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\begin{document}

\title{The correlation of monocyte to high-density lipoprotein ratio with uric
acid and possible atherosclerotic pathway in patients treated with
isotretinoin}



\author[1]{Nurcan Metin}%
\author[2]{Cagri Turan}%
\affil[1]{Affiliation not available}%
\affil[2]{Erzurum Training and Research Hospital}%


\vspace{-1em}



  
  \date{June 02, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Purpose: We aimed to reveal the relationship of uric acid with MHR and
other inflammatory markers acne patients before and after isotretinoin
treatment. In this way, we can try to shed light on the relationship
between isotretinoin treatment and atherosclerosis. Methods: Two hundred
twenty-four acne patients who administered isotretinoin (0.5-1
mg/kg/day) were enrolled in the study. In the pre-treatment phase and 3
months after treatment, MHR, SUA, mean platelet volume, plateletcrit,
neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio,
monocyte-lymphocyte ratio, serum triglyceride, total cholesterol,
high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels
of the patients were analyzed. Results: Compared to the pre-treatment
phase, three months after treatment, there was a statistically decrease
in neutrophil count and an increase in lymphocyte count (p: 0.002, p:
0.011; respectively). Accordingly, there was a statistically significant
decrease in NLR (p: 0.001). It was noteworthy that MHR and SUA levels
increased significantly (p: 0.042, p: 0.010; respectively) and there was
a positive correlation between SUA level and MHR (r: 0.212, p: 0.012).
Serum total cholesterol, LDL, and triglyceride levels increased and HDL
levels decreased significantly after treatment (p: 0,001). Conclusion:
This study contributes to the comprehension of the relationship between
isotretinoin treatment and atherosclerosis, which has been frequently
reported in the literature. It was thought that the isotretinoin-induced
uric acid increase might be related to dyslipidemia. Isotretinoin may
initiate the atherosclerotic process in vascular endothelial and smooth
muscles, with uric acid increase and HDL decrease. An increase in MHR is
also an inflammatory marker indicating this process.%
\end{abstract}%



\sloppy


\section*{Introduction}

{\label{introduction}}

Acne is a common chronic inflammatory disease of the pilosebaceous unit.
Four key factors play a role in pathogenesis with interrelated
mechanisms, such as increased sebum production, hyperkeratinization of
the follicular infundibulum, inflammation, and \emph{Cutibacterium
acnes} proliferation. Primary lesion types in acne are comedones and
inflammatory lesions (papules, pustules, and nodules). The typical
distribution of acnes includes the face, upper back, chest, and
shoulders rich in sebaceous glands. The treatment approach can vary
depending on the type, distribution, severity, and degree of effect on
the patient.\textsuperscript{1}

Isotretinoin (ISO) is a synthetic analogue of vitamin
A\textsuperscript{2}. ISO treatment is effective in all four steps of
acne pathogenesis.\textsuperscript{2} However, it has numerous side
effects related to many systems such as hepatic, renal, musculoskeletal,
hematological, neuropsychiatric, and gastrointestinal systems. Also,
some conflicting publications have been reported on its relationship
with some inflammatory diseases such as inflammatory bowel disease and
sacroiliitis.\textsuperscript{2-4} In clinical practice, patients are
followed up with laboratory tests such as complete blood count (CBC),
liver and kidney function tests, and lipid profile.

Mean platelet volume (MPV) and plateletcrit (PTC) indicate the platelet
function and percentage of platelet volume in the blood; respectively.
MPV, PTC, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte
ratio (PLR) were used as inflammatory markers in various studies for
many diseases and drugs, including ISO
treatment.\textsuperscript{5-7}Monocyte to high-density lipoprotein
ratio (MHR) is a recently defined inflammatory biomarker associated with
metabolic syndrome and atherosclerosis.\textsuperscript{6,8} Separate
studies have reported an increase in MHR and carotid intima-media
thickness (CIMT) in acne patients after ISO
treatment.\textsuperscript{9,10} Although ISO is known to predispose to
hyperuricemia, there is not enough clear information in the literature
about the mechanism of triggering the increase in serum uric acid (SUA)
level.\textsuperscript{11} Lately, some studies emphasize that
hyperuricemia is a risk factor for both metabolic syndrome and
cardiovascular diseases (CVD), which is also associated with values such
as MHR and PLR.\textsuperscript{6,12,13} In a recent study consisting of
more than 8000 participants was reported for the first time in the
literature that MHR has a positive correlation with SUA and that it can
be used in predicting the risk stratification of
hyperuricemia.\textsuperscript{14}

