Volume 75, No.1: 2023 Siriraj Medical Journal https://he02.tci-thaijo.org/index.php/sirirajmedj/index
38
Prachya Maneeprasopchoke, M.D.*, Phoupong Phousamran, M.D.*, Warut Pongsapich, MD*, Paveena Pithuksurachai,
M.D.*, Jakrit Worrakulpanit, M.D.**, Tippanate Keawvijit***, Naravat Poungvarin, M.D., Ph.D.****, Kanchana
Amornpichetkul, M.D.*****, Cheerasook Chongkolwatana, M.D.*
*Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **Department of Otorhinolaryngology,
Bhumibol Adulyadej Hospital, Bangkok, ailand, ***Clinical Toxicology Laboratory, Siriraj Poison Control Center, Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok, ailand, ****Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok,
ailand, *****Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand.
A Comparison of Serum Copper Levels in Patients
with Papillary Thyroid Carcinoma, Nodular Goiter,
and Healthy Volunteers
ABSTRACT
Objective: Serum copper (Cu) is an essential trace element that plays a key role in thyroid hormone production. An
inappropriate level of serum Cu might be related to development of both benign and malignant thyroid neoplasm.
Nodular goiter and papillary thyroid carcinoma (PTC) are common benign and malignant tumors of the thyroid,
respectively. is study aims to compare the serum Cu levels of healthy women with women with PTC or nodular
goiter.
Materials and Methods: A total of 205 ai women were recruited for this cross-sectional study. e reference
group was comprised of 100 healthy volunteers. ere were 61 nodular goiter and 41 PTC patients that had been
treated with surgery. Serum Cu was measured using an atomic absorption spectrophotometer and the three groups
were compared.
Results: e serum Cu levels of the PTC, nodular goiter and the reference group were 0.93 (0.85, 1.11) μg/ml, 1.03
(0.90, 1.14) μg/ml and 0.97 (0.80, 1.11) μg/ml, respectively. e results were not statistically dierent (P = 0.10). A
post hoc subgroup analysis in the PTC group showed only serum Cu levels were signicantly higher in the blood
vessel invasion group (P = 0.02).
Conclusion: e serum Cu levels of patients with PTC and nodular goiter were not dierent and did not dier
signicantly from the reference group. Despite related to withonly one pattern of histopathologically aggressive PTC-
Blood vessel invasion, serum Cu levels cannot be used as an assistive tool for diagnosis and the prognosis of PTC.
Keywords: Serum copper (Cu); nodular goiter; papillary thyroid carcinoma; thyroid cancer; BRAF mutation (Siriraj
Med J 2023; 75: 38-45)
Corresponding author: Cheerasook Chongkolwatana
E-mail: cheerasook.cho@mahidol.ac.th
Received 8 September 2022 Revised 6 December 2022 Accepted 8 December 2022
ORCID ID:http://orcid.org/0000-0002-8423-6357
http://dx.doi.org/ 10.33192/smj.v75i1.260528
All material is licensed under terms of
the Creative Commons Attribution 4.0
International (CC-BY-NC-ND 4.0)
license unless otherwise stated.
INTRODUCTION
Serum Cu is an arbitrary marker for many types of
malignancies and is more available and less expensive
than genetic testing. Serum Cu levels rise signicantly in
many types of malignancies, such as esophageal cancer,
gynecologic cancer, pancreatic cancer, and melanoma.1-4
Why serum Cu is elevated in the presence of malignancy
is not yet clear. Copper may be a key factor in tumor
angiogenesis.5,6 Ceruloplasmin, the Cu-binding protein,
can increase in malignancies due to decreased metabolism
Maneeprasopchoke et al.
