanjutnya,
data kuantitatif dinyatakan sebagai mean ± Standar Deviasi (SD), sedangkan data
kualitatif dinyatakan sebagai frekuensi dan persentase.

3. HASIL

Penelitian ini melibatkan 68 pasien dengan AV (41 perempuan dan 27 laki-

laki). Tabel 1 menyajikan demografi dasar peserta dan karakteristik klinis [15].
Penelitian ini mengungkapkan peningkatan yang tidak signifikan secara
keseluruhan dalam kadar vitamin D, profil lipid, dan enzim hati pada semua pasien
tanpa memandang tingkat keparahan penyakit tiga bulan setelah memulai
pengobatan isotretinoin (Tabel 2).
Pada awal, kadar vitamin D adalah 26±9.4ng/ml untuk pasien pada
kelompok acne ringan dan 31,4±6.9 ng/ml untuk pasien dalam kelompok acne
sedang, sedangkan pada pasien dengan acne berat adalah 28,4±6,7 ng/ml. Tidak ada
variasi yang signifikan dalam kadar vitamin D serum antara kelompok acne ringan,
sedang, dan berat (P=0,067), karena kadarnya dipertahankan setelah pengobatan
dengan isotretinoin (P=0,773). Tiga bulan setelah memulai pengobatan isotretinoin,
terdapat peningkatan nilai rata-rata kadar vitamin D serum pada acne ringan,
 6

sedang, dan berat (masing-masing 35,6±6,5, 32,14±7.1, dan 32,9±4,9). Namun, hal
ini hanya signifikan pada kelompok acne ringan (P=0,003; Tabel 3 dan 4).

Tabel 1. Karakteristik demografi dan klinis awal pasien acne vulgaris [15].

Tabel 2. Perbandingan antara mean ± SD konsentrasi serum vitamin D [25(OH)D],

profil lipid, dan enzim hati sebelum dan 3 bulan setelah pengobatan isotretinoin
pada pasien dengan acne vulgaris.
 7

Tabel 3. Hubungan antara keparahan acne vulgaris pasien dan konsentrasi serum
vitamin D [25(OH)D] sebelum dan 3 bulan setelah pengobatan isotretinoin.

Tabel 4. Perbandingan mean ± SD konsentrasi serum vitamin D [25(OH)D]

sebelum dan 3 bulan setelah pengobatan isotretinoin pada pasien acne vulgaris
ringan, sedang, dan berat.

Tidak ada perubahan signifikan dalam nilai rata-rata profil lipid yang
terdeteksi pada semua subkelompok acne ringan, sedang, dan berat selama
 8

penelitian sementara pada enzim hati, hanya serum AST yang signifikan pada acne
vulgaris berat setelah pengobatan dengan nilai P 0,011 (Tabel 5).

Tabel 5. Perbandingan antara mean ± SD profil lipid, dan enzim hati pada awal dan
3 bulan setelah pengobatan isotretinoin pada pasien dengan acne vulgaris ringan,
sedang, dan berat.

4. DISKUSI

Peran vitamin D dalam patogenesis acne telah dilaporkan dalam penelitian

yang berbeda. Vitamin D mengatur sistem kekebalan dan pertumbuhan berbagai
jenis sel, termasuk proliferasi, diferensiasi sebosit, dan keratinosit. Vitamin D
menunjukkan efek antikomedogenik dan antioksidan, dan memberikan
pengaruhnya dengan mengikat reseptor vitamin D intranuklear (vitamin D receptor
/VDR), yang merupakan bagian dari superfamili faktor regulasi transkripsional
trans-acting yang juga mencakup reseptor steroid, reseptor hormon tiroid, Retinoic
Acid Receptors (RAR), dan Retinoid-X Receptor (RXR) [12, 16].
Ada interaksi yang baik antara reseptor ini. RXR memberikan efek
dimerisasi pada reseptor VDR, dan heterodimer juga dapat terbentuk di antaranya
(VDR/RXR) [17]. Selain berdampak pada gen responsif RXR, retinoid selektif
RXR juga dapat memengaruhi gen responsif vitamin D. Selanjutnya, vitamin D
juga dapat mengatur gen responsif RXR [18]. Meskipun isotretinoin memiliki
 9