In this study, we aimed to reveal the relationship of uric acid with MHR
and other inflammatory markers stated above, in moderate-severe acne
patients before and after ISO treatment. In this way, we can try to shed
light on the frequently reported relationship between ISO treatment and
atherosclerosis.

\section*{Materials and Methods}

{\label{materials-and-methods}}

Between 1 June- 31 December 2019, 224 patients with moderate-severe acne
vulgaris who administered oral ISO (0.5-1 mg/kg/day) at the Department
of Dermatology and Venereology of the Regional Training and Research
Hospital were included in this study. Written consent forms were
obtained from 203 adult patients and parents of 21 adolescent patients.
Patients who used any medication (iron, vitamin supplements, statins,
etc.) that could affect hematological parameters and lipid profile in
the last 3 months were excluded. All patients were selected from the
group of 15-35 years of age to be able to minimize the possibility of
atherosclerosis comorbidity as it may affect the inflammatory
parameters. Patients with cancer, severe infection, hematological
diseases (including iron-deficiency anemia), heart failure, and lung
diseases were excluded. Data such as gender, age, CBC, lipid profile,
and the serum alanine aminotransferase (ALT), aspartate aminotransferase
(AST), blood urea nitrogen (BUN), creatinine, and uric acid levels were
obtained from the electronic registration database. In the pre-treatment
phase and 3 months after treatment, white blood cell (WBC), neutrophil,
lymphocyte, monocyte and platelet counts, MPV, PTC, NLR, PLR,
monocyte/lymphocyte ratio (MLR), MHR, serum triglyceride (TG), total
cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein
(LDL) levels were analyzed.

This single-center cross-sectional retrospective-study was approved by
the Ethics Committee of the Regional Training and Research Hospital,
Erzurum, Turkey (Decision No: 2020/12-134). This study was conducted per
the latest version of the ''Helsinki Declaration'' and ''Guidelines for
Good Clinical Practice''.

Laboratory measurements

Blood samples of the patients were taken in ethylenediaminetetraacetic
acid (EDTA) tubes and CBC values, including the platelet, lymphocyte,
neutrophil, and monocyte counts, and MPV were measured using an
automated blood counting system (Beckman Coulter LH 780, Brea,
California, USA).

Statistical analysis

All data were analyzed using the IBM Statistical Package for the Social
Sciences (SPSS) version 21.0 and MS-Excel 2010 software. The normality
distribution of scale variables was checked using the Kolmogorov-Smirnov
test. Data were expressed as median (interquartile range) or mean \selectlanguage{ngerman}±
standard deviation for those with non-parametric or parametric
distribution, respectively. The paired sample t-test or Wilcoxon test
was used for dependent samples, whichever is appropriate. Independent
samples were compared with the Mann-Whitney U test. Pearson's chi-square
test was used for categorical variables. Scale data were compared with
Pearson's or Spearman's correlation tests according to their
distributions. Two-sided p-values less than 0.05 were considered
statistically significant.