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Original Article SMJ
or an inammatory response state.7,8 Zhu et al. found that
Cu transportation in tumor cells increased as a result of
elevated expressions of transporter genes.9 Coates and
coauthors reported that the sensitivity and specicity of
high serum copper for the risk of developing a cancer
were 40% and 80.4%, respectively, but a cuto value was
not determined.10
Serum copper plays a key role in thyroid hormone
production.11 is trace element controls T4 levels by
regulating calcium homeostasis.12 An inappropriate
serum Cu level also stimulates the growth of transformed
cell by providing energy (ATP) in cell cycle process.13
Furthermore, Cu is an essential nutrient that be integrated
in the antioxidant process as a cofactor of the enzyme
superoxide dismutase, eliminating free radicals caused by
various tissue damage in the body.14 However, excessively
high Cu levels can cause abnormal cell growth by creating
free radicals and damaging DNA.15,16
Several studies have reported that the serum Cu
levels of patients with thyroid carcinoma were higher
than those of normal subjects.17-20 Additionally, Baltaci
et al. also found that serum Cu decreased aer removal
of thyroid tumors.21 In contrast, Al-Sayer et al. did not
identify a dierence between the serum Cu levels of patients
with thyroid cancer and healthy controls, and serum Cu
increased aer thyroidectomy.22 Due to insucient data
and inconclusive evidence, the association between serum
copper and thyroid cancer needs further investigation.
erefore, we aimed to compare the serum copper levels
of patients with PTC, nodular goiter and healthy ai
women.
MATERIALS AND METHODS
Study design
is cross-sectional study was conducted at the
Department of Otorhinolaryngology, Faculty of Medicine
Siriraj Hospital, from July 2018 to June 2021. Serum Cu
was measured by the Clinical Toxicology Laboratory of
the Faculty of Medicine Siriraj Hospital. e laboratory
has been certied to the ISO 15189 accreditation standard
since 2013. is study was approved by the Institutional
Review Board, Faculty of Medicine Siriraj Hospital,
Mahidol University (COA no. Si 367/2017) and was
conducted in accordance with the Declaration of Helsinki.
Study population
Diseases of the thyroid gland are generally more
common in females than males. In the ai population,
the female to male ratio of incidence of thyroid cancer
is approximately 4.3:1, and the gender ratio of thyroid
surgery was 5.2:1 during 2018-2020.23 Because serum Cu
levels can vary by gender,24 we investigated only female
patients. e sample size calculationwas based on the
primary assumption of dierences betweenserum Cu
in thyroid disease and the normal population.Totally,
we aimed to collect data from 100 patientswiththyroid
disease (PTC and nodular goiter) and 100 normal controls.
e thyroid disease group was consisted of ai women
aged 18 years and older who had thyroid nodules. Fine
needle aspiration was performed prior to surgery. All
patients with pathological reports of PTC or nodular goiter
who needed surgical treatment for thyroid diseases were
eligible. Patients with incidental papillary microcarcinoma,
thyroid carcinoma other than PTC, or other thyroid
or systemic diseases that could alter serum Cu levels
(i.e., thyroiditis, Wilson’s disease, pulmonary disease,
cardiovascular disease, infectious disease, and other
types of cancer) were excluded. Patients with current
medications or supplements that would alter serum Cu
levels, a history of previous thyroid surgery, or abnormal
levels of FT4 or TSH were also excluded. e reference
group consisted of healthy female volunteers with normal
thyroid glands conrmed by ultrasonography and blood
tests showing FT4, TSH, Cr, and eGFR within normal
limits. All study subjects were fully informed about the
treatment options and study protocol before signing
informed-consent forms.
Data collection
Demographic data and ultrasonographic ndings
of the thyroid gland were recorded. Blood samples were
tested for FT4, TSH, Cr, eGFR, and serum Cu levels. For
the cancer group, a pathology-conrmed specimen was
sent for detection of the BRAFV600E mutation using the
PCR-based Sanger sequencing technique combined with
allele-specic, real-time PCR. Adverse features such as
multifocality, blood vessel invasion, capsular invasion,
extrathyroidal extension and evidence of transformation
from coexisting nodular goiter were noted. e maximum
diameter of the tumors was recorded in centimeters. e
risk of recurrence was classied according to the 2015
guidelines of the American yroid Association.25 Stage
was classied using the 8th edition of the AJCC/TNM
staging system of thyroid cancer.26 If indicated, post-
treatment I-131 total body scans and serum thyroglobulin
(Tg) levels were used to detect residual diseases and
distant metastases.