afinitas rendah terhadap reseptor retinoid, isotretinoin diubah secara intraseluler,

menunjukkan efek agonis pada reseptor RAR dan RXR [19].
Isotretinoin sistemik adalah pengobatan acne ampuh yang mempengaruhi
keempat faktor patogen penyakit, menekan produksi sebum dan deskuamasi
abnormal dari epitel folikel sebasea dan mengurangi cutibacterium acne dan
inflamasi [20]. Isotretinoin sistemik juga menunjukkan efek penghambatan pada
pengembangan Th17 dan IL-17 [21].
Hasil penelitian ini mengungkapkan bahwa terjadi peningkatan kadar
vitamin D setelah tiga bulan pengobatan isotretinoin, dengan perbedaan yang
signifikan hanya pada kelompok acne ringan (P=0,0003). Yang menarik, tidak ada
penjelasan teoritis oleh penulis di balik ini yang dapat diselidiki lebih lanjut oleh
penelitian masa depan. Hasil kami hampir mirip dengan penelitian El-Hamd et al.
[22]. Di sisi lain, sebuah penelitian oleh Moravvej H et al. menunjukkan tidak ada
efek pada kadar vitamin D serum setelah dosis yang direkomendasikan dari
isotretinoin oral [23], sedangkan hasil penelitian lain dari Ertugrul et al.
menunjukkan peningkatan kadar 1,25-dihidroksivitamin D dan penurunan kadar
25-hidroksivitamin D setelah pengobatan isotretinoin [24]. Alasan yang mungkin
di balik hasil yang bertentangan dari penelitian ini adalah bahwa mungkin ada
perbedaan dalam kriteria inklusi dan eksklusi atau dalam metodologi lain dari
penelitian yang telah mempengaruhi hasil.
Hasil penelitian kami dan penelitian lain berfokus pada peran aktif defisiensi
vitamin D dan pengaruhnya terhadap perkembangan AV, yang dapat diilustrasikan
dengan peran cutibacterium acnes dalam meningkatkan ekspresi gen faktor
imunologis untuk memblokir produksi vitamin D [25, 26].
Hal ini menyoroti peran vitamin D yang menjanjikan dalam pengobatan AV.
Dalam hasil kami, tidak adanya perbedaan yang signifikan secara statistik antara
tingkat keparahan vitamin D dan AV sebagian besar disebabkan oleh ukuran sampel
yang kecil.
Hasil dalam penelitian ini untuk profil lipid dan fungsi hati menunjukkan
peningkatan yang tidak signifikan setelah tiga bulan pengobatan isotretinoin oral
yang serupa dengan penelitian lain [22].
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KESIMPULAN

Vitamin D berperan dalam patogenesis acne dan kadarnya berubah pada

acne vulgaris. Kadar serum 25-hidroksivitamin D meningkat setelah tiga bulan
terapi isotretinoin oral, dan efeknya signifikan pada pasien acne ringan. Isotretinoin
oral dan pengaruhnya pada kadar serum vitamin D pada pasien acne mungkin
menyoroti vitamin D sebagai target yang mungkin untuk terapi acne. Selanjutnya,
vitamin D dapat dianggap sebagai biomarker untuk aktivitas penyakit dan remisi.
Penelitian lebih lanjut dalam skala yang lebih besar diperlukan untuk
menunjukkan efek isotretinoin dalam meningkatkan kadar vitamin D dan peran
yang tepat dari defisiensi vitamin D dalam patogenesis acne, serta kemungkinan
efek terapi dari persiapan vitamin D pada acne vulgaris.