\section*{Results}

{\label{results}}

Of the 244 acne patients participating in the study, 173 were women
(77.2\%). The mean age of the patients was 21.0 ± 3.5 years. There was
no difference between genders in terms of age (p: 0.263). The changes in
laboratory parameters in the 3\textsuperscript{rd} month of ISO
treatment compared to the 0\textsuperscript{th} month are presented in
Table 1. After treatment, there was a statistically decrease in
neutrophil count and an increase in lymphocyte count (p: 0.002, p:
0.011; respectively). Accordingly, there was a statistically significant
decrease in NLR (p: 0.001). A statistically significant increase in
total cholesterol, LDL, triglyceride levels, and a significant decrease
in HDL levels were found (p \textless{} 0.001). It was noteworthy that
MHR and SUA levels increased significantly (p: 0.042, p: 0.010;
respectively). Correlations of SUA levels with laboratory parameters
before and after treatment were presented in Table 2. SUA and hemoglobin
levels were moderately positively correlated (r: 0.439, p \textless{}
0.001 and r: 0.473, p \textless{} 0.001; respectively). Although there
was no significant relationship between SUA level with total
cholesterol, LDL, and triglyceride levels before treatment, a weakly
significant relationship was found between them after treatment (Table
2). The correlation between MHR and SUA levels before and after
treatment was statistically significant (r: 0.157, p: 0.048; r: 0.212,
p: 0.012; respectively).

\section*{Discussion}

{\label{discussion}}

Chiang et al. stated that hyperuricemia could be a sign of a metabolic
disorder that is a precursor of hypertension, hypertriglyceridemia and
diabetes mellitus, and high SUA levels may play a role in CVD
development.\textsuperscript{15} Kang et al. emphasized that
hyperuricemia can induce CRP mRNA expression in vascular endothelium and
smooth muscle cells and reduce nitric oxide (NO)
release.\textsuperscript{16} In another study of a murine model with
metabolic syndrome, hyperuricemia was reported to cause a
proinflammatory endocrine imbalance in adipose
tissue.\textsuperscript{17} Although the association of atherogenic
dyslipidemia (high TG and LDL and low HDL levels) and hyperuricemia was
reported in many other studies, the physiopathology of this association
has not been fully elucidated yet.\textsuperscript{18,19} Inconsistent
with the previous studies, we have found that there was a statistically
significant increase in SUA levels in the 3\textsuperscript{rd} month of
ISO treatment. We have also found higher SUA levels in patients with
atherogenic dyslipidemia.

Various studies reported that ISO treatment could increase the
inflammatory response and oxidative stress.\textsuperscript{20,21} Among
the inflammation biomarkers, we have found that only MHR values
significantly increased. MPV, PLR, and PCT values did not change, and
NLR values decreased significantly. We have found no correlation between
hyperuricemia and these inflammation biomarkers other than MHR. There
are contradictory studies in the literature about the effects of ISO on
CBC test parameters.\textsuperscript{10,22,23} In contrast to the study
of Önder et al., we have found a significant decrease in NLR values in
the 3\textsuperscript{rd} month of ISO treatment, similar to the study
of Duman et al.\textsuperscript{10,23} ISO was reported to have an
anti-inflammatory effect on patients with acne vulgaris by suppressing
the chemotaxis of WBCs.\textsuperscript{24} It was thought that the
decrease in NLR values indicated the anti-inflammatory effect of ISO.

Recent clinical and epidemiological studies have shown that MHR could
predict various inflammatory diseases such as metabolic syndrome,
diabetes mellitus, CVD, and acne
vulgaris.\textsuperscript{8,10,13,25,26} Similarly, we have found a
statistically significant increase in MHR values in the
3\textsuperscript{rd} month of ISO treatment. Monocytes interact with
the damaged endothelium and cause gene overexpression of proinflammatory
cytokines and adhesion molecules. On the other hand, HDL-cholesterol has
anti-inflammatory, antioxidant, and vasorelaxant
effects.\textsuperscript{27,28} The relationships between MHR and SUA
with inflammatory diseases are similar.\textsuperscript{15} We have
found that MHR values and SUA levels showed a weakly positive
correlation both before and after ISO treatment. As far as we know, the
relationship between MHR and SUA has not been reported in patients
receiving ISO treatment to date. Both of these parameters are associated
with atherosclerosis and metabolic syndrome. It was found that CIMT
increases after 4 months in acne patients receiving ISO treatment, so it
has been suggested that long-term ISO use increased atherosclerosis
risk.\textsuperscript{9} In another study, it was claimed that ISO
triggered the development of subclinical atherosclerosis in
men.\textsuperscript{29} In the light of all these data and the findings
of our study, we can explain the atherosclerosis pathway seen in Figure
1. It was thought that the ISO-induced uric acid increase might be
related to dyslipidemia. ISO may initiate the atherosclerotic process in
vascular endothelial and smooth muscles, with uric acid increase and HDL
decrease. An increase in MHR value is also an inflammatory marker
indicating this process.