Serum Cu level analysis
Blood samples 5 ml were collected with the standard
method in accordance with the Clinical and Laboratory
Standards Institute guidelines for trace element analysis.27
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40
Collection and access procedures were performed in the
patient ward one day before surgery with talc-free gloves,
a 21-gauge needle, and a BD Vacutainer plastic blood
collection tube for trace element testing (K2EDTA). e
tubes were kept upright and either immediately sent to the
Clinical Toxicology Laboratory or stored in a refrigerator
at 2º to 8º C for no longer than 24 hours. e samples
were prepared by centrifugation process (3500 round
per minute) for 10 minutes then the extracted plasma
0.5 ml was collected and diluted with deionized water
1 ml (1:2). Before analysis, internal quality assurance
for trace elements was routinely performed using Clin
Check Controls. Next, the sample was analyzed with a
ame atomic absorption spectrophotometer to produce
free atoms of Cu in the gaseous state. e absorbance of
light with the specic wavelength of Cu was measured.
e intensity of the absorbed light wave was proportional
to the amount of copper in the sample. Subsequently,
a standard calibration curve was plotted with linear
regression. Serum Cu levels were reported as mg/dl and
converted to μg/ml as a standard unit.
Statistical analysis
Demographic data are presented using descriptive
statistics. One-way analysis of variance was used to
compare the three groups (Reference, PTC, and nodular
goiter). If the P values were less than 0.05, post hoc analysis
was applied. Serum Cu levels (μg/ml) are reported as
median and interquartile range. Subgroup analyses of the
serum Cu levels of the PTC group were performed for
histopathological aggressiveness and BRAFV600E mutation
using the Mann-Whitney U test. Variant of PTC, risk
of recurrence and the TNM staging were compared by
one-way analysis of variance. Pearson’s correlation was
used to test the association between the size of the PTC
or nodular goiter and the serum Cu level. A P value of
< 0.05 was considered statistically signicant. Statistical
analyses were carried out using PASW Statistics for
Windows (version 18; SPSS Inc., Chicago, IL, USA).
RESULTS
Two hundred and twenty-two subjects were enrolled
and 17 were later excluded. e excluded subjects comprised
10 cases with papillary thyroid microcarcinoma, ve
cases with follicular thyroid carcinoma, and two cases
with thyroiditis. erefore, the study population was
205 subjects, consisting of 105 patients with thyroid
disease (44 with PTC and 61 with nodular goiter),
and 100 healthy controls. The unequal distribution
between PTC (n=44) and nodular goiter (n=61) was
due tothe enrollment nature of our cross-sectional
studydesignthataimed to recruit consecutive cases and
could notpreoperativelypredictthepathological results
of patients.
Serum Cu levels
e serum Cu levels of the PTC group, the nodular
goiter group and the reference group, were 0.93 (0.85,
1.11) μg/ml, 1.03 (0.90, 1.14) μg/ml and 0.97 (0.80, 1.11)
μg/ml, respectively (Fig 1). e results were not statistically
dierent (P = 0.10). Age, serum creatinine and eGFR
were signicantly dierent among the PTC, nodular
goiter and reference groups (Table 1). Aer adjustment
for age, serum creatinine and eGFR, there was still no
statistical dierence.
Fig 1. e serum Cu levels of the PTC
group, nodular goiter group and the
reference group were 0.93 (0.85, 1.11)
μg/ml, 1.03 (0.90, 1.14) μg/ml and 0.97
(0.80, 1.11) μg/ml, respectively
Maneeprasopchoke et al.
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TABLE 1. Demographic data and characteristics of PTC, nodular goiter, and the reference group.
Patient characteristics PTC Nodular goiter Reference P value
Median (IQR25,75) (n = 44) (n = 61) (n = 100)
Age (years) 45.00 (36.25, 56.25) 48.00 (36.00, 58.00) 37.00 (29.00, 51.00) 0.001*,a,b
Weight (kg) 57.55 (53.20, 68.80) 58.00 (50.00, 66.00) 54.00 (50.00, 65.00) 0.47
Height (cm) 157.00 (152.00, 161.50) 155.00 (153.00, 160.00) 156.00 (153.00, 160.00) 0.83
FT4 (ng/dL) 1.21 (1.08, 1.35) 1.20 (1.10, 1.29) 1.20 (1.08, 1.29) 0.42
TSH (uIU/mL) 1.44 (0.91, 2.76) 1.28 (0.80, 1.92) 1.79 (1.28, 2.49) 0.14
Cr (mg/dL) 0.71 (0.67, 0.83) 0.68 (0.60, 0.77) 0.67 (0.60, 0.74) < 0.001*,a,c
eGFR(L/min/1.73m2) 96.54 (86.08, 108.51) 101.18 (89.74, 110.12) 109.07 (99.94, 120.34) < 0.001*,a,b
* P values less than .05 considered statistically signicant.
a P value between reference and PTC was < 0.05
b P value between reference and nodular goiter was < 0.05
c P value between PTC and nodular goiter was < 0.05
Abbreviations: PTC, papillary thyroid carcinoma; FT4, free thyroxine; TSH, thyroid stimulating hormone; Cr, creatinine; eGFR, estimated
glomerular ltration rate.