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25. Agak GW, Qin M, Nobe J, et al. Propionibacterium acnes induces an IL-17
response in acne vulgaris that is regulated by vitamin A and vitamin D. J Invest
Dermatol 2014; 134(2): 366-73. [http://dx.doi.org/10.1038/jid.2013.334]
[PMID: 23924903]
26. Thiboutot DM, Layton AM, Anne Eady E. IL-17: A key player in the P. acnes
inflammatory cascade? J Invest Dermatol 2014; 134(2): 307-10.
[http://dx.doi.org/10.1038/jid.2013.400] [PMID: 24424453]
1874-3722/21 Send Orders for Reprints to reprints@benthamscience.net

11

The Open Dermatology Journal

Content list available at: https://opendermatologyjournal.com

RESEARCH ARTICLE

Serum Vitamin D Levels at Different Stages of Acne Vulgaris Patients Treated

with Isotretinoin: A Prospective Study
Mohammed Al-Dhubaibi1, Ghadah Alhetheli2,*, Adel Alsenaid1 and Ahmed Abd Elneam3,4
1
Department of Dermatology, College of Medicine, Shaqra, Saudi Arabia
2
Division of Dermatology and Cutaneous Surgery, College of Medicine, Qassim University, Buraydah, Saudi Arabia
3
Department of Basic Medical Sciences, College of Medicine, Shaqra University, Shaqra, Saudi Arabia
4
Human Genetics Division, National Research Centre, Giza, Egypt

Abstract:
Background:
Acne vulgaris is a common chronic inflammatory skin disorder of pilosebaceous units. Isotretinoin (13-cis retinoic acid) is the most effective
multifunctional treatment for moderate-to-severe and nodulocystic acne. Vitamin D plays a role in the immune system, and its deficiency might
contribute to the pathogenesis of acne.

Objective:
To investigate whether isotretinoin improves serum 25-hydroxyvitamin D levels in acne vulgaris patients.

Methods:
This prospective cohort study included 68 patients with acne vulgaris. Lipid profiles, liver function tests, and serum 25-hydroxyvitamin D [25
(OH) D] levels were measured at baseline and three months after starting isotretinoin treatment.

Results:
There was a significant increase in serum vitamin D levels three months after starting isotretinoin treatment in mild acne patients (P=0.0003).

Conclusion:
Vitamin D levels are altered in acne vulgaris. Isotretinoin therapy is associated with an increase in vitamin D levels, which was statistically
significant in mild acne patients. Considering the role of vitamin D in acne, effective treatment with isotretinoin might highlight vitamin D as a
possible target for acne therapy or as a biomarker for disease activity and remission.

Keywords: Acne vulgaris, Vitamin D, Vitamin D deficiency, Isotretinoin, Acne therapy, Isotretinoin therapy.

Article History Received: December 16, 2020 Revised: February 11, 2021 Accepted: February 15, 2021

1. INTRODUCTION involves four primary factors: increased sebum production,

Acne Vulgaris (AV) is a common primary inflammatory
skin disorder of pilosebaceous units. Clinically, AV is
characterized by open-and-closed comedones, papules,
pustules, and nodules [1, 2]. AV affects both genders equally,
and it usually starts in adolescence between 14 and 17 years of
age in females and 16 and 19 years of age in males; however,
its emergence may be delayed until 25 to 30 years of age. The
time at which AV fades varies [3]. The pathogenesis of acne
* Address correspondence to this author at the Division of Dermatology and
Cutaneous Surgery, College of Medicine, Qassim University, Buraydah, Saudi
Arabia; E-mail: ghthly@qu.edu.sa
increased follicular hyperkeratinization, colonization with
cutibacterium acnes (formerly known as propionibacterium
acnes), and inflammatory process [4].
Several treatment modalities have been used to treat AV.
Topical therapies include antibiotics, azelaic acid, benzoyl
peroxide, and retinoids. Systemic treatments include
antibiotics, hormonal therapy, and isotretinoin [5].
Isotretinoin (13-cis-retinoic acid) is a systemic non-
aromatic retinoid that is highly effective in the treatment of
nodulocystic and moderate-to-severe acne, and it affects all
four underlying factors of AV pathogenesis. Therefore,