The limitations of our study were that the study was retrospective, and
other commonly used systemic inflammatory markers such as high sensitive
C-reactive protein, erythrocyte sedimentation rate, and d-dimer were not
evaluated. We could not create a ''healthy control group'' because our
study was retrospective and a comprehensive study reported that there
was already a relationship between SUA and MHR.

In conclusion, this study contributes to the comprehension of the
relationship between ISO treatment and atherosclerosis, which has been
frequently reported in the literature. However, our study is
insufficient to establish a cause-result link. More comprehensive
studies are needed.

\textbf{References}

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2. Brzezinski P, Borowska K, Chiriac A, Smigielski J. Adverse effects of
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3. Crockett SD, Porter CQ, Martin CF, Sandler RS, Kappelman MD.
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4. Baykal Selçuk L, Aksu Ar\selectlanguage{polish}ı\selectlanguage{english}ca D, Baykal \selectlanguage{polish}Ş\selectlanguage{english}ahin H, Yayl\selectlanguage{polish}ı \selectlanguage{english}S, Bahad\selectlanguage{polish}ı\selectlanguage{english}r S.
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15. Chiang K-M, Tsay Y-C, Vincent Ng T-C, et al. Is hyperuricemia, an
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16. Kang D-H, Park S-K, Lee I-K, Johnson RJ. Uric acid--induced
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17. Baldwin W, McRae S, Marek G, et al. Hyperuricemia as a mediator of
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19. Peng T-C, Wang C-C, Kao T-W, et al. Relationship between
hyperuricemia and lipid profiles in US adults. Biomed Res Int 2015;2015.

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Isotretinoin therapy induces DNA oxidative damage. Clin Chem Lab Med
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21. Ozkol HU, Ozkol H, Karadag AS, Bilgili SG, Tuluce Y, Calka O. Oral
isotretinoin therapy of acne patients decreases serum paraoxonase-1
activity through increasing oxidative stress. Drug Chem Toxicol
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22. Tamer F, Yüksel ME, Avc\selectlanguage{polish}ı \selectlanguage{english}E. Is mean platelet volume an inflammatory
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23. Duman N, Uzunali E, Manav V. A comparative study on hematological
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24. Karadag A, Ertugrul D, Bilgili S, Takci Z, Akin K, Calka O.
Immunoregulatory effects of isotretinoin in patients with acne. Br J
Dermatol 2012;167(2):433-435.

25. Satilmis S. Role of the monocyte-to-high-density lipoprotein ratio
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26. Turkmen D, Altunisik N, Sener S. Investigation of monocyte HDL ratio
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27. Thacker SG, Zarzour A, Chen Y, et al. High-density lipoprotein
reduces inflammation from cholesterol crystals by inhibiting
inflammasome activation. Immunology 2016;149(3):306-319.

28. Mestas J, Ley K. Monocyte-endothelial cell interactions in the
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2008;18(6):228-232.

29. Karap\selectlanguage{polish}ı\selectlanguage{english}nar T, Polat M, Bu\selectlanguage{polish}ğ\selectlanguage{english}dayc\selectlanguage{polish}ı \selectlanguage{english}G. Evaluation of subclinical
atherosclerosis in Turkish patients with acne vulgaris receiving
systemic isotretinoin. Dermatol Ther 2020;33(3):e13307.