PTC group
Histopathological aggressiveness
Of the 44 PTC cases, the classical variant was found
in 88.6% (n = 39) and the follicular variant in 6.8% (n =
3). Two patients (4.5%) had non-invasive encapsulated
follicular variant of papillary thyroid carcinoma (NIFTP).
Multifocal cancers were identied in 70.5% (n = 31) of
cases with no statistical dierence (P = 0.24). e serum
Cu in the blood vessel invasion group was signicantly
higher than those without invasion (Table 2). ere
were no signicant dierences in serum Cu levels for
coexisting nodular goiter, capsular invasion, extrathyroidal
extension, high- risk of recurrence and TNM staging.
ere was no correlation between tumor size and serum
Cu levels (r =-0.04; P = 0.81). Four patients (9.1%) had
distant metastases detected by I-131 total body scan.
eir serum Culevels were higher than those in the no
metastasis group, but no signicant dierence of 1.05
(0.91, 1.38) μg/ml, and 0.93 (0.84, 1.08) μg/ml, respectively
(P=0.26).Meanwhile,there was also no signicant
dierence of serum Cu levels among the subgroup of
PTC histopathological aggressiveness, nodular goiter
and healthy groups.
Molecular testing
e BRAFV600E mutation was positive in 20 patients
(45.5%) and negative in 24 (54.5%). e serum Cu levels
of BRAF-positive cases were not signicantly higher than
in the negative groups. 1.02 (0.86, 1.17) μg/ml, and 0.92
(0.83, 0.97) μg/ml, respectively; P = 0.06). Nevertheless, the
results from both groups remained within the reference
range.
Nodular goiter group
e correlation coecient between the diameters
of the nodular goiter and serum Cu levels was (r=
0.02; P = 0.89). e median serum Cu level in cases
of PTC with nodular goiter was 0.92 (0.87, 1.10) μg/ml
(n = 17), while the median serum Cu level for cases with
pure nodular goiter was 1.03 (0.90, 1.14) μg/ml (n = 61)
(P = 0.76).
DISCUSSION
We compared serum Cu levels of patients with PTC,
nodular goiter and normal healthy subjects. Zhang24 and
Shen12 reported that gender and ethnicity inuence serum
Cu levels and so we investigated only ai women, the
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TABLE 2. Comparison of the histopathological, molecular status, risk of recurrence and staging of 44 PTC cases
and their serum copper levels.
Histopathological n (%) Serum copper level (μg/ml) P value
aggressiveness
Coexisting nodular goiter Yes 17 (38.6) 0.92 (0.87, 1.10) 0.77
No 27 (61.4) 0.93 (0.84, 1.12)
Multifocal (Foci > 1) Yes 31 (70.5) 0.93 (0.85, 1.07) 0.24
No 13 (29.5) 0.93 (0.83, 1.17)
Blood vessel invasion Yes 26 (59.1) 1.01 (0.87, 1.16) 0.02*
No 18 (40.9) 0.89 (0.82, 0.96)
Capsular invasion Yes 25 (56.8) 0.93 (0.85, 1.16) 0.484
No 19 (43.2) 0.92 (0.85, 1.04)
Extrathyroidal extension Yes 20 (45.5) 0.92 (0.84, 1.04) 0.289
No 24 (54.5) 0.95 (0.86, 1.17)
Variant Classic 39 (88.6) 0.93 (0.85, 1.12) 0.50
Follicular 3 (6.8) 0.92 (0.87, 1.17)a
NIFTP 2 (4.5) 0.84 (0.75, 0.92)a
BRAFV600E mutation Yes 20 (45.5) 1.02 (0.86, 1.17) 0.06
No 24 (54.5) 0.92 (0.83, 0.97)
Risk of recurrence Low 11 (25) 0.92 (0.85, 1.04) 0.89
Intermediate 23 (52.3) 0.93 (0.82, 1.15)
High 10 (22.7) 0.92 (0.86, 1.24)
Tumor (T) T1 15 (34.1) 0.92 (0.84, 1.04) 0.59
T2 14 (31.8) 0.95 (0.86, 1.15)
T3 12 (27.3) 0.99 (0.83, 1.17)
T4 3 (6.8) 0.87 (0.86, 0.88)a
Node (N) N0 21 (47.7) 0.93 (0.86, 1.06) 0.99
N1 23 (52.3) 0.93 (0.83, 1.14)
Metastasis M0 40 (90.9) 0.93 (0.84, 1.08) 0.26
M1 4 (9.1) 1.05 (0.91, 1.38)
Stage 1 34 (77.3) 0.92 (0.84, 1.03) 0.76
2 7 (15.9) 1.08 (0.91, 1.15)
3 1 (2.3) 1.00†
4 2 (4.5) 1.19 (0.92, 1.45)a
* P values less than .05 considered statistically signicant.