DOI: 10.2174/1874372202115010011, 2021, 15, 11-15

12 The Open Dermatology Journal, 2021, Volume 15
isotretinoin is regarded as the most effective medication
currently available for acne, and it is also an effective treatment
for many other dermatological conditions [6]. Isotretinoin is
indicated mainly for severe cases of acne but can be used in
moderate cases to minimize scarring. The recommended dose
for isotretinoin treatment is 0.5–1 mg/kg daily, with a
cumulative dose between 120 and 150 mg/kg [7, 8].
Isotretinoin has many side effects, the most important of which
are its hepatotoxicity, psychological effects, social effects,
teratogenicity, and xerosis [9].
Vitamin D is a fat-soluble steroid hormone derived from
dietary intake and synthesized through the skin via exposure to
sunlight. Vitamin D3 (cholecalciferol) and vitamin D2
(ergocalciferol) are manufactured through solar ultraviolet B
radiation (UVB). Absorption of UVB radiation in the skin
leads to the conversion of provitamin D to pre-vitamin D,
followed by the production of vitamin D3 [10].
Vitamin D has both anticomedogenic and antioxidant
properties; it demonstrates a regulatory effect on the immune
system, proliferation, differentiation of sebocytes and
keratinocytes. Therefore, its deficiency may contribute to the
pathogenesis of acne [11, 12].
In this study, the effect of isotretinoin in the improvement
of serum vitamin D levels in AV patients is explored. It is
known that this is the first study in the Kingdom of Saudi
Arabia to address this issue.
2. MATERIALS AND METHODS
2.1. Subjects
This prospective cohort study was conducted in the
outpatient dermatology clinic at Qassim University, Saudi
Arabia, between October 2016 and March 2017. The Medical
Research Ethics Committee in the College of Medicine at
Qassim University approved the study with the approval
number 15/18/13. The study was conducted in the cold weather
seasons to minimize the effect of seasonal variation on vitamin
D levels. Of the enrolled AV patients (n=68), 30.88%, 38.24%,
and 30.88% had mild, moderate, and severe acne, respectively.
Before initiating the study, a written informed consent was
received from the participants after explaining the aim, value,
and necessary steps in a simplified manner and the potential
side effects of isotretinoin drugs.
Acne was graded and classified as mild, moderate, or
severe. Mild acne was marked by <20 comedones, <15
inflammatory lesions, or a total lesion count <30. Moderate
acne was characterized by 20–100 comedones, 15–50
inflammatory lesions, or a total lesion count of 30–125. Severe
acne required >5 pseudocysts, a total comedones count >100, a
total inflammatory count >50, or a total lesion count >125 [13].
All 68 subjects completed a data collection form to provide
their demographics, family history of acne, sun exposure >2
hours/day, age of onset, duration of disease, site of acne (face,
chest, or back), past medical history, and other relevant
variables.
Inclusion Criteria: Patients from 15 to 35 years of age with
Al-Dhubaibi et al.
AV, irrespective of sex, and who did not opt for acne
treatments for at least the previous four weeks and patients who
were unresponsive to conventional topical therapies or
systemic antibiotics (other than systemic isotretinoin) were
included in this study.
Exclusion Criteria: Pregnant and breastfeeding, patients
taking vitamin D supplements for any reason, and patients who
were on a concurrent treatment for acne were excluded.
2.2. Treatment
All patients were treated with isotretinoin (0.5–1 mg/kg/d)
adjusted to 30–40 mg/day for three months. Serum beta HCG
tests were performed for all female patients before starting the
treatment.
2.3. Biochemical and Laboratory Analysis
2.3.1. Serum Vitamin D Concentration Measurements
Patients had their baseline serum 25-hydroxyvitamin D
(25(OH)D) concentrations measured. Blood samples were
collected from veins and analyzed within 24 h of sampling
using the Roche Cobas e411 (Roche Diagnostics System,
Switzerland). Based on the guidelines of the Food and
Nutrition Board of the Institute of Medicine, 25(OH)D serum
levels were categorized into adequate (>20 ng/ml), inadequate
(12–20 ng/ml), or deficient (<12 ng/ml) categories [14].
2.3.2. Lipid Profile Measurements
Estimation of lipid profile: Plasma levels for triglycerides
(TG) and Total Cholesterol (TC) were measured by
standardized enzymatic procedures, using kits supplied by
Roche Diagnostics (Mannheim, Germany) on the Olympus AU
400 automated clinical chemistry analyzer.
2.3.3. Liver Function Test measurements.
Serum AST was estimated using the Aspartate
Aminotransferase (AST) Activity Assay Kit Catalog Number
MAK055 (Sigma-Aldrich, USA). Serum ALT was evaluated
using the Alanine Aminotransferase Activity Assay Kit
Catalog Number MAK052 (Sigma-Aldrich, USA).
2.3.4. Statistical Analysis
Recorded data were analyzed using the Statistical Package
for Social Sciences, version 20.0 (SPSS Inc., Chicago, Illinois,
USA). An analysis of variance (ANOVA) test was performed
between more than two means t-tests and chi-squares to
analyze the mean and percentage differences. A significance
level of P≤0.001 was considered highly significant, and P
≥0.05 was deemed to be insignificant. Furthermore, the
quantitative data were expressed as a mean ± Standard
Deviation (SD), while the qualitative data were expressed as
frequency and percentage.
3. RESULTS
The study included 68 patients with AV (41 females and
27 males). Table 1 presents the participants’ baseline
demographics and clinical characteristics [15].
Different Stages of Acne Vulgaris Patients Treated with Isotretinoin The Open Dermatology Journal, 2021, Volume 15 13