\section*{Tables}

{\label{tables}}

\textbf{Table 1. Change in blood parameters compared to
0\textsuperscript{th} month in the 3\textsuperscript{rd} month of ISO
treatment}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Parameters} & \textbf{n} & \textbf{Isotretinoin treatment} &
\textbf{Isotretinoin treatment} & \emph{p}\textbf{-value}\tabularnewline
& & \textbf{0\textsuperscript{th} month (Basal)} &
\textbf{3\textsuperscript{rd} month} &\tabularnewline
Hemoglobin (g/dl) & 224 & 14.2 (2.1) & 14.3 (1.7) & 0.094\tabularnewline
White blood cell (10\textsuperscript{6}/l) & 224 & 7580 (2430) & 7420
(2380) & 0.250\tabularnewline
Neutrophil (10\textsuperscript{6}/l) & 222 & 4400 (1870) & 3910 (1790) &
\textbf{0.002}\tabularnewline
Lymphocyte (10\textsuperscript{6}/l) & 224 & 2330 (840) & 2400 (950) &
\textbf{0.011}\tabularnewline
Monocytes (10\textsuperscript{6}/l) & 222 & 600 (270) & 590 (250) &
0.778\tabularnewline
Platelet (10\textsuperscript{9}/l) & 224 & 304 (84) & 311 (96) &
0.216\tabularnewline
PCT (10\textsuperscript{-2}) & 197 & 31 (9) & 31 (9) &
0.234\tabularnewline
MPV (fl) & 217 & 10.2 (1.3) & 10.2 (1.3) & 0.327\tabularnewline
NLR (10\textsuperscript{-2}) & 222 & 189 (88) & 161 (87) &
\textbf{0.001}\tabularnewline
MLR (10\textsuperscript{-2}) & 224 & 25 (15) & 25 (13) &
0.203\tabularnewline
PLR & 224 & 126.6 (53.4) & 128.9 (49.3) & 0.085\tabularnewline
Total cholesterol (mg/dl) & 220 & 161 (44) & 177 (48) &
\textbf{\textless{}0.001}\tabularnewline
HDL (mg/dl) & 199 & 51 (17) & 49 (16) &
\textbf{\textless{}0.001}\tabularnewline
LDL (mg/dl) & 220 & 92 (42) & 108 (39) &
\textbf{\textless{}0.001}\tabularnewline
Triglyceride (mg/dl) & 220 & 84 (47) & 106 (82) &
\textbf{\textless{}0.001}\tabularnewline
MHR (10\textsuperscript{5}/mg) & 198 & 11.9 (6.7) & 12.5 (7.3) &
\textbf{0.042}\tabularnewline
ALT (U/l) & 224 & 13 (7) & 13 (9) & 0.074\tabularnewline
AST (U/l) & 224 & 17 (4) & 18 (5) & 0.087\tabularnewline
BUN (mg/dl) & 224 & 13.3 \selectlanguage{ngerman}± 4.1 & 12.5 \selectlanguage{ngerman}± 3.9 & 0.156*\tabularnewline
Creatinine (mg/dl) & 224 & 0.75 \selectlanguage{ngerman}± 0.10 & 0.75 \selectlanguage{ngerman}± 0.07 &
0.405*\tabularnewline
Uric acid (mg/dl) & 135 & 4.39 \selectlanguage{ngerman}± 1.30 & 4.54 \selectlanguage{ngerman}± 1.38 &
\textbf{0.010*}\tabularnewline
Data are expressed as median (interquartile range) or mean \selectlanguage{ngerman}± standard
deviation for those with non-parametric or parametric distribution,
respectively. *Paired sample t-test was used. Wilcoxon test was used for
all others. Significant values were shown in bold. PCT: Plateletcrit;
MPV: Mean platelet volume; NLR: Neutrophil/lymphocyte ratio; MLR:
Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio; HDL: High