† No min, max as there was only one data item for that category.
a Use min, max instead of interquartile range.
Abbreviations: NIFTP, Noninvasive follicular thyroid neoplasm with papillary-like nuclear features
Maneeprasopchoke et al.
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Original Article SMJ
gender most oen aected by this disease. e median
serum Cu levels of our reference group were comparable
to those in diverse populations (Table 3). e most
common method to measured serum Cu was the atomic
absorption spectrometry, so the median serum Cu levels
in healthy subjects of our study were very close to the
mean value of the studies that used this technique as well
as the biggest dataset in a Chinese population.20,24,28 e
results in the reference group showed reliable; However,
we did not identify any statistically signicant dierences
in the serum Cu levels among the PTC, nodular goiter,
and reference groups.
e use of Cu to support the diagnosis of thyroid
cancer remains inconclusive. Baltaci et al.21 showed
that serum Cu levels of women with thyroid cancer
were signicantly higher than those of healthy controls.
Additionally, the serum Cu levels of female patients with
thyroid cancer signicantly decreased to levels close
to those of the control group within two weeks aer
surgery. Vesna and colleagues17 compared 35 cases of
PTC and 13 cases of papillary thyroid microcarcinoma
with 82 cases of benign thyroid tumor. e serum Cu
levels of patients with PTC and microcarcinoma were
signicantly higher than patients with benign thyroid
tumor. However, because incidental microcarcinoma was
included in the PTC group, their ndings are challenging
to interpret and to compare with our study.
In 2015, Shen and colleagues published a meta-
analysis of ve case-control studies investigating serum
Cu levels.12 One study was carried out in China, three
in Poland, and one in Turkey. Overall, patients with
thyroid cancer had higher serum Cu levels than healthy
controls. However, consistent with our results, the Polish
studies did not nd higher serum Cu levels in patients
with thyroid cancer relative to their controls. A 2004
study from Kuwait also reported that serum Cu levels in
thyroid cancer patients were not dierent from healthy
controls and rose signicantly aer thyroidectomy.22
Hence, ethnicity can inuence serum Cu levels. Normally,
Cu is actively recycled in the digestive tract, body uids
and tissues, and is mainly excreted from the body via
bile. Copper levels are primarily controlled by recycling
and resorption, and dietary Cu represents only a small
proportion of total Cu resorption.15 erefore, dietary
intake of Cu has an insignicant eect on serum Cu
levels and does not need to be controlled.
In the post hoc subgroup analysis of PTC, we found
signicantly higher serum Cu levels in patients with blood
vessel invasion. Cu is postulated to be a potent stimulator
of tumor growth through its activation of angiogenic
factors.29 Nevertheless, the median serum Cu levels were
not statistically signicant in the presence of adverse
features such as positive capsular invasion, extrathyroidal
extension, lymph node involvement, distant metastases
and high stage. Although, this incidental nding is less
likely to demonstrate a relationship between serum Cu
levels and the aggressiveness of PTC, the association
between serum Cu levels and angiogenesis in thyroid
cancer requires further exploration. Furthermore, the
additional comparison of serum Cu in each subgroup of
TABLE 3. Serum copper levels in healthy subjects.