Table 1. Baseline demographic and clinical characteristics However, this was only significant in the mild acne group
of acne vulgaris patients [15]. (P=0.003; Tables 3 and 4).
Table 3. The relationship between acne vulgaris severity
Characteristic Patients with Acne patients and serum concentration of vitamin D [25 (OH) D]
Vulgaris before and 3 months after isotretinoin treatment.
N (68)
Gender Moderate Severe
Male N (%) 27 (39.7%) Mild Acne
Acne Acne ANOVA -
Female N (%) 41 (60.3%) Vulgaris
Parameters Vulgaris Vulgaris Test P-
Patients
Age, year N Patients Patients value
(N=21)
Male N (mean±SD) (20.7±3.8) (N=26) (N=21)
Female N (mean±SD) (21.3±3.6) Serum vitamin D 26±9.4 31.4±6.9 28.4±6.7 0.067
Sun–exposure ˃2 hours per day N (%) 14 (20.5%) level (ng/ml)
Positive family history of acne N (%) 29 (42.65%) before
isotretinoin
Age at onset of disease, years 16.55±4.99 treatment.
Duration of the disease, years (mean±SD) 4.8±0.8 (mean±SD)
Site of acne Serum vitamin D 35.6±6.5 32.14±7.1 32.9±4.9 0.773
Face N (%) 68 (100%) level
Chest N (%) 24 (35.3%) (ng/ml) 3 months
Back N (%) 40 (54.41) after isotretinoin
The severity of the disease treatment.
Mild N (%) 21 (30.88%) (mean±SD)
Moderate N (%) 26 (38.24%) N=Number and SD=Standard deviation.
Severe N (%) 21 (30.88%)
N=Number, SD=Stander deviation, % =percentage.
Table 4. Comparison between means ± SD of serum
The study reveals an overall non-significant increase in concentration of vitamin D [25 (OH) D] before and 3
vitamin D levels, lipid profiles, and liver enzymes in all months after isotretinoin treatment in patients with mild,
patients regardless of disease severity three months after moderate, and severe acne vulgaris.
starting isotretinoin treatment (Table 2).
Serum vitamin D
Table 2. Comparison between means ± SD of serum Serum vitamin D
level (ng/ml)
concentration of vitamin D [25 (OH) D], lipid profiles, and level (ng/ml) T-test
Parameters (mean±SD)
liver enzymes before and 3 months after isotretinoin (mean±SD) P-value
Before
After Treatment
treatment in patients with acne vulgaris. Treatment
Mild Acne vulgaris 26±9.4 35.6±6.5 0.003**
Before After 3 months T-Test (N=21)
Parameters
treatment of treatment P-value Moderate Acne 31.4±6.9 32.14±7.1 0.990
Serum vitamin D level 28.8±7.9 33.4±6.8 0.327 vulgaris (N=26)
(ng/ml) (mean±SD) Severe Acne 28.4±6.7 32.9±4.9 0.081
Serum AST (u/l) 29.69±8.4 36.46±11 0.305 vulgaris (N=21)
(mean±SD) N = Number, SD = Standard deviation.
Serum ALT (u/l) 26.6±7 32.5±9.09 0.132 No significant change in lipid profile mean values were
(mean±SD)
detected in all subgroups mild, moderate, and severe acne
Triglyceride (mg/dl) 102.23±12.3 106.46±16.6 0.838 throughout the study while in liver enzymes, only serum AST
(mean±SD)
were significant in severe acne vulgaris after treatment with P-
Cholesterol (mg/dl) 170.5±13.9 236.8±18.4 0.412 value 0.011 (Table 5).
(mean±SD)
SD=Standard deviation, AST=Aspartate Aminotransferase, and ALT=Alanine
Aminotransferase.
4. DISCUSSION