density lipoprotein; LDL: Low density lipoprotein; MHR: Monocytes/ high
density lipoprotein ratio; ALT: Alanine aminotransferase; AST: Aspartate
aminotransferase; BUN: Blood urea nitrogen & Data are expressed as
median (interquartile range) or mean \selectlanguage{ngerman}± standard deviation for those with
non-parametric or parametric distribution, respectively. *Paired sample
t-test was used. Wilcoxon test was used for all others. Significant
values were shown in bold. PCT: Plateletcrit; MPV: Mean platelet volume;
NLR: Neutrophil/lymphocyte ratio; MLR: Monocytes/lymphocyte ratio; PLR:
Platelet/lymphocyte ratio; HDL: High density lipoprotein; LDL: Low
density lipoprotein; MHR: Monocytes/ high density lipoprotein ratio;
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN:
Blood urea nitrogen & Data are expressed as median (interquartile range)
or mean \selectlanguage{ngerman}± standard deviation for those with non-parametric or parametric
distribution, respectively. *Paired sample t-test was used. Wilcoxon
test was used for all others. Significant values were shown in bold.
PCT: Plateletcrit; MPV: Mean platelet volume; NLR: Neutrophil/lymphocyte
ratio; MLR: Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio;
HDL: High density lipoprotein; LDL: Low density lipoprotein; MHR:
Monocytes/ high density lipoprotein ratio; ALT: Alanine
aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea
nitrogen & Data are expressed as median (interquartile range) or mean \selectlanguage{ngerman}±
standard deviation for those with non-parametric or parametric
distribution, respectively. *Paired sample t-test was used. Wilcoxon
test was used for all others. Significant values were shown in bold.
PCT: Plateletcrit; MPV: Mean platelet volume; NLR: Neutrophil/lymphocyte
ratio; MLR: Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio;
HDL: High density lipoprotein; LDL: Low density lipoprotein; MHR:
Monocytes/ high density lipoprotein ratio; ALT: Alanine
aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea
nitrogen & Data are expressed as median (interquartile range) or mean \selectlanguage{ngerman}±
standard deviation for those with non-parametric or parametric
distribution, respectively. *Paired sample t-test was used. Wilcoxon
test was used for all others. Significant values were shown in bold.
PCT: Plateletcrit; MPV: Mean platelet volume; NLR: Neutrophil/lymphocyte
ratio; MLR: Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio;
HDL: High density lipoprotein; LDL: Low density lipoprotein; MHR:
Monocytes/ high density lipoprotein ratio; ALT: Alanine
aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea
nitrogen\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}