Studies Year Country Measurement N Sex Serum copper levels
technique (mean ± SD; μg/ml)
Maneeprasopchoke et al. 2022 Thailand AAS 100 Female 0.97 (0.80, 1.11) †
Zhang et al.24 2009 China AAS 890 Female 1.01 ± 0.24
Baltaci et al.21 2017 Turkey AES 15 Female 0.74 ± 0.24
Przybylik-Mazurek et al.28 2011 Poland AAS 20 All 1.11 ± 0.19
Kosova et al.20 2012 Turkey AAS 37 All 1.06 ± 0.11
Leung et al.19 1996 China AES 50 All 0.74 ± 0.19
Kucharzewski et al.18 2003 Poland TRXRF 50 All 0.69 ± 0.06
† Median and interquartile range
Abbreviations: AAS, atomic absorption spectrometry; AES, atomic emission spectrometry; TRXRF,
total reection uorescence
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44
PTC with nodular goiter to that of the healthy population
showed no signicant dierences. us, we cannot infer
that high serum Cu can be used to prognosticate the
invasiveness of PTC.
e potential relationship between serum Cu levels
and gene mutation in humans has not been studied.
Since copper regulates the function of follicular cells,
aberrant levels of serum Cu may be associated with
molecular alterations. Currently, there are several genetic
mutations reported in thyroid cancer and the BRAFV600E
mutation is the most common biomarker for PTC.
Brady et al. demonstrated that Cu is required for BRAF
signaling and tumorigenesis. A reduction in serum Cu
levels caused the size of BRAFV600E-driven melanomas to
decrease in laboratory animals.30 A recent investigation by
Baldari et al. also found that Cu-chelating agents reduced
the proliferation, survival, and migration of human
colon cancer cells carrying the BRAFV600E mutation.31
We hypothesized that in thyroid cancer, the BRAFV600E
mutation would be associated with increased serum
Cu levels, as is seen in melanoma and colon cancer.
Besides,no signicantelevation ofserum Culevels was
observedin PTC with BRAFV600Emutation, suggesting
that serum copperdoes not indicatethe severity of PTC.
To our knowledge, this is the rst study to report
serum Cu levels in terms of histopathological aggressiveness,
risk of recurrence, staging, and molecular status in
PTC. In addition, we screened all healthy subjects with
ultrasonography of the thyroid gland to avoid unexpected
thyroid nodules in the control group. is ensured that
the reference serum Cu values of the healthy ai women
were reliable and could be used as a standard for further
studies. On the other hand, our analyses suggest that
serum Cu levels are not appropriate for diagnostic and
the prognosis of PTC.
Our study has some limitations. Our subjects were
ai women with PTC and nodular goiter. We did not
address the role of serum Cu levels in men, other types
of thyroid cancer, and in advanced-stage thyroid cancers
such as tracheal or recurrent laryngeal nerve invasion.
In addition to Cu, other essential trace elements such
as selenium, cadmium, zinc were likely involved in
the carcinogenesis of thyroid.32 e expand study of
multiple trace element levels and their ratios would give
more informative data about the relation between trace
elements and thyroid cancer.
CONCLUSION
The role of serum Cu in the pathogenesis and
prognosis of thyroid tumors remains unclear. Serum Cu
levels in patients with PTC and nodular goiter were not
dierent, and also were not dierent from the reference
group. However, serum Cu was associated withonly one
pattern of histopathologically aggressive PTC- Blood
vessel invasion.erefore, serum Cu levels cannot be
used as an assistive tool for diagnosis and the prognosis
of PTC.
ACKNOWLEDGMENTS
e authors appreciate the assistance provided by
Dr. Saowalak Hunnangkul, Ph.D., Division of Clinical
Epidemiology, Department of Health Research and
Development, Faculty of Medicine Siriraj Hospital,
Mahidol University, for her assistance with the sample
size calculation and statistical analyses. We also thank
Miss Jeerapa Kerdnoppakhun of the Department of
Otorhinolaryngology, Faculty of Medicine Siriraj Hospital,
for secretarial support. The authors also gratefully
acknowledge the professional English editing of this
paper by Mr. Mark Simmerman.
Conicts of interest: e authors declare that they do
not have any conict of interest regarding this research.
Funding statement: is work was supported by Faculty
of Medicine Siriraj Hospital, Mahidol University [grant
number R016133003]
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