At baseline, the vitamin D level was 26±9.4ng/ml for
patients in the mild acne group and 31.4±6.9ng/ml for patients
in the moderate acne group, while in patients with severe acne,
it was 28.4±6.7 ng/ml. There were no significant variations in
serum vitamin D levels between the mild, moderate, and severe
acne groups (P=0.067), as levels were maintained post-
treatment with isotretinoin (P=0.773). Three months after
starting isotretinoin treatment, an increase in the mean value of
serum vitamin D levels in mild, moderate, and severe acne was
reported (35.6±6.5, 32.14±7.1, and 32.9±4.9, respectively).
The role of vitamin D in acne pathogenesis has been
reported in different studies. Vitamin D regulates the immune
system and the growth of various cell types, including
proliferation, differentiation of sebocytes, and keratinocytes.
Vitamin D demonstrates both anticomedogenic and antioxidant
effects, and it exerts its influence by binding to intranuclear
vitamin D receptor (VDR), which is part of the trans-acting
transcriptional regulatory factors superfamily that also includes
a steroid receptor, thyroid hormone receptors, both Retinoic
Acid Receptors (RAR), and Retinoid-X Receptor (RXR) [12,
16].
14 The Open Dermatology Journal, 2021, Volume 15 Al-Dhubaibi et al.

Table 5. Comparison between means ± SD of lipid profiles, and liver enzymes at baseline and 3 months after isotretinoin
treatment in patients with mild, moderate, and severe acne vulgaris.

T-test
Parameters At baseline 3 Months
P-value
Mild Acne (N=21)
Serum AST (u/l) (mean±SD) 24±1.14 24±2.3 0.353
Serum ALT (u/l) (mean±SD) 29±5.7 28±2.3 0.987
Triglyceride (mg/dl) (mean±SD) 60±2.8 66.5±1.5 0.759
Cholesterol (mg/dl) (mean±SD) 132±12.1 143±13.5 0.432
Moderate Acne (N=26)
Serum AST (u/l) (mean±SD) 23.2±4.8 25±4.6 0.484
Serum ALT (u/l) (mean±SD) 22±7.6 29±6.2 0.247
Triglyceride (mg/dl) (mean±SD) 111±12.8 140±11.6 0.392
Cholesterol (mg/dl) (mean±SD) 165±13.2 171±12.7 0.368
- Severe Acne (N=21)
Serum AST (u/l) (mean±SD) 28.5±8.3 41±2.3 0.011**
Serum ALT (u/l) (mean±SD) 30±2.3 41.5±5.6 0.222
Triglyceride (mg/dl) (mean±SD) 132±18.5 104±15.3 0.479
Cholesterol (mg/dl) (mean±SD) 180±9.7 197±1.3 0.463
N = Number, SD = Standard deviation, AST =Aspartate Aminotransferase and ALT =Alanine Aminotransferase.
** mild significant differences P ≤ 0.005