\textbf{Table 2. Correlation of blood parameters with SUA levels at
0\textsuperscript{th} and 3\textsuperscript{rd} months}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Parameters} & \textbf{Correlation with uric acid} &
\textbf{Correlation with uric acid} & \textbf{Correlation with uric
acid} & \textbf{Correlation with uric acid}\tabularnewline
& \textbf{0\textsuperscript{th} month} (n: 137) &
\textbf{0\textsuperscript{th} month} (n: 137) &
\textbf{3\textsuperscript{rd} month} (n: 143) &
\textbf{3\textsuperscript{rd} month} (n: 143)\tabularnewline
& \textbf{r} & \emph{p}\textbf{-value} & \textbf{r} &
\emph{p}\textbf{-value}\tabularnewline
Hemoglobin (g/dl) & \textbf{+0.439} & \textbf{\textless{}0.001} &
\textbf{+0.473} & \textbf{\textless{}0.001}\tabularnewline
White blood cell (10\textsuperscript{6}/l) & - 0.007 & 0.936 & +0.086 &
0.126\tabularnewline
Neutrophil (10\textsuperscript{6}/l) & +0.033 & 0.700 & +0.130 &
0.123\tabularnewline
Lymphocyte (10\textsuperscript{6}/l) & - 0.046 & 0.591 & +0.046 &
0.584\tabularnewline
Monocytes (10\textsuperscript{6}/l) & +0.072 & 0.400 & +0.117 &
0.166\tabularnewline
Platelet (10\textsuperscript{9}/l) & - 0.097 & 0.260 & - 0.073 &
0.139\tabularnewline
PCT (10\textsuperscript{-2}) & - 0.092 & 0.288 & - 0.112 &
0.191\tabularnewline
MPV (fl) & +0.054 & 0.532 & +0.111 & 0.190\tabularnewline
NLR (10\textsuperscript{-2}) & +0.077 & 0.375 & +0.047 &
0.579\tabularnewline
MLR (10\textsuperscript{-2}) & +0.154 & 0.073 & +0.030 &
0.719\tabularnewline
PLR & +0.029 & 0.734 & - 0.129 & 0.125\tabularnewline
Total cholesterol (mg/dl) & +0.146 & 0.089 & +0.210 &
\textbf{0.012}\tabularnewline
HDL (mg/dl) & - \textbf{0.173} & \textbf{0.044} & \textbf{- 0.268} &
\textbf{0.001}\tabularnewline
LDL (mg/dl) & +0.154 & 0.074 & +0.285 & \textbf{0.001}\tabularnewline
Triglyceride (mg/dl) & +0.134 & 0.119 & +0.286 &
\textbf{0.001}\tabularnewline
MHR (10\textsuperscript{5}/mg) & \textbf{+0.157} & \textbf{0.048} &
\textbf{+0.212} & \textbf{0.012}\tabularnewline
BUN (mg/dl) & \textbf{+0.252} & \textbf{0.009*} & \textbf{+0.557} &
\textbf{\textless{}0.001*}\tabularnewline
Creatinine (mg/dl) & \textbf{+0.456} & \textbf{0.010}* & \textbf{+0.591}
& \textbf{\textless{}0.001*}\tabularnewline
*Pearson's correlation was used. Spearman correlation was used for all
others. Significant values were shown in bold. PCT: Plateletcrit; MPV:
Mean platelet volume; NLR: Neutrophil/lymphocyte ratio; MLR:
Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio; HDL: High
density lipoprotein; LDL: Low density lipoprotein; MHR: Monocytes/ high
density lipoprotein ratio; BUN: Blood urea nitrogen & *Pearson's
correlation was used. Spearman correlation was used for all others.
Significant values were shown in bold. PCT: Plateletcrit; MPV: Mean
platelet volume; NLR: Neutrophil/lymphocyte ratio; MLR:
Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio; HDL: High
density lipoprotein; LDL: Low density lipoprotein; MHR: Monocytes/ high
density lipoprotein ratio; BUN: Blood urea nitrogen & *Pearson's
correlation was used. Spearman correlation was used for all others.
Significant values were shown in bold. PCT: Plateletcrit; MPV: Mean
platelet volume; NLR: Neutrophil/lymphocyte ratio; MLR:
Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio; HDL: High
density lipoprotein; LDL: Low density lipoprotein; MHR: Monocytes/ high
density lipoprotein ratio; BUN: Blood urea nitrogen & *Pearson's
correlation was used. Spearman correlation was used for all others.
Significant values were shown in bold. PCT: Plateletcrit; MPV: Mean
platelet volume; NLR: Neutrophil/lymphocyte ratio; MLR:
Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio; HDL: High
density lipoprotein; LDL: Low density lipoprotein; MHR: Monocytes/ high
density lipoprotein ratio; BUN: Blood urea nitrogen & *Pearson's
correlation was used. Spearman correlation was used for all others.
Significant values were shown in bold. PCT: Plateletcrit; MPV: Mean
platelet volume; NLR: Neutrophil/lymphocyte ratio; MLR:
Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio; HDL: High
density lipoprotein; LDL: Low density lipoprotein; MHR: Monocytes/ high
density lipoprotein ratio; BUN: Blood urea nitrogen\tabularnewline
\bottomrule
\end{longtable}



\textbf{Figures}

\textbf{Figure Legend}

\textbf{Figure 1.} Possible atherosclerotic pathway induced by
isotretinoin\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