There is an established interaction between these receptors.
RXR exerts a dimerizing effect on VDR receptors, and
heterodimers can also be formed between them (VDR/RXR)
[17]. In addition to the impact on RXR responsive genes, RXR
selective retinoids could also influence vitamin D responsive
genes. Furthermore, vitamin D could also regulate RXR
responsive genes [18]. Although isotretinoin has a low affinity
to retinoid receptors, it is converted intracellularly,
demonstrating an agonist effect on RAR and RXR receptors
[19].
Systemic isotretinoin is a potent acne treatment that affects
all four pathogenic factors of the disease, suppressing sebum
production and the abnormal desquamation of the sebaceous
follicle epithelium and decreasing cutibacterium acne and
inflammation [20]. Systemic isotretinoin also demonstrates an
inhibitory effect on Th17 development and IL-17 [21].
The results of this study revealed that there was an increase
in vitamin D levels after three months of isotretinoin treatment,
with a significant difference in the mild acne group only
(P=0.0003). What is interesting, no existed theoretical
explanation by authors behind this which could be further
investigated by future studies. Our results were nearly similar
to El-Hamd et al. study [22]. On the other hand, a study by
Moravvej H et al. showed no effect on serum vitamin D levels
after recommended dose of oral isotretinoin [23], while the
result of another study of Ertugrul et al. showed increased
1,25-dihydroxyvitamin D levels and decreased 25-
hydroxyvitamin D levels after isotretinoin treatment [24]. The
possible rationale behind the contradicting results of these
studies is that there might be differences in inclusions and
exclusions criteria or in other methodologies’ sittings of those
studies that had affected the results.
The results of our study and other studies focus on the
active role of vitamin D deficiency and its effect on the
development of AV, which can be illustrated by the role of
cutibacterium acnes in increasing the gene expression of
immunological factors to block vitamin D production [25, 26].
This highlights the promising role of vitamin D in AV
treatment. In our results, the absence of statistically significant
differences between vitamin D and AV severity is mostly due
to the small sample size.
The results in this study for lipid profiles and liver function
showed an insignificant increase after three months of oral
isotretinoin treatment which is similar to other studies [22].
CONCLUSION
Vitamin D plays a role in acne pathogenesis and its level
are altered in acne vulgaris. Serum 25-hydroxyvitamin D levels
increased after three months of oral isotretinoin therapy, and
the effect was significant in mild acne patients. Oral
isotretinoin and its influence on vitamin D serum levels in acne
patients might highlight vitamin D as a possible target for acne
therapy. Furthermore, vitamin D might be considered a
biomarker for disease activity and remission.
Further studies on a larger scale are needed to address the
effect of isotretinoin in improving vitamin D levels and the
exact role of vitamin D deficiency in the pathogenesis of acne,
as well as the possible therapeutic effect of vitamin D
preparations in acne vulgaris.
ETHICS APPROVAL AND CONSENT TO PARTI-
CIPATE
The Medical Research Ethics Committee in the College of
Medicine at Qassim University approved the study with the
approval number 15/18/13.
HUMAN AND ANIMAL RIGHTS
No Animals were used in this research. All human research
procedures followed were in accordance with the ethical
Different Stages of Acne Vulgaris Patients Treated with Isotretinoin
standards of the committee responsible for human
experimentation (institutional and national), and with the
Helsinki Declaration of 1975, as revised in 2013.
CONSENT FOR PUBLICATION
Informed consent was obtained from all the participants.
AVAILABILITY OF DATA AND MATERIALS
The data that support the findings of this study are
available from the corresponding author (G.A) upon reasonable
request.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Thanks for Clinical, Cosmetic and Investigational
Dermatology Journal and Dove press Ltd and authors of the
article titled “Vitamin D Levels in Patients with and without
Acne and Its Relation to Acne Severity: A Case-Control
Study” for the permission to use their data in Table 1 as a
reference in our research article.
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available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the
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